SHANK3SH3 and multiple ankyrin repeat domains 3
Autism Reports / Total Reports
95 / 166Rare Variants / Common Variants
357 / 9Aliases
SHANK3, PSAP2, PROSAP2, SPANK-2, KIAA1650Associated Syndromes
Phelan-McDermid syndrome, Rett syndrome-like phenotype, Pediatric Acute-Onset Neuropsychiatric Syndrome (P, Phelan-McDermid syndrome, ASDChromosome Band
22q13.33Associated Disorders
DD/NDD, BPD, ID, EPS, ASDGenetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association, FunctionalRelevance to Autism
Recurrent mutations in the SHANK3 gene have been identified in multiple individuals with ASD as described below. SHANK3 lies within a multi-genic region on chromosome 22 that is deleted in Phelan-McDermid syndrome, a disorder which is frequently accompanied by ASD. De novo and inherited point mutations and copy number variants involving SHANK3 have been identified in individuals with ASD in multiple reports (PMIDs 17173049, 17999366, 18615476, 20186804, 20385823, 21378602, 21624971, 22558107, 22892527, 23758760), including de novo SHANK3 variants in PMIDs 17173049, 17999366 and 18615476 that were predicted to be loss-of-function variants or shown experimentally to disrupt SHANK3 function. An additional seven de novo loss-of-function variants in SHANK3 were identified in simplex ASD cases in Leblond et al., 2014 (PMID 25188300); in contrast, no truncating variants in SHANK3 were observed in 1,031 controls. Individuals with truncating SHANK3 variants were found to display ASD with moderate to severe/profound intellectual disability (mean IQ of 31 8) in this report. Furthermore, in a screen and meta-analysis of SHANK copy number variants in ASD, SHANK3 deletions were shown to be statistically enriched in ASD cases compared to controls [10/5,657 cases (0.18%) vs. 2/19,163 controls (0.01); P=0.019, OR=4.05 (1.26-13.01)] (PMID 25188300). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Multiple inconsistent associations have been reported with idiopathic ASD in other studies (PMIDs 19384346, 19566951, 22892527, 24398551, 27876814). A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified SHANK3 as a gene reaching exome-wide significance (P < 2.5E-06). De novo SHANK3 mutations in individuals with schizophrenia have also been reported in Gauthier et al., 2010 (PMID 20385823), and association of SHANK3 with schizophrenia has been reported as well (PMID 28371232).
Molecular Function
Shank proteins are multidomain scaffold proteins of the postsynaptic density that connect neurotransmitter receptors, ion channels, and other membrane proteins to the actin cytoskeleton and G-protein-coupled signaling pathways. Shank proteins also play a role in synapse formation and dendritic spine maturation.
External Links
SFARI Genomic Platforms
Reports related to SHANK3 (166 Reports)
| # | Type | Title | Author, Year | Autism Report | Associated Disorders |
|---|---|---|---|---|---|
| 1 | Highly Cited | Proline-rich synapse-associated proteins ProSAP1 and ProSAP2 interact with synaptic proteins of the SAPAP/GKAP family | Boeckers TM , et al. (1999) | No | - |
| 2 | Recent Recommendation | An architectural framework that may lie at the core of the postsynaptic density | Baron MK , et al. (2006) | No | - |
| 3 | Primary | Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders | Durand CM , et al. (2006) | Yes | - |
| 4 | Support | Contribution of SHANK3 mutations to autism spectrum disorder | Moessner R , et al. (2007) | Yes | - |
| 5 | Recent Recommendation | Smaller dendritic spines, weaker synaptic transmission, but enhanced spatial learning in mice lacking Shank1 | Hung AY , et al. (2008) | No | - |
| 6 | Recent Recommendation | Heterogeneous dysregulation of microRNAs across the autism spectrum | Abu-Elneel K , et al. (2008) | No | - |
| 7 | Support | Novel de novo SHANK3 mutation in autistic patients | Gauthier J , et al. (2008) | Yes | - |
| 8 | Negative Association | Copy number variation and association analysis of SHANK3 as a candidate gene for autism in the IMGSAC collection | Sykes NH , et al. (2009) | Yes | - |
| 9 | Recent Recommendation | Chromosome 22q13.3 deletion syndrome with a de novo interstitial 22q13.3 cryptic deletion disrupting SHANK3 | Delahaye A , et al. (2009) | No | - |
| 10 | Recent Recommendation | ProSAPiP2, a novel postsynaptic density protein that interacts with ProSAP2/Shank3 | Liebau S , et al. (2009) | No | - |
| 11 | Negative Association | Association study of SHANK3 gene polymorphisms with autism in Chinese Han population | Qin J , et al. (2009) | Yes | - |
| 12 | Recent Recommendation | Disruption of glutamate receptors at Shank-postsynaptic platform in Alzheimer's disease | Gong Y , et al. (2009) | No | - |
| 13 | Recent Recommendation | Synaptic cross-talk between N-methyl-D-aspartate receptors and LAPSER1-beta-catenin at excitatory synapses | Schmeisser MJ , et al. (2009) | No | - |
| 14 | Recent Recommendation | 22q13.3 deletion syndrome: clinical and molecular analysis using array CGH | Dhar SU , et al. (2010) | No | MR |
| 15 | Recent Recommendation | De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia | Gauthier J , et al. (2010) | No | - |
| 16 | Support | Direct measure of the de novo mutation rate in autism and schizophrenia cohorts | Awadalla P , et al. (2010) | Yes | - |
| 17 | Negative Association | Analysis of a purported SHANK3 mutation in a boy with autism: clinical impact of rare variant research in neurodevelopmental disabilities | Kolevzon A , et al. (2010) | Yes | - |
| 18 | Support | Novel variants of the SHANK3 gene in Japanese autistic patients with severe delayed speech development | Waga C , et al. (2011) | Yes | - |
| 19 | Recent Recommendation | Shank3 mutant mice display autistic-like behaviours and striatal dysfunction | Pea J , et al. (2011) | No | - |
| 20 | Negative Association | Association study of the CNS patterning genes and autism in Han Chinese in Taiwan | Chien YL , et al. (2011) | Yes | - |
| 21 | Support | SHANK3 mutations identified in autism lead to modification of dendritic spine morphology via an actin-dependent mechanism | Durand CM , et al. (2011) | No | - |
| 22 | Support | Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders | Schaaf CP , et al. (2011) | Yes | - |
| 23 | Support | High-throughput sequencing of mGluR signaling pathway genes reveals enrichment of rare variants in autism | Kelleher RJ 3rd , et al. (2012) | Yes | - |
| 24 | Recent Recommendation | Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders | Boccuto L , et al. (2012) | Yes | - |
| 25 | Support | Bipolar affective disorder and early dementia onset in a male patient with SHANK3 deletion | Vucurovic K , et al. (2012) | No | ID |
| 26 | Negative Association | Lack of association between NLGN3, NLGN4, SHANK2 and SHANK3 gene variants and autism spectrum disorder in a Chinese population | Liu Y , et al. (2013) | Yes | - |
| 27 | Recent Recommendation | Shank3-Rich2 interaction regulates AMPA receptor recycling and synaptic long-term potentiation | Raynaud F , et al. (2013) | No | - |
| 28 | Recent Recommendation | Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency | Soorya L , et al. (2013) | Yes | ID, epilepsy/seizures |
| 29 | Recent Recommendation | SHANK3 gene mutations associated with autism facilitate ligand binding to the Shank3 ankyrin repeat region | Mameza MG , et al. (2013) | Yes | - |
| 30 | Support | Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with autism spectrum disorder | Koshimizu E , et al. (2013) | Yes | ID, epilepsy |
| 31 | Recent Recommendation | Shank3 deficiency induces NMDA receptor hypofunction via an actin-dependent mechanism | Duffney LJ , et al. (2013) | No | - |
| 32 | Recent Recommendation | Epigenetic dysregulation of SHANK3 in brain tissues from individuals with autism spectrum disorders | Zhu L , et al. (2013) | No | - |
| 33 | Recent Recommendation | The PSD protein ProSAP2/Shank3 displays synapto-nuclear shuttling which is deregulated in a schizophrenia-associated mutation | Grabrucker S , et al. (2014) | No | - |
| 34 | Positive Association | A commonly carried genetic variant, rs9616915, in SHANK3 gene is associated with a reduced risk of autism spectrum disorder: replication in a Chinese population | Shao S , et al. (2014) | Yes | - |
| 35 | Recent Recommendation | Transcriptional and functional complexity of Shank3 provides a molecular framework to understand the phenotypic heterogeneity of SHANK3 causing autism and Shank3 mutant mice | Wang X , et al. (2014) | No | - |
| 36 | Support | Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing | Redin C , et al. (2014) | No | - |
| 37 | Recent Recommendation | Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments | Leblond CS , et al. (2014) | Yes | - |
| 38 | Support | Refining analyses of copy number variation identifies specific genes associated with developmental delay | Coe BP , et al. (2014) | Yes | - |
| 39 | Support | Synaptic, transcriptional and chromatin genes disrupted in autism | De Rubeis S , et al. (2014) | Yes | - |
| 40 | Support | Recurrent de novo mutations implicate novel genes underlying simplex autism risk | O'Roak BJ , et al. (2014) | Yes | - |
| 41 | Support | Large-scale discovery of novel genetic causes of developmental disorders | Deciphering Developmental Disorders Study (2014) | No | Speech delay |
| 42 | Support | Whole-genome sequencing of quartet families with autism spectrum disorder | Yuen RK , et al. (2015) | Yes | - |
| 43 | Support | Whole genome sequencing reveals a de novo SHANK3 mutation in familial autism spectrum disorder | Nemirovsky SI , et al. (2015) | Yes | - |
| 44 | Recent Recommendation | Two knockdown models of the autism genes SYNGAP1 and SHANK3 in zebrafish produce similar behavioral phenotypes associated with embryonic disruptions of brain morphogenesis | Kozol RA , et al. (2015) | No | - |
| 45 | Support | De novo SHANK3 mutation causes Rett syndrome-like phenotype in a female patient | Hara M , et al. (2015) | No | DD, autistic features, stereotyped hand movements, |
| 46 | Support | Phenotypic and functional analysis of SHANK3 stop mutations identified in individuals with ASD and/or ID | Cochoy DM , et al. (2015) | Yes | - |
| 47 | Recent Recommendation | Autism-Associated Insertion Mutation (InsG) of Shank3 Exon 21 Causes Impaired Synaptic Transmission and Behavioral Deficits | Speed HE , et al. (2015) | No | - |
| 48 | Recent Recommendation | Low load for disruptive mutations in autism genes and their biased transmission | Iossifov I , et al. (2015) | Yes | - |
| 49 | Support | Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci | Sanders SJ , et al. (2015) | Yes | - |
| 50 | Support | Case report: an unexpected link between partial deletion of the SHANK3 gene and Heller's dementia infantilis, a rare subtype of autism spectrum disorder | Philippe A , et al. (2015) | No | Developmental regression |
| 51 | Support | Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities | Zhang Y , et al. (2015) | No | - |
| 52 | Recent Recommendation | Autism-associated SHANK3 haploinsufficiency causes Ih channelopathy in human neurons | Yi F , et al. (2016) | No | - |
| 53 | Support | Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability | Lelieveld SH et al. (2016) | No | - |
| 54 | Support | Copy number variation analysis in adults with catatonia confirms haploinsufficiency of SHANK3 as a predisposing factor | Breckpot J , et al. (2016) | No | - |
| 55 | Support | Genome-wide characteristics of de novo mutations in autism | Yuen RK et al. (2016) | Yes | - |
| 56 | Support | The spectrum of epilepsy and electroencephalographic abnormalities due to SHANK3 loss-of-function mutations | Holder JL Jr and Quach MM (2016) | No | - |
| 57 | Recent Recommendation | Shank3 Is Part of a Zinc-Sensitive Signaling System That Regulates Excitatory Synaptic Strength | Arons MH , et al. (2016) | No | - |
| 58 | Positive Association | A genome-wide investigation into parent-of-origin effects in autism spectrum disorder identifies previously associated genes including SHANK3 | Connolly S , et al. (2016) | Yes | - |
| 59 | Support | Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder | C Yuen RK et al. (2017) | Yes | - |
| 60 | Support | SHANK proteins limit integrin activation by directly interacting with Rap1 and R-Ras | Lilja J , et al. (2017) | No | - |
| 61 | Support | Investigation of SHANK3 in schizophrenia | de Sena Cortabitarte A , et al. (2017) | No | - |
| 62 | Support | Neurogenetic analysis of childhood disintegrative disorder | Gupta AR , et al. (2017) | No | - |
| 63 | Support | Genomic diagnosis for children with intellectual disability and/or developmental delay | Bowling KM , et al. (2017) | No | - |
| 64 | Support | Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder | Lim ET , et al. (2017) | Yes | - |
| 65 | Positive Association | Learning-dependent chromatin remodeling highlights noncoding regulatory regions linked to autism | Koberstein JN , et al. (2018) | Yes | - |
| 66 | Negative Association | Association between SHANK3 polymorphisms and susceptibility to autism spectrum disorder | Qiu S , et al. (2018) | Yes | - |
| 67 | Support | Two de novo novel mutations in one SHANK3 allele in a patient with autism and moderate intellectual disability | Zhu W , et al. (2018) | Yes | - |
| 68 | Recent Recommendation | Delineation of the genetic and clinical spectrum of Phelan-McDermid syndrome caused by SHANK3 point mutations | De Rubeis S , et al. (2018) | No | ASD |
| 69 | Support | Genetic Diagnostic Evaluation of Trio-Based Whole Exome Sequencing Among Children With Diagnosed or Suspected Autism Spectrum Disorder | Du X , et al. (2018) | Yes | DD/ID |
| 70 | Recent Recommendation | An autism-linked missense mutation in SHANK3 reveals the modularity of Shank3 function | Wang L , et al. (2019) | Yes | - |
| 71 | Recent Recommendation | Altered spinogenesis in iPSC-derived cortical neurons from patients with autism carrying de novo SHANK3 mutations | Gouder L , et al. (2019) | No | - |
| 72 | Support | Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype correlations | Zhou WZ , et al. (2019) | Yes | - |
| 73 | Support | Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population | Monies D , et al. (2019) | No | - |
| 74 | Recent Recommendation | Atypical behaviour and connectivity in SHANK3-mutant macaques | Zhou Y , et al. (2019) | Yes | - |
| 75 | Support | Characterization of intellectual disability and autism comorbidity through gene panel sequencing | Aspromonte MC , et al. (2019) | Yes | - |
| 76 | Recent Recommendation | Shank3 Mice Carrying the Human Q321R Mutation Display Enhanced Self-Grooming, Abnormal Electroencephalogram Patterns, and Suppressed Neuronal Excitability and Seizure Susceptibility | Yoo YE , et al. (2019) | No | - |
| 77 | Support | Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks | Ruzzo EK , et al. (2019) | Yes | - |
| 78 | Support | Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder | Munnich A , et al. (2019) | Yes | - |
| 79 | Support | Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes | Feliciano P et al. (2019) | Yes | - |
| 80 | Recent Recommendation | Shank Proteins Couple the Endocytic Zone to the Postsynaptic Density to Control Trafficking and Signaling of Metabotropic Glutamate Receptor 5 | Scheefhals N , et al. (2019) | No | - |
| 81 | Support | A 22q13.33 duplication harbouring the SHANK3 gene: does it cause neuropsychiatric disorders? | Johannessen M , et al. (2019) | Yes | Tourette syndrome, BPD |
| 82 | Support | Meta-Analyses Support Previous and Novel Autism Candidate Genes: Outcomes of an Unexplored Brazilian Cohort | da Silva Montenegro EM , et al. (2019) | Yes | - |
| 83 | Support | Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism | Satterstrom FK et al. (2020) | Yes | - |
| 84 | Support | Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use | Husson T , et al. (2020) | Yes | - |
| 85 | Support | Truncating mutations in SHANK3 associated with global developmental delay interfere with nuclear ?-catenin signaling | Hassani Nia F et al. (2020) | No | - |
| 86 | Support | Utility of clinical exome sequencing in a complex Emirati pediatric cohort | Mahfouz NA et al. (2020) | Yes | - |
| 87 | Support | Next-Generation Sequencing in Korean Children With Autism Spectrum Disorder and Comorbid Epilepsy | Lee J et al. (2020) | Yes | - |
| 88 | Support | Targeted next-generation sequencing identifies the disruption of the SHANK3 and RYR2 genes in a patient carrying a de novo t(1;22)(q43;q13.3) associated with signs of Phelan-McDermid syndrome | Bonaglia MC et al. (2020) | No | Autistic features, stereotypy |
| 89 | Support | A 29 Mainland Chinese cohort of patients with Phelan-McDermid syndrome: genotype-phenotype correlations and the role of SHANK3 haploinsufficiency in the important phenotypes | Xu N et al. (2020) | No | - |
| 90 | Support | - | Mojarad BA et al. (2021) | No | ID |
| 91 | Support | - | Brunet T et al. (2021) | No | - |
| 92 | Support | - | Bucher M et al. (2021) | Yes | - |
| 93 | Support | - | Zou D et al. (2021) | Yes | - |
| 94 | Support | - | Lee DK et al. (2021) | Yes | - |
| 95 | Support | - | Golden CEM et al. (2021) | No | - |
| 96 | Support | - | Moutin E et al. (2021) | Yes | - |
| 97 | Support | - | Valentino F et al. (2021) | Yes | DD, epilepsy/seizures |
| 98 | Support | - | Trakadis Y et al. (2021) | No | ADHD, DD |
| 99 | Support | - | Kankuri-Tammilehto M et al. (2021) | No | ASD, ID, epilepsy/seizures |
| 100 | Support | - | Levy T et al. (2021) | No | - |
| 101 | Support | - | Pode-Shakked B et al. (2021) | Yes | - |
| 102 | Support | - | Mitani T et al. (2021) | No | Autistic behavior |
| 103 | Support | - | Salomaa SI et al. (2021) | No | - |
| 104 | Support | - | Mahjani B et al. (2021) | Yes | - |
| 105 | Recent Recommendation | - | Loureiro LO et al. (2021) | Yes | ADHD, epilepsy/seizures |
| 106 | Support | - | Lin R et al. (2021) | No | - |
| 107 | Support | - | Balasco L et al. (2021) | Yes | - |
| 108 | Support | - | Bruno LP et al. (2021) | Yes | - |
| 109 | Support | - | Woike D et al. (2022) | No | ASD |
| 110 | Support | - | Krüttner S et al. (2022) | Yes | - |
| 111 | Support | - | Brea-Fernández AJ et al. (2022) | No | - |
| 112 | Support | - | Kim H et al. (2022) | Yes | - |
| 113 | Support | - | Wu CH et al. (2022) | No | - |
| 114 | Support | - | Nevado J et al. (2022) | No | ASD |
| 115 | Support | - | Kim S et al. (2022) | Yes | - |
| 116 | Support | - | Malara M et al. (2022) | No | - |
| 117 | Support | - | Hu C et al. (2022) | Yes | - |
| 118 | Support | - | Trifiletti R et al. (2022) | No | OCD |
| 119 | Negative Association | - | Siddiqua H et al. (2022) | Yes | - |
| 120 | Support | - | Zhou X et al. (2022) | Yes | ADHD, SCZ, epilepsy/seizures |
| 121 | Support | - | Lord JS et al. (2022) | No | - |
| 122 | Support | - | Medina E et al. (2022) | Yes | - |
| 123 | Support | - | Garrido D et al. (2022) | Yes | - |
| 124 | Support | - | Wang Y et al. (2022) | Yes | - |
| 125 | Support | - | Ma B et al. (2022) | Yes | - |
| 126 | Support | - | Ortiz-Cruz CA et al. (2022) | Yes | - |
| 127 | Support | - | Atanasova E et al. (2023) | Yes | - |
| 128 | Support | - | Bauer HF et al. (2023) | Yes | - |
| 129 | Support | - | Okuzono S et al. (2023) | No | - |
| 130 | Support | - | Spataro N et al. (2023) | No | Autistic features |
| 131 | Support | - | Hu C et al. (2023) | Yes | - |
| 132 | Support | - | Ferhat AT et al. (2023) | Yes | - |
| 133 | Support | - | Zhang Y et al. (2023) | Yes | ID |
| 134 | Support | - | Contestabile A et al. (2023) | Yes | - |
| 135 | Support | - | Landry O et al. (2023) | No | - |
| 136 | Support | - | Kareklas K et al. (2023) | Yes | - |
| 137 | Support | - | Wang J et al. (2023) | Yes | - |
| 138 | Support | - | Hussein Y et al. (2023) | Yes | - |
| 139 | Support | - | Cirnigliaro M et al. (2023) | Yes | - |
| 140 | Support | - | Pagano J et al. (2023) | No | - |
| 141 | Support | - | Sanchis-Juan A et al. (2023) | No | Epilepsy/seizures |
| 142 | Support | - | Woike D et al. (2023) | No | - |
| 143 | Support | - | Ana Margarida Gonçalves et al. (2023) | Yes | - |
| 144 | Support | - | Amerh S Alqahtani et al. (2023) | Yes | - |
| 145 | Support | - | Karthika Ajit Valaparambil et al. () | Yes | Epilepsy/seizures |
| 146 | Support | - | Lucie Sedlackova et al. (2024) | No | - |
| 147 | Recent Recommendation | - | Kuokuo Li et al. (2024) | Yes | - |
| 148 | Support | - | Valentin Ioannidis et al. (2024) | No | - |
| 149 | Support | - | Manish Kumar Tripathi et al. (2024) | Yes | - |
| 150 | Support | - | Denisa Mihalj et al. (2024) | Yes | - |
| 151 | Support | - | Luigi Vetri et al. (2024) | No | - |
| 152 | Support | - | Feipeng Zhu et al. (2024) | Yes | - |
| 153 | Support | - | Marketa Wayhelova et al. (2024) | Yes | DD |
| 154 | Support | - | Yi-Zhi Wang et al. () | No | - |
| 155 | Support | - | Marta Viggiano et al. (2024) | Yes | ID, epilepsy/seizures |
| 156 | Support | - | Kirsten Furley et al. () | No | ASD, ID |
| 157 | Support | - | Shanshan Wu et al. (2024) | Yes | - |
| 158 | Support | - | Baolin Guo et al. (2024) | Yes | - |
| 159 | Support | - | Amandine Thibaudeau et al. (2024) | No | - |
| 160 | Support | - | Myung Chung et al. (2024) | Yes | Unnamed: 4 |
| 161 | Support | - | Jingjing Liu et al. (2024) | Yes | - |
| 162 | Support | - | Xiaona Lu et al. (2024) | Yes | - |
| 163 | Support | - | Axel Schmidt et al. (2024) | No | ID, epilepsy/seizures, autistic behavior |
| 164 | Support | - | Roger Esmel-Vilomara et al. (2024) | Yes | Epilepsy/seizures |
| 165 | Support | - | Suhua Chang et al. () | Yes | - |
| 166 | Support | - | Karen Lob et al. () | Yes | ADHD, DD, ID |
Rare Variants (357)
| Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Parental Transmission | Family Type | PubMed ID | Author, Year |
|---|---|---|---|---|---|---|---|---|
| - | - | intron_variant | - | - | - | 21378602 | Waga C , et al. (2011) | |
| - | - | copy_number_loss | - | - | - | 20186804 | Dhar SU , et al. (2010) | |
| - | - | copy_number_gain | - | - | - | 17173049 | Durand CM , et al. (2006) | |
| - | - | copy_number_loss | - | - | - | 17173049 | Durand CM , et al. (2006) | |
| - | - | copy_number_loss | De novo | - | - | 33256793 | Xu N et al. (2020) | |
| - | - | copy_number_loss | Unknown | - | - | 33256793 | Xu N et al. (2020) | |
| - | - | copy_number_loss | Unknown | - | - | 32477112 | Lee J et al. (2020) | |
| - | - | intron_variant | De novo | - | - | 21378602 | Waga C , et al. (2011) | |
| - | - | translocation | De novo | - | - | 32536973 | Bonaglia MC et al. (2020) | |
| - | - | copy_number_loss | De novo | - | - | 23758760 | Soorya L , et al. (2013) | |
| - | - | copy_number_loss | De novo | - | - | 22892527 | Boccuto L , et al. (2012) | |
| - | - | copy_number_gain | Unknown | - | - | 31406558 | Munnich A , et al. (2019) | |
| - | - | copy_number_loss | De novo | - | - | 31406558 | Munnich A , et al. (2019) | |
| - | - | copy_number_loss | De novo | - | - | 25188300 | Leblond CS , et al. (2014) | |
| - | - | copy_number_loss | De novo | - | - | 27519580 | Breckpot J , et al. (2016) | |
| - | - | copy_number_loss | Unknown | - | - | 27519580 | Breckpot J , et al. (2016) | |
| - | - | copy_number_loss | Unknown | - | Unknown | 25217958 | Coe BP , et al. (2014) | |
| - | - | copy_number_gain | Unknown | - | - | 31678916 | Johannessen M , et al. (2019) | |
| - | - | copy_number_loss | Familial | Maternal | - | 21378602 | Waga C , et al. (2011) | |
| - | - | copy_number_loss | De novo | - | Simplex | 32094338 | Husson T , et al. (2020) | |
| - | - | copy_number_loss | De novo | - | Simplex | 17173049 | Durand CM , et al. (2006) | |
| - | - | copy_number_loss | De novo | - | Simplex | 17999366 | Moessner R , et al. (2007) | |
| - | - | copy_number_loss | De novo | - | Simplex | 19454329 | Delahaye A , et al. (2009) | |
| - | - | copy_number_loss | De novo | - | Simplex | 25188300 | Leblond CS , et al. (2014) | |
| c.734T>C | p.Ile245Thr | missense_variant | - | - | - | 21378602 | Waga C , et al. (2011) | |
| c.483C>T | p.Asn161= | synonymous_variant | - | - | - | 21378602 | Waga C , et al. (2011) | |
| c.750C>T | p.Gly250= | synonymous_variant | - | - | - | 21378602 | Waga C , et al. (2011) | |
| - | - | copy_number_loss | De novo | - | Simplex | 22922660 | Vucurovic K , et al. (2012) | |
| c.3526G>T | p.Ala1176Ser | stop_gained | De novo | - | - | 33256793 | Xu N et al. (2020) | |
| c.3727C>T | p.Pro1243Ser | stop_gained | De novo | - | - | 35741772 | Hu C et al. (2022) | |
| c.1684+2T>G | - | splice_site_variant | Unknown | - | - | 35982159 | Zhou X et al. (2022) | |
| c.2451+1G>A | - | splice_site_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.2451+1G>A | - | splice_site_variant | Unknown | - | - | 35982159 | Zhou X et al. (2022) | |
| c.2451+1G>C | - | splice_site_variant | Unknown | - | - | 35982159 | Zhou X et al. (2022) | |
| c.1478G>A | p.Glu505= | synonymous_variant | - | - | - | 21378602 | Waga C , et al. (2011) | |
| - | - | copy_number_loss | De novo | - | Multiplex | 17999366 | Moessner R , et al. (2007) | |
| - | - | copy_number_loss | De novo | - | - | 39094681 | Roger Esmel-Vilomara et al. (2024) | |
| c.3432G>A | p.Ala1157Thr | missense_variant | - | - | - | 21378602 | Waga C , et al. (2011) | |
| c.3788G>T | p.Pro1263Leu | missense_variant | - | - | - | 21378602 | Waga C , et al. (2011) | |
| c.4409G>A | p.Gly1482= | synonymous_variant | - | - | - | 21378602 | Waga C , et al. (2011) | |
| c.4850C>T | p.Ser1629= | synonymous_variant | - | - | - | 21378602 | Waga C , et al. (2011) | |
| c.4910C>T | p.Pro1649= | synonymous_variant | - | - | - | 21378602 | Waga C , et al. (2011) | |
| - | - | copy_number_loss | Unknown | Not maternal | - | 23758760 | Soorya L , et al. (2013) | |
| - | - | copy_number_loss | Unknown | Not paternal | - | 23758760 | Soorya L , et al. (2013) | |
| - | - | copy_number_loss | Unknown | - | Simplex | 37541188 | Sanchis-Juan A et al. (2023) | |
| c.3796C>T | p.Gln1266Ter | stop_gained | Unknown | - | - | 35982159 | Zhou X et al. (2022) | |
| c.1481C>G | p.Gly506= | missense_variant | - | - | - | 20385823 | Gauthier J , et al. (2010) | |
| - | - | copy_number_loss | Unknown | Not maternal | - | 26489495 | Philippe A , et al. (2015) | |
| c.734T>C | p.Ile245Thr | missense_variant | - | - | - | 20385823 | Gauthier J , et al. (2010) | |
| c.1804C>T | p.Arg602Trp | missense_variant | Unknown | - | - | 35741772 | Hu C et al. (2022) | |
| c.1527G>A | p.Trp509Ter | stop_gained | De novo | - | - | 23758760 | Soorya L , et al. (2013) | |
| c.1758C>A | p.Cys586Ter | stop_gained | Unknown | - | - | 34615535 | Mahjani B et al. (2021) | |
| c.2832T>A | p.Tyr944Ter | stop_gained | De novo | - | - | 36980980 | Spataro N et al. (2023) | |
| c.2163G>A | p.Asp734Asn | missense_variant | - | - | - | 20385823 | Gauthier J , et al. (2010) | |
| c.2858G>C | p.Glu965Asp | missense_variant | - | - | - | 20385823 | Gauthier J , et al. (2010) | |
| c.1023G>A | p.Ser341= | synonymous_variant | - | - | - | 20385823 | Gauthier J , et al. (2010) | |
| c.1856C>T | p.Ile631= | synonymous_variant | - | - | - | 20385823 | Gauthier J , et al. (2010) | |
| c.2006C>G | p.Pro681= | synonymous_variant | - | - | - | 20385823 | Gauthier J , et al. (2010) | |
| c.2273G>A | p.Pro770= | synonymous_variant | - | - | - | 20385823 | Gauthier J , et al. (2010) | |
| c.2912C>T | p.Arg983= | synonymous_variant | - | - | - | 20385823 | Gauthier J , et al. (2010) | |
| c.4850C>T | p.Pro1617Leu | missense_variant | Unknown | - | - | 35741772 | Hu C et al. (2022) | |
| c.715G>C | p.Asp239His | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.973G>T | p.Gly325Cys | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.993G>T | p.Gln331His | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| G>A | p.? | splice_site_variant | De novo | - | Simplex | 28263302 | C Yuen RK et al. (2017) | |
| c.3034G>T | p.Arg1024Leu | missense_variant | - | - | - | 20385823 | Gauthier J , et al. (2010) | |
| c.3316C>A | p.Ala1118Asp | missense_variant | - | - | - | 20385823 | Gauthier J , et al. (2010) | |
| c.3961T>G | p.Val1333Gly | missense_variant | - | - | - | 20385823 | Gauthier J , et al. (2010) | |
| c.4923C>A | p.Pro1654Thr | missense_variant | - | - | - | 20385823 | Gauthier J , et al. (2010) | |
| c.2981G>A | p.Gly1006= | synonymous_variant | - | - | - | 20385823 | Gauthier J , et al. (2010) | |
| c.3365C>T | p.Pro1134= | synonymous_variant | - | - | - | 20385823 | Gauthier J , et al. (2010) | |
| c.3443T>C | p.Ala1160= | synonymous_variant | - | - | - | 20385823 | Gauthier J , et al. (2010) | |
| c.3560G>A | p.Leu1199= | synonymous_variant | - | - | - | 20385823 | Gauthier J , et al. (2010) | |
| c.4910C>T | p.Pro1649= | synonymous_variant | - | - | - | 20385823 | Gauthier J , et al. (2010) | |
| c.4567+1G>T | - | splice_site_variant | De novo | - | - | 31452935 | Feliciano P et al. (2019) | |
| c.2451+1G>A | - | splice_site_variant | De novo | - | - | 34356170 | Valentino F et al. (2021) | |
| c.*74C>A | - | stop_gained | Unknown | - | - | 37943464 | Karthika Ajit Valaparambil et al. () | |
| c.1792C>T | p.Arg598Trp | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.2681C>T | p.Ser894Leu | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.769-7C>G | - | intron_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.3238C>T | p.Thr1092Ile | missense_variant | De novo | - | - | 29423971 | Zhu W , et al. (2018) | |
| c.4826C>T | p.Ser1609Leu | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.5135G>A | p.Gly1712Asp | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.5315T>C | p.Leu1772Pro | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.593C>G | p.Ala198Gly | missense_variant | Unknown | - | - | 30763456 | Zhou WZ , et al. (2019) | |
| c.898C>T | p.Arg300Cys | missense_variant | Unknown | - | - | 30763456 | Zhou WZ , et al. (2019) | |
| c.3351C>T | p.Pro1130Ser | stop_gained | De novo | - | - | 20797689 | Awadalla P , et al. (2010) | |
| - | - | copy_number_loss | Familial | Paternal | Simplex | 17999366 | Moessner R , et al. (2007) | |
| c.1031-14C>T | - | intron_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.1992+10C>A | - | intron_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.2228+20G>A | - | intron_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.3913C>T | p.Gln1305Ter | stop_gained | De novo | - | Simplex | 35982159 | Zhou X et al. (2022) | |
| c.421C>G | p.Pro141Ala | missense_variant | De novo | - | - | 22892527 | Boccuto L , et al. (2012) | |
| c.*1279_*1280dup | - | frameshift_variant | De novo | - | - | 38256219 | Luigi Vetri et al. (2024) | |
| c.3459C>T | p.Pro1166Ser | stop_gained | De novo | - | - | 31209962 | Aspromonte MC , et al. (2019) | |
| c.4317G>T | p.Ala1452Ser | missense_variant | Unknown | - | - | 22892527 | Boccuto L , et al. (2012) | |
| c.1569C>T | p.Arg536Trp | missense_variant | De novo | - | - | 20385823 | Gauthier J , et al. (2010) | |
| c.1608C>T | p.Arg549Trp | missense_variant | De novo | - | - | 20797689 | Awadalla P , et al. (2010) | |
| c.1010C>G | p.Thr337Ser | missense_variant | De novo | - | - | 28554332 | Bowling KM , et al. (2017) | |
| del(G) | Splice-site | splice_site_variant | De novo | - | - | 20797689 | Awadalla P , et al. (2010) | |
| c.1303-282G>T | - | missense_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.1400G>A | p.Val479= | stop_gained | De novo | - | Simplex | 25363760 | De Rubeis S , et al. (2014) | |
| c.63+148G>A | - | intron_variant | Unknown | - | - | 28371232 | de Sena Cortabitarte A , et al. (2017) | |
| c.1723G>A | p.Val575Met | missense_variant | Familial | Maternal | - | 37007974 | Hu C et al. (2023) | |
| c.2936G>T | p.Arg979Leu | missense_variant | Familial | Maternal | - | 37007974 | Hu C et al. (2023) | |
| c.4984C>T | p.Pro1662Ser | stop_gained | De novo | - | Simplex | 32382396 | Mahfouz NA et al. (2020) | |
| c.2425G>T | p.Glu809Ter | stop_gained | De novo | - | Simplex | 25188300 | Leblond CS , et al. (2014) | |
| c.4977G>T | p.Asp1672Tyr | missense_variant | De novo | - | - | 29719671 | De Rubeis S , et al. (2018) | |
| c.4622C>T | p.Pro1541Leu | missense_variant | De novo | - | - | 35773312 | Trifiletti R et al. (2022) | |
| c.3120del | p.Gly1041AlafsTer99 | frameshift_variant | Unknown | - | - | 33256793 | Xu N et al. (2020) | |
| c.3942del | p.Ser1315AlafsTer31 | frameshift_variant | De novo | - | - | 33256793 | Xu N et al. (2020) | |
| c.2477dup | p.Gly827ArgfsTer531 | frameshift_variant | De novo | - | - | 35741772 | Hu C et al. (2022) | |
| c.4209del | p.Ser1404AlafsTer44 | frameshift_variant | De novo | - | - | 37007974 | Hu C et al. (2023) | |
| c.3690C>T | p.Gln1243Ter | stop_gained | De novo | - | Simplex | 25188300 | Leblond CS , et al. (2014) | |
| c.1535C>A | p.Cys524Ter | stop_gained | Unknown | - | Unknown | 25363760 | De Rubeis S , et al. (2014) | |
| c.271C>T | p.Pro91Ser | stop_gained | Unknown | - | Simplex | 37541188 | Sanchis-Juan A et al. (2023) | |
| c.2411G>A | p.Pro816= | intron_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.2451+1G>A | - | splice_site_variant | De novo | - | - | 39094681 | Roger Esmel-Vilomara et al. (2024) | |
| c.3088del | p.Ala1030ProfsTer110 | frameshift_variant | De novo | - | - | 33256793 | Xu N et al. (2020) | |
| c.3372dup | p.Thr1125HisfsTer233 | frameshift_variant | De novo | - | - | 33256793 | Xu N et al. (2020) | |
| c.3679dup | p.Ser1227LysfsTer131 | frameshift_variant | De novo | - | - | 33256793 | Xu N et al. (2020) | |
| c.3679dup | p.Ser1227LysfsTer131 | frameshift_variant | Unknown | - | - | 33256793 | Xu N et al. (2020) | |
| c.1139del | p.Arg380LeufsTer75 | frameshift_variant | Unknown | - | - | 35982159 | Zhou X et al. (2022) | |
| c.4481del | p.Pro1494ArgfsTer3 | frameshift_variant | Unknown | - | - | 35982159 | Zhou X et al. (2022) | |
| c.962A>G | p.Gln321Arg | missense_variant | De novo | - | Simplex | 28263302 | C Yuen RK et al. (2017) | |
| c.1303-280dup | - | frameshift_variant | Familial | Maternal | - | 21062623 | Kolevzon A , et al. (2010) | |
| c.4568-2A>G | - | splice_site_variant | De novo | - | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
| c.5186C>T | - | 3_prime_UTR_variant | Unknown | - | - | 28371232 | de Sena Cortabitarte A , et al. (2017) | |
| c.3102del | p.Ser1035AlafsTer105 | frameshift_variant | Unknown | - | - | 34145886 | Zou D et al. (2021) | |
| c.3679dupG | p.Ala1227GlyfsTer69 | frameshift_variant | De novo | - | - | 39136901 | Karen Lob et al. () | |
| c.2862dup | p.Ala967GlyfsTer329 | frameshift_variant | De novo | - | - | 29423971 | Zhu W , et al. (2018) | |
| c.1050del | p.Asp350GlufsTer105 | frameshift_variant | Unknown | - | - | 35982159 | Zhou X et al. (2022) | |
| c.2543del | p.Asp848AlafsTer107 | frameshift_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.3730del | p.Arg1244GlyfsTer13 | frameshift_variant | Unknown | - | - | 35982159 | Zhou X et al. (2022) | |
| c.3814dup | p.Ile1272AsnfsTer86 | frameshift_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.3828del | p.Thr1277ProfsTer69 | frameshift_variant | Unknown | - | - | 35982159 | Zhou X et al. (2022) | |
| c.4579del | p.Tyr1527ThrfsTer29 | frameshift_variant | Unknown | - | - | 35982159 | Zhou X et al. (2022) | |
| c.1930G>A | p.Arg656His | missense_variant | Familial | Paternal | - | 21378602 | Waga C , et al. (2011) | |
| c.3599G>C | p.Arg1200Pro | missense_variant | De novo | - | Simplex | 26544041 | Zhang Y , et al. (2015) | |
| c.1420G>T | p.Glu474Ter | missense_variant | Unknown | - | Simplex | 31130284 | Monies D , et al. (2019) | |
| c.3312C>T | p.Arg1117Ter | stop_gained | De novo | - | Multiplex | 20385823 | Gauthier J , et al. (2010) | |
| c.1620C>A | p.Ala540%3D | stop_gained | Unknown | - | Simplex | 37541188 | Sanchis-Juan A et al. (2023) | |
| c.249G>T | p.Thr83= | synonymous_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.4051C>T | p.Gln1351Ter | stop_gained | De novo | - | - | 39094681 | Roger Esmel-Vilomara et al. (2024) | |
| c.3148dup | p.Thr1050AsnfsTer308 | frameshift_variant | Unknown | - | - | 35982159 | Zhou X et al. (2022) | |
| c.3730dup | p.Arg1244ProfsTer114 | frameshift_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.3726C>G | p.Arg1255Gly | missense_variant | De novo | - | Multiplex | 28714951 | Lim ET , et al. (2017) | |
| c.962A>G | p.Gln321Arg | missense_variant | De novo | - | Simplex | 17999366 | Moessner R , et al. (2007) | |
| c.670G>A | p.Ala224Thr | missense_variant | Unknown | - | Unknown | 18615476 | Gauthier J , et al. (2008) | |
| c.734T>C | p.Ile245Thr | missense_variant | Unknown | - | Unknown | 18615476 | Gauthier J , et al. (2008) | |
| c.3532A>C | p.Asp1190Ala | frameshift_variant | De novo | - | - | 31209962 | Aspromonte MC , et al. (2019) | |
| c.2181G>A | p.Val740Ile | splice_site_variant | De novo | - | - | 31209962 | Aspromonte MC , et al. (2019) | |
| c.4608G>A | p.Trp1536Ter | stop_gained | De novo | - | Simplex | 34580403 | Pode-Shakked B et al. (2021) | |
| c.4871C>A | p.Ser1624Ter | stop_gained | De novo | - | Simplex | 38519481 | Marta Viggiano et al. (2024) | |
| c.612C>A | p.Asp204Glu | missense_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.763C>T | p.His255Tyr | missense_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.898C>T | p.Arg300Cys | missense_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.920C>G | p.Ala307Gly | missense_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.522C>T | p.Ala174= | synonymous_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.3679dup | p.Ala1227GlyfsTer56 | frameshift_variant | De novo | - | - | 30763456 | Zhou WZ , et al. (2019) | |
| c.2499del | p.Arg846AlafsTer47 | frameshift_variant | De novo | - | - | 23758760 | Soorya L , et al. (2013) | |
| c.5008A>T | p.Lys1670Ter | stop_gained | Unknown | Not maternal | - | 26045941 | Cochoy DM , et al. (2015) | |
| - | p.Ser1566Gly | missense_variant | Familial | Paternal | Simplex | 17173049 | Durand CM , et al. (2006) | |
| c.4934C>A | p.Ser1645Ter | missense_variant | Unknown | - | Simplex | 17173049 | Durand CM , et al. (2006) | |
| c.3586G>A | p.Gly1208Asp | missense_variant | Unknown | - | Simplex | 21624971 | Schaaf CP , et al. (2011) | |
| c.3630A>T | p.Arg1223Trp | missense_variant | Unknown | - | Simplex | 21624971 | Schaaf CP , et al. (2011) | |
| c.3856G>A | p.Arg1298Lys | missense_variant | Unknown | - | Simplex | 21624971 | Schaaf CP , et al. (2011) | |
| c.4020G>A | p.Ala1353Thr | missense_variant | Unknown | - | Simplex | 21624971 | Schaaf CP , et al. (2011) | |
| c.4536C>T | p.Pro1525Ser | missense_variant | Unknown | - | Simplex | 21624971 | Schaaf CP , et al. (2011) | |
| c.4678C>T | p.Ala1572Val | missense_variant | Unknown | - | Simplex | 21624971 | Schaaf CP , et al. (2011) | |
| c.4778A>T | p.Thr1593Ile | missense_variant | Unknown | - | Simplex | 21624971 | Schaaf CP , et al. (2011) | |
| c.4873A>T | p.Pro1625Ser | missense_variant | Unknown | - | Simplex | 21624971 | Schaaf CP , et al. (2011) | |
| c.4879C>T | p.Pro1639Leu | missense_variant | Unknown | - | Simplex | 21624971 | Schaaf CP , et al. (2011) | |
| c.4918G>A | p.Gly1652Asp | missense_variant | Unknown | - | Simplex | 21624971 | Schaaf CP , et al. (2011) | |
| c.4962C>A | p.Leu1667Ile | missense_variant | Unknown | - | Simplex | 21624971 | Schaaf CP , et al. (2011) | |
| c.3552A>G | p.Ser1197Gly | missense_variant | De novo | - | Simplex | 25418537 | O'Roak BJ , et al. (2014) | |
| c.2124G>A | p.Ala721Thr | missense_variant | Unknown | - | Unknown | 18615476 | Gauthier J , et al. (2008) | |
| c.1645C>T | p.Ser561Leu | missense_variant | Unknown | - | Unknown | 25188300 | Leblond CS , et al. (2014) | |
| c.2256G>A | p.Gly765Ser | missense_variant | Unknown | - | Unknown | 25188300 | Leblond CS , et al. (2014) | |
| c.2647T>C | p.Leu895Pro | missense_variant | Unknown | - | Unknown | 25188300 | Leblond CS , et al. (2014) | |
| c.920C>G | p.Ala307Gly | missense_variant | Unknown | - | Unknown | 25363760 | De Rubeis S , et al. (2014) | |
| c.985T>A | p.Phe329Ile | missense_variant | Unknown | - | Unknown | 25363760 | De Rubeis S , et al. (2014) | |
| c.3171C>T | p.Leu1070= | missense_variant | Unknown | - | Unknown | 24066114 | Koshimizu E , et al. (2013) | |
| c.1317C>T | p.Pro452Ser | missense_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.1254G>A | p.Glu418= | synonymous_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.1337G>T | p.Pro458= | synonymous_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.2451+1G>A | - | splice_site_variant | De novo | - | Simplex | 38321498 | Marketa Wayhelova et al. (2024) | |
| c.3839_3840dup | p.Gln1281GlyfsTer66 | frameshift_variant | De novo | - | - | 33256793 | Xu N et al. (2020) | |
| c.4086_4087del | p.Glu1362AspfsTer11 | frameshift_variant | Unknown | - | - | 33256793 | Xu N et al. (2020) | |
| c.2568_2573dup | p.Gly857_Arg858dup | inframe_insertion | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.1655_1656dup | p.Pro553SerfsTer9 | frameshift_variant | Unknown | - | - | 35982159 | Zhou X et al. (2022) | |
| c.2276_2277del | p.Thr759SerfsTer2 | frameshift_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.2276_2277del | p.Thr759SerfsTer2 | frameshift_variant | Unknown | - | - | 35982159 | Zhou X et al. (2022) | |
| c.4962C>A | p.Leu1667Ile | missense_variant | Unknown | - | Unknown | 18615476 | Gauthier J , et al. (2008) | |
| c.2995G>T | p.Gly1011Val | missense_variant | Unknown | - | Unknown | 25188300 | Leblond CS , et al. (2014) | |
| c.3706C>A | p.Ala1248Glu | missense_variant | Unknown | - | Unknown | 25188300 | Leblond CS , et al. (2014) | |
| c.3759G>A | p.Ala1266Thr | missense_variant | Unknown | - | Unknown | 25188300 | Leblond CS , et al. (2014) | |
| c.3788A>T | p.Glu1275Asp | missense_variant | Unknown | - | Unknown | 25188300 | Leblond CS , et al. (2014) | |
| c.1984G>A | p.Arg674Gln | missense_variant | Unknown | - | Unknown | 25363760 | De Rubeis S , et al. (2014) | |
| c.2020G>T | p.Ser686Ile | missense_variant | Unknown | - | Unknown | 25363760 | De Rubeis S , et al. (2014) | |
| c.3676C>T | p.Ala1238Val | missense_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.3766C>T | p.Pro1268Leu | missense_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.3838C>T | p.Ser1292Phe | missense_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.4027C>T | p.Ser1355Phe | missense_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.4405G>A | p.Arg1481Gln | missense_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.4407G>C | p.Gly1482Arg | missense_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.4408G>T | p.Gly1482Val | missense_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.4722G>A | p.Val1587Met | missense_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.3275C>T | p.Pro1104= | synonymous_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.3680G>A | p.Pro1239= | synonymous_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.3710G>A | p.Glu1249= | synonymous_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.4052C>T | p.Arg1363= | synonymous_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.4283C>T | p.Ser1440= | synonymous_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.4394C>T | p.Pro1477= | synonymous_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.4556C>T | p.Ile1531= | synonymous_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.5021C>T | p.Arg1686= | synonymous_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.3424_3425del | p.Leu1142GlyfsTer215 | frameshift_variant | Unknown | - | - | 35741772 | Hu C et al. (2022) | |
| c.1014_1015del | p.Gln339AlafsTer44 | frameshift_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.4259_4260del | p.Glu1420GlyfsTer3 | frameshift_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.5233_5243del | p.Gly1745ArgfsTer7 | frameshift_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.4348G>A | p.Arg1462His | missense_variant | Unknown | - | Unknown | 25363760 | De Rubeis S , et al. (2014) | |
| c.421C>G | p.Pro141Ala | missense_variant | De novo | - | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
| c.869G>A | p.Cys290Tyr | missense_variant | De novo | - | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
| - | - | copy_number_loss | De novo | - | Simplex | 25533962 | Deciphering Developmental Disorders Study (2014) | |
| c.3799_3811del | p.Arg1267SerfsTer75 | frameshift_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.3812_3824del | p.Leu1271ProfsTer71 | frameshift_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.3812_3824dup | p.Ala1276HisfsTer86 | frameshift_variant | Unknown | - | - | 35982159 | Zhou X et al. (2022) | |
| c.4134_4135del | p.Val1379ProfsTer27 | frameshift_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.3856G>A | p.Arg1298Lys | missense_variant | Familial | Maternal | - | 18615476 | Gauthier J , et al. (2008) | |
| c.3642dup | p.Ala1227GlyfsTer69 | frameshift_variant | De novo | - | - | 31452935 | Feliciano P et al. (2019) | |
| c.3192del | p.Leu1077Ter | frameshift_variant | De novo | - | Simplex | 25188300 | Leblond CS , et al. (2014) | |
| c.2474del | p.Phe838SerfsTer55 | frameshift_variant | De novo | - | - | 29719671 | De Rubeis S , et al. (2018) | |
| c.4232del | p.Lys1424ArgfsTer4 | frameshift_variant | De novo | - | - | 29719671 | De Rubeis S , et al. (2018) | |
| c.1903T>G | p.Val647Gly | missense_variant | De novo | - | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
| c.3630dup | p.Leu1211AlafsTer72 | frameshift_variant | De novo | - | Simplex | 30555518 | Du X , et al. (2018) | |
| c.3472_3473del | p.Pro1158ThrfsTer199 | frameshift_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.4891_4892del | p.Tyr1631ProfsTer124 | frameshift_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.4728_4740del | p.Glu1576AspfsTer26 | frameshift_variant | De novo | - | - | 37035742 | Zhang Y et al. (2023) | |
| c.1818G>A | p.Ala619Thr | splice_site_variant | Familial | Maternal | - | 22892527 | Boccuto L , et al. (2012) | |
| c.3679dup | p.Ser1227LysfsTer131 | frameshift_variant | De novo | - | - | 34737294 | Loureiro LO et al. (2021) | |
| c.3729dup | p.Ala1256GlyfsTer40 | frameshift_variant | De novo | - | - | 27479843 | Lelieveld SH et al. (2016) | |
| c.3681dup | p.Ala1240GlyfsTer56 | frameshift_variant | De novo | - | - | 29719671 | De Rubeis S , et al. (2018) | |
| c.4776dup | p.Ile1593HisfsTer12 | frameshift_variant | De novo | - | - | 35773312 | Trifiletti R et al. (2022) | |
| c.3552A>G | p.Ser1197Gly | missense_variant | De novo | - | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
| c.484G>A | p.Ala162Thr | missense_variant | Unknown | - | - | 28371232 | de Sena Cortabitarte A , et al. (2017) | |
| c.34C>T | p.Arg12Cys | missense_variant | Familial | Maternal | Simplex | 17173049 | Durand CM , et al. (2006) | |
| c.3638dup | p.Glu1214ArgfsTer144 | frameshift_variant | Unknown | - | - | 35773312 | Trifiletti R et al. (2022) | |
| c.3679dupG | p.Ala1227GlyfsTer69 | frameshift_variant | De novo | - | - | 39039281 | Axel Schmidt et al. (2024) | |
| c.2804G>C | p.Pro947= | synonymous_variant | Unknown | - | - | 28371232 | de Sena Cortabitarte A , et al. (2017) | |
| c.3631dup | p.Arg1211ProfsTer147 | frameshift_variant | De novo | - | Simplex | 37393044 | Wang J et al. (2023) | |
| c.3102del | p.Leu1047TyrfsTer31 | frameshift_variant | De novo | - | Simplex | 25931020 | Hara M , et al. (2015) | |
| c.4494dup | p.Leu1511ProfsTer32 | frameshift_variant | De novo | - | Simplex | 27525107 | Yuen RK et al. (2016) | |
| c.3424_3425del | p.Ser1142ProfsTer140 | frameshift_variant | De novo | - | - | 30763456 | Zhou WZ , et al. (2019) | |
| c.2434_2449del | p.Thr812AlafsTer29 | frameshift_variant | De novo | - | - | 34363551 | Trakadis Y et al. (2021) | |
| c.4174del | p.Thr1404IlefsTer24 | frameshift_variant | De novo | - | - | 31209962 | Aspromonte MC , et al. (2019) | |
| NM_033517.1:c.3642dup | - | frameshift_variant | De novo | - | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
| c.2982C>T | p.Leu1007Phe | missense_variant | Unknown | - | - | 28371232 | de Sena Cortabitarte A , et al. (2017) | |
| c.3034G>T | p.Arg1024Leu | missense_variant | Unknown | - | - | 28371232 | de Sena Cortabitarte A , et al. (2017) | |
| c.3181C>G | p.Pro1073Arg | missense_variant | Unknown | - | - | 28371232 | de Sena Cortabitarte A , et al. (2017) | |
| c.3531G>A | p.Asp1190Asn | missense_variant | Unknown | - | - | 28371232 | de Sena Cortabitarte A , et al. (2017) | |
| c.3727G>A | p.Arg1255Gln | missense_variant | Unknown | - | - | 28371232 | de Sena Cortabitarte A , et al. (2017) | |
| c.4387G>T | p.Gly1475Val | missense_variant | Unknown | - | - | 28371232 | de Sena Cortabitarte A , et al. (2017) | |
| c.4917G>A | p.Gly1652Ser | missense_variant | Unknown | - | - | 28371232 | de Sena Cortabitarte A , et al. (2017) | |
| c.4862C>T | p.Arg1633= | synonymous_variant | Unknown | - | - | 28371232 | de Sena Cortabitarte A , et al. (2017) | |
| c.2765del | p.Glu922GlyfsTer33 | frameshift_variant | De novo | - | Simplex | 32094338 | Husson T , et al. (2020) | |
| c.4865_4868dup | p.Phe1624AlafsTer70 | frameshift_variant | Unknown | - | - | 38536866 | Kirsten Furley et al. () | |
| c.898C>T | p.Arg300Cys | missense_variant | Familial | Maternal | Simplex | 17173049 | Durand CM , et al. (2006) | |
| c.2717_2718dup | p.Gly907ArgfsTer49 | frameshift_variant | De novo | - | - | 34356170 | Valentino F et al. (2021) | |
| c.4044_4045del | p.Pro1349CysfsTer8 | frameshift_variant | De novo | - | - | 38256219 | Luigi Vetri et al. (2024) | |
| c.203T>C | p.Leu68Pro | missense_variant | Familial | Paternal | Simplex | 18615476 | Gauthier J , et al. (2008) | |
| c.3679dup | p.Ser1227LysfsTer131 | frameshift_variant | Unknown | - | Unknown | 30763456 | Zhou WZ , et al. (2019) | |
| c.3679dup | p.Ser1227LysfsTer131 | frameshift_variant | De novo | - | Simplex | 33619735 | Brunet T et al. (2021) | |
| c.2811dup | p.Arg950ProfsTer346 | frameshift_variant | Unknown | - | Simplex | 28263302 | C Yuen RK et al. (2017) | |
| c.*197G>A | - | missense_variant | Familial | Maternal | Multi-generational | 31406558 | Munnich A , et al. (2019) | |
| c.3251_3254del | p.Glu1084GlyfsTer55 | frameshift_variant | De novo | - | - | 34356170 | Valentino F et al. (2021) | |
| c.2948_2951del | p.Gly996SerfsTer81 | frameshift_variant | De novo | - | - | 29719671 | De Rubeis S , et al. (2018) | |
| c.4579_4580del | p.Ser1539ThrfsTer3 | frameshift_variant | De novo | - | - | 29719671 | De Rubeis S , et al. (2018) | |
| c.3368del | p.Gly1123AlafsTer17 | frameshift_variant | De novo | - | - | 38008000 | Lucie Sedlackova et al. (2024) | |
| c.3088del | p.Ala1030ProfsTer110 | frameshift_variant | De novo | - | Simplex | 32094338 | Husson T , et al. (2020) | |
| c.3679dup | p.Ser1227LysfsTer131 | frameshift_variant | Unknown | - | Simplex | 32094338 | Husson T , et al. (2020) | |
| c.3034G>T | p.Arg1024Leu | missense_variant | Familial | Maternal | Simplex | 17173049 | Durand CM , et al. (2006) | |
| c.3473C>G | p.Pro1158Arg | missense_variant | Familial | Maternal | Simplex | 17173049 | Durand CM , et al. (2006) | |
| c.3679dup | p.Ala1227GlyfsTer56 | frameshift_variant | De novo | - | Simplex | 31406558 | Munnich A , et al. (2019) | |
| c.593C>G | p.Ala198Gly | missense_variant | Familial | Maternal | Multiplex | 17173049 | Durand CM , et al. (2006) | |
| c.1022C>T | p.Ser341Leu | missense_variant | Familial | Paternal | Simplex | 17999366 | Moessner R , et al. (2007) | |
| c.2871G>T | p.Ala970Ser | missense_variant | Familial | Paternal | Simplex | 17999366 | Moessner R , et al. (2007) | |
| c.3098_3110del | p.Ser1046ProfsTer28 | frameshift_variant | De novo | - | - | 29719671 | De Rubeis S , et al. (2018) | |
| c.3767_3779del | p.Gly1269GlnfsTer11 | frameshift_variant | De novo | - | - | 29719671 | De Rubeis S , et al. (2018) | |
| c.4910_4925dup | p.Gly1655ArgfsTer44 | frameshift_variant | De novo | - | - | 29719671 | De Rubeis S , et al. (2018) | |
| c.4040_4041del | p.Leu1347ProfsTer10 | frameshift_variant | De novo | - | Simplex | 37393044 | Wang J et al. (2023) | |
| c.1322_1340del | p.Ala454ProfsTer20 | inframe_deletion | Familial | Maternal | - | 21378602 | Waga C , et al. (2011) | |
| c.829G>A | p.Gly277Arg | missense_variant | Familial | Both parents | Simplex | 28392909 | Gupta AR , et al. (2017) | |
| c.2832del | p.Gln957SerfsTer121 | frameshift_variant | De novo | - | Multiplex | 28263302 | C Yuen RK et al. (2017) | |
| c.3720dup | p.Lys1241GlufsTer117 | frameshift_variant | De novo | - | Simplex | 25418537 | O'Roak BJ , et al. (2014) | |
| c.3751C>T | p.Pro1263Leu | missense_variant | Familial | Paternal | Simplex | 17999366 | Moessner R , et al. (2007) | |
| c.4243T>C | p.Val1427Ala | missense_variant | Familial | Maternal | Simplex | 17999366 | Moessner R , et al. (2007) | |
| c.4584G>A | p.Gly1541Ser | missense_variant | Familial | Paternal | Simplex | 17999366 | Moessner R , et al. (2007) | |
| c.3387del | p.Leu1142CysfsTer53 | frameshift_variant | De novo | - | Simplex | 25188300 | Leblond CS , et al. (2014) | |
| c.3570del | p.Leu1203CysfsTer81 | frameshift_variant | De novo | - | Simplex | 25188300 | Leblond CS , et al. (2014) | |
| c.3729del | p.Ala1256ProfsTer28 | frameshift_variant | De novo | - | Simplex | 25188300 | Leblond CS , et al. (2014) | |
| c.3679dup | p.Ala1227GlyfsTer69 | frameshift_variant | De novo | - | Simplex | 34737294 | Loureiro LO et al. (2021) | |
| c.2267del | p.Lys768AsnfsTer16 | splice_site_variant | De novo | - | Simplex | 18615476 | Gauthier J , et al. (2008) | |
| c.3426_3427del | p.Ser1155ProfsTer140 | frameshift_variant | De novo | - | - | 29719671 | De Rubeis S , et al. (2018) | |
| c.3424_3425del | p.Leu1142GlyfsTer215 | frameshift_variant | De novo | - | - | 39039281 | Axel Schmidt et al. (2024) | |
| c.1987G>A | p.Arg675His | missense_variant | Familial | Paternal | Simplex | 25363760 | De Rubeis S , et al. (2014) | |
| c.2611G>T | p.Glu871Ter | stop_gained | Unknown | Not paternal | Simplex | 38519481 | Marta Viggiano et al. (2024) | |
| c.1302+46_1302+47insGGGGGGGGG | - | intron_variant | De novo | - | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
| c.3950_3962del | p.Arg1317LeufsTer25 | frameshift_variant | De novo | - | Simplex | 39126614 | Suhua Chang et al. () | |
| c.1807_1811del | p.Glu603ProfsTer26 | frameshift_variant | De novo | - | Simplex | 34948243 | Bruno LP et al. (2021) | |
| c.925_926del | p.Arg309GlyfsTer21 | frameshift_variant | De novo | - | Multiplex | 25621899 | Yuen RK , et al. (2015) | |
| c.3655G>A | p.Arg1231His | missense_variant | Familial | Maternal | Multiplex | 17173049 | Durand CM , et al. (2006) | |
| c.3642dup | p.Ala1227GlyfsTer69 | frameshift_variant | De novo | - | Multiplex | 17173049 | Durand CM , et al. (2006) | |
| c.3826C>T | p.Ala1288Val | missense_variant | Familial | Maternal | Simplex | 25363760 | De Rubeis S , et al. (2014) | |
| c.3868C>T | p.Ala1302Val | missense_variant | Familial | Maternal | Simplex | 25363760 | De Rubeis S , et al. (2014) | |
| c.3973_3974del | p.Pro1325GlyfsTer32 | frameshift_variant | De novo | - | Simplex | 34582790 | Mitani T et al. (2021) | |
| c.4861G>A | p.Arg1633His | missense_variant | Unknown | Not paternal | Simplex | 21624971 | Schaaf CP , et al. (2011) | |
| c.4899G>A | p.Ala1646Thr | missense_variant | Unknown | Not paternal | Simplex | 21624971 | Schaaf CP , et al. (2011) | |
| c.1313_1324del | p.Ala451_Ala454del | inframe_deletion | Unknown | - | Unknown | 25188300 | Leblond CS , et al. (2014) | |
| c.3480G>A | p.Ala1173Thr | missense_variant | Familial | Maternal | Multiplex | 17999366 | Moessner R , et al. (2007) | |
| c.4179C>G | p.Leu1406Val | missense_variant | Familial | Maternal | Multiplex | 17999366 | Moessner R , et al. (2007) | |
| c.4923C>A | p.Pro1654Thr | missense_variant | Familial | Maternal | Multiplex | 17999366 | Moessner R , et al. (2007) | |
| c.4962C>A | p.Leu1667Ile | missense_variant | Familial | Paternal | Multiplex | 17999366 | Moessner R , et al. (2007) | |
| c.3218del | p.Gly1073AlafsTer67 | frameshift_variant | De novo | - | Simplex | 32202324 | Hassani Nia F et al. (2020) | |
| c.3865dup | p.Ala1289GlyfsTer69 | frameshift_variant | De novo | - | - | 35322241 | Brea-Fernández AJ et al. (2022) | |
| c.3286del | p.Ala1096ProfsTer44 | frameshift_variant | De novo | - | - | 39094681 | Roger Esmel-Vilomara et al. (2024) | |
| c.2957_2972dup | p.Gly1004LeufsTer297 | frameshift_variant | De novo | - | Simplex | 25167861 | Redin C , et al. (2014) | |
| c.2183_2184del | p.Arg728LysfsTer33 | frameshift_variant | Unknown | - | Unknown | 33526774 | Mojarad BA et al. (2021) | |
| c.3571_3572insTT | p.Gln1204CysfsTer81 | frameshift_variant | De novo | - | - | 31209962 | Aspromonte MC , et al. (2019) | |
| c.3933del | p.Ala1324LeufsTer62 | frameshift_variant | Unknown | Not maternal | - | 22892527 | Boccuto L , et al. (2012) | |
| c.3770_3774dup | p.Gly1271AlafsTer15 | frameshift_variant | De novo | - | Simplex | 25188300 | Leblond CS , et al. (2014) | |
| c.3263del | p.Lys1100AsnfsTer95 | frameshift_variant | De novo | - | Multiplex | 25646853 | Nemirovsky SI , et al. (2015) | |
| c.3610_3611del | p.Leu1204ValfsTer153 | frameshift_variant | De novo | - | - | 38321498 | Marketa Wayhelova et al. (2024) | |
| c.1390C>A | p.Pro464Thr | missense_variant | Familial | Maternal | Multi-generational | 35042901 | Woike D et al. (2022) | |
| c.3681dup | p.Ala1240GlyfsTer56 | frameshift_variant | Unknown | Not paternal | - | 29719671 | De Rubeis S , et al. (2018) | |
| c.3730dup | p.Arg1244ProfsTer114 | frameshift_variant | Unknown | - | Unknown | 37799141 | Amerh S Alqahtani et al. (2023) | |
| c.2313+1G>A | p.? | splice_site_variant | Familial | Paternal | Multiplex | 34369668 | Kankuri-Tammilehto M et al. (2021) | |
| c.3715_3727del | p.Leu1251ArgfsTer29 | frameshift_variant | De novo | - | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
| c.4539_4540del | p.Ala1526GlnfsTer16 | frameshift_variant | De novo | - | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
| c.3610_3611del | p.Leu1204ValfsTer153 | frameshift_variant | De novo | - | - | 39094681 | Roger Esmel-Vilomara et al. (2024) | |
| c.3679dup | p.Ala1227GlyfsTer69 | frameshift_variant | Familial | Maternal | Simplex | 34737294 | Loureiro LO et al. (2021) | |
| c.3470_3479del | p.His1157ProfsTer97 | frameshift_variant | Unknown | - | - | 37943464 | Karthika Ajit Valaparambil et al. () | |
| c.1806G>A | p.Val615Met | missense_variant | De novo | - | Multiplex (monozygotic twins) | 31398340 | Ruzzo EK , et al. (2019) | |
| c.3095C>G | p.Ala1032Gly | missense_variant | Familial | Paternal | Multi-generational | 17173049 | Durand CM , et al. (2006) | |
| c.4938C>A | p.Pro1659Thr | missense_variant | Familial | Paternal | Multi-generational | 17173049 | Durand CM , et al. (2006) | |
| c.3679dup | p.Ala1227GlyfsTer69 | frameshift_variant | Familial | Paternal | Multiplex | 34737294 | Loureiro LO et al. (2021) | |
| c.521del | p.Gln174ArgfsTer18 | frameshift_variant | Familial | Maternal | Multiplex | 37506195 | Cirnigliaro M et al. (2023) | |
| c.4835_4839dup | p.Pro1614AlafsTer14 | frameshift_variant | De novo | - | Simplex | 38321498 | Marketa Wayhelova et al. (2024) | |
| c.2977del | p.Pro1005ArgfsTer73 | frameshift_variant | Unknown | Not maternal | Simplex | 25188300 | Leblond CS , et al. (2014) | |
| c.3977del | p.Lys1340SerfsTer46 | frameshift_variant | Unknown | Not maternal | Simplex | 25188300 | Leblond CS , et al. (2014) | |
| NM_001372044.1:c.4948_4949insGGCCCC | p.Gln1652_Leu1653insGlySic | inframe_insertion | - | - | - | 21378602 | Waga C , et al. (2011) | |
| ENST00000414786:c.3197G>T | p.Arg1066Leu | missense_variant | Familial | Maternal | Simplex | 17173049 | Durand CM , et al. (2006) | |
| c.1837_1838insGG | p.Thr626AlafsTer9 | frameshift_variant | Familial | Paternal | Multiplex | 25363760 | De Rubeis S , et al. (2014) | |
| c.3172_3724del | p.Leu1070ProfsTer30 | frameshift_variant | De novo | - | Simplex | 31696658 | da Silva Montenegro EM , et al. (2019) | |
| c.2995G>T | p.Gly1011Val | missense_variant | Familial | Paternal | Multiplex (monozygotic twins) | 17173049 | Durand CM , et al. (2006) | |
| c.4358_4372del | p.Leu1453_Ser1458delinsPro | inframe_deletion | Familial | Maternal | Multiplex | 17999366 | Moessner R , et al. (2007) | |
| c.4067_4068del | p.His1369ProfsTer25 | frameshift_variant | De novo | - | Multiplex (monozygotic twins) | 29719671 | De Rubeis S , et al. (2018) | |
| c.1341_1342insG | p.Pro460ArgfsTer28 | frameshift_variant | Familial | Paternal | Possible multi-generational | 22892527 | Boccuto L , et al. (2012) |
Common Variants (9)
| Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Paternal Transmission | Family Type | PubMed ID | Author, Year |
|---|---|---|---|---|---|---|---|---|
| c.1304+48C>T | - | intron_variant | - | - | - | 22892527 | Boccuto L , et al. (2012) | |
| c.2134+407G>A | - | intron_variant | - | - | - | 27876814 | Connolly S , et al. (2016) | |
| c.2351-595G>C | - | intron_variant | - | - | - | 29339533 | Koberstein JN , et al. (2018) | |
| c.734T>C | p.Ile245Thr | missense_variant | - | - | - | 24398551 | Shao S , et al. (2014) | |
| c.886-60C>G | - | intron_variant | - | - | - | 28371232 | de Sena Cortabitarte A , et al. (2017) | |
| c.1612+18T>C | - | intron_variant | - | - | - | 28371232 | de Sena Cortabitarte A , et al. (2017) | |
| c.1797G>A | p.(=) | synonymous_variant | - | - | - | 28371232 | de Sena Cortabitarte A , et al. (2017) | |
| c.4947C>T | p.(=) | synonymous_variant | - | - | - | 28371232 | de Sena Cortabitarte A , et al. (2017) | |
| c.2161G>A | p.Ala721Thr | missense_variant | - | - | - | 28371232 | de Sena Cortabitarte A , et al. (2017) |
SFARI Gene score
High Confidence, Syndromic
Score Delta: Score remained at 1S
criteria met
See SFARI Gene'scoring criteriaWe considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.
The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."
4/1/2021
Score remained at 1
Description
SHANK3 lies within a multi-genic region on chromosome 22 that is deleted in Phelan-McDermid syndrome, a disorder which is frequently accompanied by ASD. De novo and inherited point mutations and copy number variants involving SHANK3 have been identified in individuals with ASD in multiple reports (PMIDs 17173049, 17999366, 18615476, 20186804, 20385823, 21378602, 21624971, 22558107, 22892527, 23758760), including de novo SHANK3 variants in PMIDs 17173049, 17999366 and 18615476 that were predicted to be loss-of-function variants or shown experimentally to disrupt SHANK3 function. An additional seven de novo loss-of-function variants in SHANK3 were identified in simplex ASD cases in Leblond et al., 2014 (PMID 25188300); in contrast, no truncating variants in SHANK3 were observed in 1,031 controls. Individuals with truncating SHANK3 variants were found to display ASD with moderate to severe/profound intellectual disability (mean IQ of 31 8) in this report. Furthermore, in a screen and meta-analysis of SHANK copy number variants in ASD, SHANK3 deletions were shown to be statistically enriched in ASD cases compared to controls [10/5,657 cases (0.18%) vs. 2/19,163 controls (0.01); P=0.019, OR=4.05 (1.26-13.01)] (PMID 25188300). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Multiple inconsistent associations have been reported with idiopathic ASD in other studies (PMIDs 19384346, 19566951, 22892527, 24398551, 27876814). De novo SHANK3 mutations in individuals with schizophrenia have also been reported in Gauthier et al., 2010 (PMID 20385823), and association of SHANK3 with schizophrenia has been reported as well (PMID 28371232). Clinical evaluation of 17 individuals with SHANK3 point mutations and features of Phelan-McDermid syndrome in De Rubeis et al., 2018 demonstrated that a diagnosis of ASD was reported in 69% of cases (11/16). Analysis of pyramidal cortical neurons derived from induced pluripotent stem cells from four ASD patients with de novo loss-of-function variants (originally reported in LeBlond et al., 2014) showed a significant decrease in SHANK3 mRNA levels (less than 50% of controls) that correlated with a significant reduction in dendritic spine densities, as well as in whole spine and spine head volumes, in patient-derived neurons (Gouder et al., 2019).
1/1/2021
Score remained at 1
Description
SHANK3 lies within a multi-genic region on chromosome 22 that is deleted in Phelan-McDermid syndrome, a disorder which is frequently accompanied by ASD. De novo and inherited point mutations and copy number variants involving SHANK3 have been identified in individuals with ASD in multiple reports (PMIDs 17173049, 17999366, 18615476, 20186804, 20385823, 21378602, 21624971, 22558107, 22892527, 23758760), including de novo SHANK3 variants in PMIDs 17173049, 17999366 and 18615476 that were predicted to be loss-of-function variants or shown experimentally to disrupt SHANK3 function. An additional seven de novo loss-of-function variants in SHANK3 were identified in simplex ASD cases in Leblond et al., 2014 (PMID 25188300); in contrast, no truncating variants in SHANK3 were observed in 1,031 controls. Individuals with truncating SHANK3 variants were found to display ASD with moderate to severe/profound intellectual disability (mean IQ of 31 8) in this report. Furthermore, in a screen and meta-analysis of SHANK copy number variants in ASD, SHANK3 deletions were shown to be statistically enriched in ASD cases compared to controls [10/5,657 cases (0.18%) vs. 2/19,163 controls (0.01); P=0.019, OR=4.05 (1.26-13.01)] (PMID 25188300). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Multiple inconsistent associations have been reported with idiopathic ASD in other studies (PMIDs 19384346, 19566951, 22892527, 24398551, 27876814). De novo SHANK3 mutations in individuals with schizophrenia have also been reported in Gauthier et al., 2010 (PMID 20385823), and association of SHANK3 with schizophrenia has been reported as well (PMID 28371232). Clinical evaluation of 17 individuals with SHANK3 point mutations and features of Phelan-McDermid syndrome in De Rubeis et al., 2018 demonstrated that a diagnosis of ASD was reported in 69% of cases (11/16). Analysis of pyramidal cortical neurons derived from induced pluripotent stem cells from four ASD patients with de novo loss-of-function variants (originally reported in LeBlond et al., 2014) showed a significant decrease in SHANK3 mRNA levels (less than 50% of controls) that correlated with a significant reduction in dendritic spine densities, as well as in whole spine and spine head volumes, in patient-derived neurons (Gouder et al., 2019).
10/1/2020
Score remained at 1
Description
SHANK3 lies within a multi-genic region on chromosome 22 that is deleted in Phelan-McDermid syndrome, a disorder which is frequently accompanied by ASD. De novo and inherited point mutations and copy number variants involving SHANK3 have been identified in individuals with ASD in multiple reports (PMIDs 17173049, 17999366, 18615476, 20186804, 20385823, 21378602, 21624971, 22558107, 22892527, 23758760), including de novo SHANK3 variants in PMIDs 17173049, 17999366 and 18615476 that were predicted to be loss-of-function variants or shown experimentally to disrupt SHANK3 function. An additional seven de novo loss-of-function variants in SHANK3 were identified in simplex ASD cases in Leblond et al., 2014 (PMID 25188300); in contrast, no truncating variants in SHANK3 were observed in 1,031 controls. Individuals with truncating SHANK3 variants were found to display ASD with moderate to severe/profound intellectual disability (mean IQ of 31 8) in this report. Furthermore, in a screen and meta-analysis of SHANK copy number variants in ASD, SHANK3 deletions were shown to be statistically enriched in ASD cases compared to controls [10/5,657 cases (0.18%) vs. 2/19,163 controls (0.01); P=0.019, OR=4.05 (1.26-13.01)] (PMID 25188300). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Multiple inconsistent associations have been reported with idiopathic ASD in other studies (PMIDs 19384346, 19566951, 22892527, 24398551, 27876814). De novo SHANK3 mutations in individuals with schizophrenia have also been reported in Gauthier et al., 2010 (PMID 20385823), and association of SHANK3 with schizophrenia has been reported as well (PMID 28371232). Clinical evaluation of 17 individuals with SHANK3 point mutations and features of Phelan-McDermid syndrome in De Rubeis et al., 2018 demonstrated that a diagnosis of ASD was reported in 69% of cases (11/16). Analysis of pyramidal cortical neurons derived from induced pluripotent stem cells from four ASD patients with de novo loss-of-function variants (originally reported in LeBlond et al., 2014) showed a significant decrease in SHANK3 mRNA levels (less than 50% of controls) that correlated with a significant reduction in dendritic spine densities, as well as in whole spine and spine head volumes, in patient-derived neurons (Gouder et al., 2019).
7/1/2020
Score remained at 1
Description
SHANK3 lies within a multi-genic region on chromosome 22 that is deleted in Phelan-McDermid syndrome, a disorder which is frequently accompanied by ASD. De novo and inherited point mutations and copy number variants involving SHANK3 have been identified in individuals with ASD in multiple reports (PMIDs 17173049, 17999366, 18615476, 20186804, 20385823, 21378602, 21624971, 22558107, 22892527, 23758760), including de novo SHANK3 variants in PMIDs 17173049, 17999366 and 18615476 that were predicted to be loss-of-function variants or shown experimentally to disrupt SHANK3 function. An additional seven de novo loss-of-function variants in SHANK3 were identified in simplex ASD cases in Leblond et al., 2014 (PMID 25188300); in contrast, no truncating variants in SHANK3 were observed in 1,031 controls. Individuals with truncating SHANK3 variants were found to display ASD with moderate to severe/profound intellectual disability (mean IQ of 31 8) in this report. Furthermore, in a screen and meta-analysis of SHANK copy number variants in ASD, SHANK3 deletions were shown to be statistically enriched in ASD cases compared to controls [10/5,657 cases (0.18%) vs. 2/19,163 controls (0.01); P=0.019, OR=4.05 (1.26-13.01)] (PMID 25188300). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Multiple inconsistent associations have been reported with idiopathic ASD in other studies (PMIDs 19384346, 19566951, 22892527, 24398551, 27876814). De novo SHANK3 mutations in individuals with schizophrenia have also been reported in Gauthier et al., 2010 (PMID 20385823), and association of SHANK3 with schizophrenia has been reported as well (PMID 28371232). Clinical evaluation of 17 individuals with SHANK3 point mutations and features of Phelan-McDermid syndrome in De Rubeis et al., 2018 demonstrated that a diagnosis of ASD was reported in 69% of cases (11/16). Analysis of pyramidal cortical neurons derived from induced pluripotent stem cells from four ASD patients with de novo loss-of-function variants (originally reported in LeBlond et al., 2014) showed a significant decrease in SHANK3 mRNA levels (less than 50% of controls) that correlated with a significant reduction in dendritic spine densities, as well as in whole spine and spine head volumes, in patient-derived neurons (Gouder et al., 2019).
4/1/2020
Score remained at 1
Description
SHANK3 lies within a multi-genic region on chromosome 22 that is deleted in Phelan-McDermid syndrome, a disorder which is frequently accompanied by ASD. De novo and inherited point mutations and copy number variants involving SHANK3 have been identified in individuals with ASD in multiple reports (PMIDs 17173049, 17999366, 18615476, 20186804, 20385823, 21378602, 21624971, 22558107, 22892527, 23758760), including de novo SHANK3 variants in PMIDs 17173049, 17999366 and 18615476 that were predicted to be loss-of-function variants or shown experimentally to disrupt SHANK3 function. An additional seven de novo loss-of-function variants in SHANK3 were identified in simplex ASD cases in Leblond et al., 2014 (PMID 25188300); in contrast, no truncating variants in SHANK3 were observed in 1,031 controls. Individuals with truncating SHANK3 variants were found to display ASD with moderate to severe/profound intellectual disability (mean IQ of 31 8) in this report. Furthermore, in a screen and meta-analysis of SHANK copy number variants in ASD, SHANK3 deletions were shown to be statistically enriched in ASD cases compared to controls [10/5,657 cases (0.18%) vs. 2/19,163 controls (0.01); P=0.019, OR=4.05 (1.26-13.01)] (PMID 25188300). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Multiple inconsistent associations have been reported with idiopathic ASD in other studies (PMIDs 19384346, 19566951, 22892527, 24398551, 27876814). De novo SHANK3 mutations in individuals with schizophrenia have also been reported in Gauthier et al., 2010 (PMID 20385823), and association of SHANK3 with schizophrenia has been reported as well (PMID 28371232). Clinical evaluation of 17 individuals with SHANK3 point mutations and features of Phelan-McDermid syndrome in De Rubeis et al., 2018 demonstrated that a diagnosis of ASD was reported in 69% of cases (11/16). Analysis of pyramidal cortical neurons derived from induced pluripotent stem cells from four ASD patients with de novo loss-of-function variants (originally reported in LeBlond et al., 2014) showed a significant decrease in SHANK3 mRNA levels (less than 50% of controls) that correlated with a significant reduction in dendritic spine densities, as well as in whole spine and spine head volumes, in patient-derived neurons (Gouder et al., 2019).
Reports Added
[Truncating mutations in SHANK3 associated with global developmental delay interfere with nuclear ò-catenin signaling2020] [Utility of clinical exome sequencing in a complex Emirati pediatric cohort2020] [Next-Generation Sequencing in Korean Children With Autism Spectrum Disorder and Comorbid Epilepsy2020]1/1/2020
Score remained at 1
Description
SHANK3 lies within a multi-genic region on chromosome 22 that is deleted in Phelan-McDermid syndrome, a disorder which is frequently accompanied by ASD. De novo and inherited point mutations and copy number variants involving SHANK3 have been identified in individuals with ASD in multiple reports (PMIDs 17173049, 17999366, 18615476, 20186804, 20385823, 21378602, 21624971, 22558107, 22892527, 23758760), including de novo SHANK3 variants in PMIDs 17173049, 17999366 and 18615476 that were predicted to be loss-of-function variants or shown experimentally to disrupt SHANK3 function. An additional seven de novo loss-of-function variants in SHANK3 were identified in simplex ASD cases in Leblond et al., 2014 (PMID 25188300); in contrast, no truncating variants in SHANK3 were observed in 1,031 controls. Individuals with truncating SHANK3 variants were found to display ASD with moderate to severe/profound intellectual disability (mean IQ of 31 8) in this report. Furthermore, in a screen and meta-analysis of SHANK copy number variants in ASD, SHANK3 deletions were shown to be statistically enriched in ASD cases compared to controls [10/5,657 cases (0.18%) vs. 2/19,163 controls (0.01); P=0.019, OR=4.05 (1.26-13.01)] (PMID 25188300). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Multiple inconsistent associations have been reported with idiopathic ASD in other studies (PMIDs 19384346, 19566951, 22892527, 24398551, 27876814). De novo SHANK3 mutations in individuals with schizophrenia have also been reported in Gauthier et al., 2010 (PMID 20385823), and association of SHANK3 with schizophrenia has been reported as well (PMID 28371232). Clinical evaluation of 17 individuals with SHANK3 point mutations and features of Phelan-McDermid syndrome in De Rubeis et al., 2018 demonstrated that a diagnosis of ASD was reported in 69% of cases (11/16). Analysis of pyramidal cortical neurons derived from induced pluripotent stem cells from four ASD patients with de novo loss-of-function variants (originally reported in LeBlond et al., 2014) showed a significant decrease in SHANK3 mRNA levels (less than 50% of controls) that correlated with a significant reduction in dendritic spine densities, as well as in whole spine and spine head volumes, in patient-derived neurons (Gouder et al., 2019).
Reports Added
[Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci.2015] [Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020] [Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use.2020]10/1/2019
Score remained at 1
New Scoring Scheme
Description
SHANK3 lies within a multi-genic region on chromosome 22 that is deleted in Phelan-McDermid syndrome, a disorder which is frequently accompanied by ASD. De novo and inherited point mutations and copy number variants involving SHANK3 have been identified in individuals with ASD in multiple reports (PMIDs 17173049, 17999366, 18615476, 20186804, 20385823, 21378602, 21624971, 22558107, 22892527, 23758760), including de novo SHANK3 variants in PMIDs 17173049, 17999366 and 18615476 that were predicted to be loss-of-function variants or shown experimentally to disrupt SHANK3 function. An additional seven de novo loss-of-function variants in SHANK3 were identified in simplex ASD cases in Leblond et al., 2014 (PMID 25188300); in contrast, no truncating variants in SHANK3 were observed in 1,031 controls. Individuals with truncating SHANK3 variants were found to display ASD with moderate to severe/profound intellectual disability (mean IQ of 31 8) in this report. Furthermore, in a screen and meta-analysis of SHANK copy number variants in ASD, SHANK3 deletions were shown to be statistically enriched in ASD cases compared to controls [10/5,657 cases (0.18%) vs. 2/19,163 controls (0.01); P=0.019, OR=4.05 (1.26-13.01)] (PMID 25188300). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Multiple inconsistent associations have been reported with idiopathic ASD in other studies (PMIDs 19384346, 19566951, 22892527, 24398551, 27876814). De novo SHANK3 mutations in individuals with schizophrenia have also been reported in Gauthier et al., 2010 (PMID 20385823), and association of SHANK3 with schizophrenia has been reported as well (PMID 28371232). Clinical evaluation of 17 individuals with SHANK3 point mutations and features of Phelan-McDermid syndrome in De Rubeis et al., 2018 demonstrated that a diagnosis of ASD was reported in 69% of cases (11/16). Analysis of pyramidal cortical neurons derived from induced pluripotent stem cells from four ASD patients with de novo loss-of-function variants (originally reported in LeBlond et al., 2014) showed a significant decrease in SHANK3 mRNA levels (less than 50% of controls) that correlated with a significant reduction in dendritic spine densities, as well as in whole spine and spine head volumes, in patient-derived neurons (Gouder et al., 2019).
Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [Shank Proteins Couple the Endocytic Zone to the Postsynaptic Density to Control Trafficking and Signaling of Metabotropic Glutamate Receptor 5.2019] [A 22q13.33 duplication harbouring the SHANK3 gene: does it cause neuropsychiatric disorders?2019] [Meta-Analyses Support Previous and Novel Autism Candidate Genes: Outcomes of an Unexplored Brazilian Cohort.2019] [New Scoring Scheme]7/1/2019
Score remained at 1S
Description
SHANK3 lies within a multi-genic region on chromosome 22 that is deleted in Phelan-McDermid syndrome, a disorder which is frequently accompanied by ASD. De novo and inherited point mutations and copy number variants involving SHANK3 have been identified in individuals with ASD in multiple reports (PMIDs 17173049, 17999366, 18615476, 20186804, 20385823, 21378602, 21624971, 22558107, 22892527, 23758760), including de novo SHANK3 variants in PMIDs 17173049, 17999366 and 18615476 that were predicted to be loss-of-function variants or shown experimentally to disrupt SHANK3 function. An additional seven de novo loss-of-function variants in SHANK3 were identified in simplex ASD cases in Leblond et al., 2014 (PMID 25188300); in contrast, no truncating variants in SHANK3 were observed in 1,031 controls. Individuals with truncating SHANK3 variants were found to display ASD with moderate to severe/profound intellectual disability (mean IQ of 31 8) in this report. Furthermore, in a screen and meta-analysis of SHANK copy number variants in ASD, SHANK3 deletions were shown to be statistically enriched in ASD cases compared to controls [10/5,657 cases (0.18%) vs. 2/19,163 controls (0.01); P=0.019, OR=4.05 (1.26-13.01)] (PMID 25188300). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Multiple inconsistent associations have been reported with idiopathic ASD in other studies (PMIDs 19384346, 19566951, 22892527, 24398551, 27876814). De novo SHANK3 mutations in individuals with schizophrenia have also been reported in Gauthier et al., 2010 (PMID 20385823), and association of SHANK3 with schizophrenia has been reported as well (PMID 28371232). Clinical evaluation of 17 individuals with SHANK3 point mutations and features of Phelan-McDermid syndrome in De Rubeis et al., 2018 demonstrated that a diagnosis of ASD was reported in 69% of cases (11/16). Analysis of pyramidal cortical neurons derived from induced pluripotent stem cells from four ASD patients with de novo loss-of-function variants (originally reported in LeBlond et al., 2014) showed a significant decrease in SHANK3 mRNA levels (less than 50% of controls) that correlated with a significant reduction in dendritic spine densities, as well as in whole spine and spine head volumes, in patient-derived neurons (Gouder et al., 2019).
Reports Added
[Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.2019] [Atypical behaviour and connectivity in SHANK3-mutant macaques.2019] [Characterization of intellectual disability and autism comorbidity through gene panel sequencing.2019] [Shank3 Mice Carrying the Human Q321R Mutation Display Enhanced Self-Grooming, Abnormal Electroencephalogram Patterns, and Suppressed Neuronal Excit...2019] [Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019] [Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder.2019]1/1/2019
Score remained at 1S
Description
SHANK3 lies within a multi-genic region on chromosome 22 that is deleted in Phelan-McDermid syndrome, a disorder which is frequently accompanied by ASD. De novo and inherited point mutations and copy number variants involving SHANK3 have been identified in individuals with ASD in multiple reports (PMIDs 17173049, 17999366, 18615476, 20186804, 20385823, 21378602, 21624971, 22558107, 22892527, 23758760), including de novo SHANK3 variants in PMIDs 17173049, 17999366 and 18615476 that were predicted to be loss-of-function variants or shown experimentally to disrupt SHANK3 function. An additional seven de novo loss-of-function variants in SHANK3 were identified in simplex ASD cases in Leblond et al., 2014 (PMID 25188300); in contrast, no truncating variants in SHANK3 were observed in 1,031 controls. Individuals with truncating SHANK3 variants were found to display ASD with moderate to severe/profound intellectual disability (mean IQ of 31 8) in this report. Furthermore, in a screen and meta-analysis of SHANK copy number variants in ASD, SHANK3 deletions were shown to be statistically enriched in ASD cases compared to controls [10/5,657 cases (0.18%) vs. 2/19,163 controls (0.01); P=0.019, OR=4.05 (1.26-13.01)] (PMID 25188300). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Multiple inconsistent associations have been reported with idiopathic ASD in other studies (PMIDs 19384346, 19566951, 22892527, 24398551, 27876814). De novo SHANK3 mutations in individuals with schizophrenia have also been reported in Gauthier et al., 2010 (PMID 20385823), and association of SHANK3 with schizophrenia has been reported as well (PMID 28371232). Clinical evaluation of 17 individuals with SHANK3 point mutations and features of Phelan-McDermid syndrome in De Rubeis et al., 2018 demonstrated that a diagnosis of ASD was reported in 69% of cases (11/16). Analysis of pyramidal cortical neurons derived from induced pluripotent stem cells from four ASD patients with de novo loss-of-function variants (originally reported in LeBlond et al., 2014) showed a significant decrease in SHANK3 mRNA levels (less than 50% of controls) that correlated with a significant reduction in dendritic spine densities, as well as in whole spine and spine head volumes, in patient-derived neurons (Gouder et al., 2019).
Reports Added
[Genetic Diagnostic Evaluation of Trio-Based Whole Exome Sequencing Among Children With Diagnosed or Suspected Autism Spectrum Disorder.2018] [An autism-linked missense mutation in SHANK3 reveals the modularity of Shank3 function.2019] [Altered spinogenesis in iPSC-derived cortical neurons from patients with autism carrying de novo SHANK3 mutations.2019] [Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype c...2019]10/1/2018
Score remained at 1S
Description
SHANK3 lies within a multi-genic region on chromosome 22 that is deleted in Phelan-McDermid syndrome, a disorder which is frequently accompanied by ASD. De novo and inherited point mutations and copy number variants involving SHANK3 have been identified in individuals with ASD in multiple reports (PMIDs 17173049, 17999366, 18615476, 20186804, 20385823, 21378602, 21624971, 22558107, 22892527, 23758760), including de novo SHANK3 variants in PMIDs 17173049, 17999366 and 18615476 that were predicted to be loss-of-function variants or shown experimentally to disrupt SHANK3 function. An additional seven de novo loss-of-function variants in SHANK3 were identified in simplex ASD cases in Leblond et al., 2014 (PMID 25188300); in contrast, no truncating variants in SHANK3 were observed in 1,031 controls. Individuals with truncating SHANK3 variants were found to display ASD with moderate to severe/profound intellectual disability (mean IQ of 31 8) in this report. Furthermore, in a screen and meta-analysis of SHANK copy number variants in ASD, SHANK3 deletions were shown to be statistically enriched in ASD cases compared to controls [10/5,657 cases (0.18%) vs. 2/19,163 controls (0.01); P=0.019, OR=4.05 (1.26-13.01)] (PMID 25188300). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Multiple inconsistent associations have been reported with idiopathic ASD in other studies (PMIDs 19384346, 19566951, 22892527, 24398551, 27876814). De novo SHANK3 mutations in individuals with schizophrenia have also been reported in Gauthier et al., 2010 (PMID 20385823), and association of SHANK3 with schizophrenia has been reported as well (PMID 28371232). Clinical evaluation of 17 individuals with SHANK3 point mutations and features of Phelan-McDermid syndrome in De Rubeis et al., 2018 demonstrated that a diagnosis of ASD was reported in 69% of cases (11/16).
7/1/2017
Score remained at 1S
Description
SHANK3 lies within a multi-genic region on chromosome 22 that is deleted in Phelan-McDermid syndrome, a disorder which is frequently accompanied by ASD. De novo and inherited point mutations and copy number variants involving SHANK3 have been identified in individuals with ASD in multiple reports (PMIDs 17173049, 17999366, 18615476, 20186804, 20385823, 21378602, 21624971, 22558107, 22892527, 23758760), including de novo SHANK3 variants in PMIDs 17173049, 17999366 and 18615476 that were predicted to be loss-of-function variants or shown experimentally to disrupt SHANK3 function. An additional seven de novo loss-of-function variants in SHANK3 were identified in simplex ASD cases in Leblond et al., 2014 (PMID 25188300); in contrast, no truncating variants in SHANK3 were observed in 1,031 controls. Individuals with truncating SHANK3 variants were found to display ASD with moderate to severe/profound intellectual disability (mean IQ of 31 ± 8) in this report. Furthermore, in a screen and meta-analysis of SHANK copy number variants in ASD, SHANK3 deletions were shown to be statistically enriched in ASD cases compared to controls [10/5,657 cases (0.18%) vs. 2/19,163 controls (0.01); P=0.019, OR=4.05 (1.26-13.01)] (PMID 25188300). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Multiple inconsistent associations have been reported with idiopathic ASD in other studies (PMIDs 19384346, 19566951, 22892527, 24398551, 27876814). De novo SHANK3 mutations in individuals with schizophrenia have also been reported in Gauthier et al., 2010 (PMID 20385823), and association of SHANK3 with schizophrenia has been reported as well (PMID 28371232).
4/1/2017
Score remained at 1S
Description
SHANK3 is part of a multi-genic region that is deleted in Phelan-McDermid syndrome, which is accompanied by ASD. A total of eight de novo loss-of-function variants in SHANK3 have been identified in simplex ASD cases (one in PMID 18615476, seven in PMID 25188300); in contrast, no truncating variants in SHANK3 were observed in 1,031 controls. Individuals with truncating SHANK3 variants display ASD with moderate to severe/profound intellectual disability (mean IQ of 31 ± 8) (PMID 25188300). Furthermore, in a recent screen and meta-analysis of SHANK copy number variants in ASD, SHANK3 deletions were shown to be statistically enriched in ASD cases compared to controls [10/5,657 cases (0.18%) vs. 2/19,163 controls (0.01); P=0.019, OR=4.05 (1.26-13.01)] (PMID 25188300). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Multiple inconsistent associations have been reported with idiopathic ASD in other studies (PMIDs: 19566951, 19384346, 18615476, 17999366, 17173049). De novo mutations in schizophrenia have also been reported. (PMID: 20385823).
Reports Added
[22q13.3 deletion syndrome: clinical and molecular analysis using array CGH.2010] [Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders.2006] [Contribution of SHANK3 mutations to autism spectrum disorder.2007] [Novel de novo SHANK3 mutation in autistic patients.2008] [Copy number variation and association analysis of SHANK3 as a candidate gene for autism in the IMGSAC collection.2009] [Association study of SHANK3 gene polymorphisms with autism in Chinese Han population.2009] [Analysis of a purported SHANK3 mutation in a boy with autism: clinical impact of rare variant research in neurodevelopmental disabilities.2010] [Novel variants of the SHANK3 gene in Japanese autistic patients with severe delayed speech development.2011] [Association study of the CNS patterning genes and autism in Han Chinese in Taiwan.2011] [Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders.2011] [Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders.2012] [Lack of association between NLGN3, NLGN4, SHANK2 and SHANK3 gene variants and autism spectrum disorder in a Chinese population.2013] [Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency.2013] [SHANK3 gene mutations associated with autism facilitate ligand binding to the Shank3 ankyrin repeat region.2013] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [A commonly carried genetic variant, rs9616915, in SHANK3 gene is associated with a reduced risk of autism spectrum disorder: replication in a Chine...2014] [Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments.2014] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Whole-genome sequencing of quartet families with autism spectrum disorder.2015] [Refining analyses of copy number variation identifies specific genes associated with developmental delay.2014] [Whole genome sequencing reveals a de novo SHANK3 mutation in familial autism spectrum disorder.2015] [Direct measure of the de novo mutation rate in autism and schizophrenia cohorts.2010] [Bipolar affective disorder and early dementia onset in a male patient with SHANK3 deletion.2012] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.2014] [Chromosome 22q13.3 deletion syndrome with a de novo interstitial 22q13.3 cryptic deletion disrupting SHANK3.2009] [High-throughput sequencing of mGluR signaling pathway genes reveals enrichment of rare variants in autism.2012] [De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia.2010] [Proline-rich synapse-associated proteins ProSAP1 and ProSAP2 interact with synaptic proteins of the SAPAP/GKAP family.1999] [An architectural framework that may lie at the core of the postsynaptic density.2006] [Smaller dendritic spines, weaker synaptic transmission, but enhanced spatial learning in mice lacking Shank1.2008] [Heterogeneous dysregulation of microRNAs across the autism spectrum.2008] [ProSAPiP2, a novel postsynaptic density protein that interacts with ProSAP2/Shank3.2009] [Disruption of glutamate receptors at Shank-postsynaptic platform in Alzheimer's disease.2009] [Synaptic cross-talk between N-methyl-D-aspartate receptors and LAPSER1-beta-catenin at excitatory synapses.2009] [Shank3 mutant mice display autistic-like behaviours and striatal dysfunction.2011] [Shank3-Rich2 interaction regulates AMPA receptor recycling and synaptic long-term potentiation.2013] [Shank3 deficiency induces NMDA receptor hypofunction via an actin-dependent mechanism.2013] [Epigenetic dysregulation of SHANK3 in brain tissues from individuals with autism spectrum disorders.2013] [The PSD protein ProSAP2/Shank3 displays synapto-nuclear shuttling which is deregulated in a schizophrenia-associated mutation.2014] [Transcriptional and functional complexity of Shank3 provides a molecular framework to understand the phenotypic heterogeneity of SHANK3 causing aut...2014] [Two knockdown models of the autism genes SYNGAP1 and SHANK3 in zebrafish produce similar behavioral phenotypes associated with embryonic disruption...2015] [Phenotypic and functional analysis of SHANK3 stop mutations identified in individuals with ASD and/or ID.2015] [De novo SHANK3 mutation causes Rett syndrome-like phenotype in a female patient.2015] [Autism-Associated Insertion Mutation (InsG) of Shank3 Exon 21 Causes Impaired Synaptic Transmission and Behavioral Deficits.2015] [SHANK3 mutations identified in autism lead to modification of dendritic spine morphology via an actin-dependent mechanism.2011] [Case report: an unexpected link between partial deletion of the SHANK3 gene and Heller's dementia infantilis, a rare subtype of autism spectrum dis...2015] [Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Autism-associated SHANK3 haploinsufficiency causes Ih channelopathy in human neurons.2016] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016] [Genome-wide characteristics of de novo mutations in autism2016] [Copy number variation analysis in adults with catatonia confirms haploinsufficiency of SHANK3 as a predisposing factor.2016] [The spectrum of epilepsy and electroencephalographic abnormalities due to SHANK3 loss-of-function mutations.2016] [Shank3 Is Part of a Zinc-Sensitive Signaling System That Regulates Excitatory Synaptic Strength.2016] [A genome-wide investigation into parent-of-origin effects in autism spectrum disorder identifies previously associated genes including SHANK3.2016] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder2017] [Investigation of SHANK3 in schizophrenia.2017] [Neurogenetic analysis of childhood disintegrative disorder.2017] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017]10/1/2016
Score remained at 1S
Description
SHANK3 is part of a multi-genic region that is deleted in Phelan-McDermid syndrome, which is accompanied by ASD. A total of eight de novo loss-of-function variants in SHANK3 have been identified in simplex ASD cases (one in PMID 18615476, seven in PMID 25188300); in contrast, no truncating variants in SHANK3 were observed in 1,031 controls. Individuals with truncating SHANK3 variants display ASD with moderate to severe/profound intellectual disability (mean IQ of 31 ± 8) (PMID 25188300). Furthermore, in a recent screen and meta-analysis of SHANK copy number variants in ASD, SHANK3 deletions were shown to be statistically enriched in ASD cases compared to controls [10/5,657 cases (0.18%) vs. 2/19,163 controls (0.01); P=0.019, OR=4.05 (1.26-13.01)] (PMID 25188300). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Multiple inconsistent associations have been reported with idiopathic ASD in other studies (PMIDs: 19566951, 19384346, 18615476, 17999366, 17173049). De novo mutations in schizophrenia have also been reported. (PMID: 20385823).
7/1/2016
Score remained at 1S
Description
SHANK3 is part of a multi-genic region that is deleted in Phelan-McDermid syndrome, which is accompanied by ASD. A total of eight de novo loss-of-function variants in SHANK3 have been identified in simplex ASD cases (one in PMID 18615476, seven in PMID 25188300); in contrast, no truncating variants in SHANK3 were observed in 1,031 controls. Individuals with truncating SHANK3 variants display ASD with moderate to severe/profound intellectual disability (mean IQ of 31 ± 8) (PMID 25188300). Furthermore, in a recent screen and meta-analysis of SHANK copy number variants in ASD, SHANK3 deletions were shown to be statistically enriched in ASD cases compared to controls [10/5,657 cases (0.18%) vs. 2/19,163 controls (0.01); P=0.019, OR=4.05 (1.26-13.01)] (PMID 25188300). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Multiple inconsistent associations have been reported with idiopathic ASD in other studies (PMIDs: 19566951, 19384346, 18615476, 17999366, 17173049). De novo mutations in schizophrenia have also been reported. (PMID: 20385823).
Reports Added
[Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016] [Genome-wide characteristics of de novo mutations in autism2016] [Copy number variation analysis in adults with catatonia confirms haploinsufficiency of SHANK3 as a predisposing factor.2016] [The spectrum of epilepsy and electroencephalographic abnormalities due to SHANK3 loss-of-function mutations.2016] [Shank3 Is Part of a Zinc-Sensitive Signaling System That Regulates Excitatory Synaptic Strength.2016]4/1/2016
Score remained at 1S
Description
SHANK3 is part of a multi-genic region that is deleted in Phelan-McDermid syndrome, which is accompanied by ASD. A total of eight de novo loss-of-function variants in SHANK3 have been identified in simplex ASD cases (one in PMID 18615476, seven in PMID 25188300); in contrast, no truncating variants in SHANK3 were observed in 1,031 controls. Individuals with truncating SHANK3 variants display ASD with moderate to severe/profound intellectual disability (mean IQ of 31 ± 8) (PMID 25188300). Furthermore, in a recent screen and meta-analysis of SHANK copy number variants in ASD, SHANK3 deletions were shown to be statistically enriched in ASD cases compared to controls [10/5,657 cases (0.18%) vs. 2/19,163 controls (0.01); P=0.019, OR=4.05 (1.26-13.01)] (PMID 25188300). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Multiple inconsistent associations have been reported with idiopathic ASD in other studies (PMIDs: 19566951, 19384346, 18615476, 17999366, 17173049). De novo mutations in schizophrenia have also been reported. (PMID: 20385823).
Reports Added
[22q13.3 deletion syndrome: clinical and molecular analysis using array CGH.2010] [Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders.2006] [Contribution of SHANK3 mutations to autism spectrum disorder.2007] [Novel de novo SHANK3 mutation in autistic patients.2008] [Copy number variation and association analysis of SHANK3 as a candidate gene for autism in the IMGSAC collection.2009] [Association study of SHANK3 gene polymorphisms with autism in Chinese Han population.2009] [Analysis of a purported SHANK3 mutation in a boy with autism: clinical impact of rare variant research in neurodevelopmental disabilities.2010] [Novel variants of the SHANK3 gene in Japanese autistic patients with severe delayed speech development.2011] [Association study of the CNS patterning genes and autism in Han Chinese in Taiwan.2011] [Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders.2011] [Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders.2012] [Lack of association between NLGN3, NLGN4, SHANK2 and SHANK3 gene variants and autism spectrum disorder in a Chinese population.2013] [Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency.2013] [SHANK3 gene mutations associated with autism facilitate ligand binding to the Shank3 ankyrin repeat region.2013] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [A commonly carried genetic variant, rs9616915, in SHANK3 gene is associated with a reduced risk of autism spectrum disorder: replication in a Chine...2014] [Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments.2014] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Whole-genome sequencing of quartet families with autism spectrum disorder.2015] [Refining analyses of copy number variation identifies specific genes associated with developmental delay.2014] [Whole genome sequencing reveals a de novo SHANK3 mutation in familial autism spectrum disorder.2015] [Direct measure of the de novo mutation rate in autism and schizophrenia cohorts.2010] [Bipolar affective disorder and early dementia onset in a male patient with SHANK3 deletion.2012] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.2014] [Chromosome 22q13.3 deletion syndrome with a de novo interstitial 22q13.3 cryptic deletion disrupting SHANK3.2009] [High-throughput sequencing of mGluR signaling pathway genes reveals enrichment of rare variants in autism.2012] [De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia.2010] [Proline-rich synapse-associated proteins ProSAP1 and ProSAP2 interact with synaptic proteins of the SAPAP/GKAP family.1999] [An architectural framework that may lie at the core of the postsynaptic density.2006] [Smaller dendritic spines, weaker synaptic transmission, but enhanced spatial learning in mice lacking Shank1.2008] [Heterogeneous dysregulation of microRNAs across the autism spectrum.2008] [ProSAPiP2, a novel postsynaptic density protein that interacts with ProSAP2/Shank3.2009] [Disruption of glutamate receptors at Shank-postsynaptic platform in Alzheimer's disease.2009] [Synaptic cross-talk between N-methyl-D-aspartate receptors and LAPSER1-beta-catenin at excitatory synapses.2009] [Shank3 mutant mice display autistic-like behaviours and striatal dysfunction.2011] [Shank3-Rich2 interaction regulates AMPA receptor recycling and synaptic long-term potentiation.2013] [Shank3 deficiency induces NMDA receptor hypofunction via an actin-dependent mechanism.2013] [Epigenetic dysregulation of SHANK3 in brain tissues from individuals with autism spectrum disorders.2013] [The PSD protein ProSAP2/Shank3 displays synapto-nuclear shuttling which is deregulated in a schizophrenia-associated mutation.2014] [Transcriptional and functional complexity of Shank3 provides a molecular framework to understand the phenotypic heterogeneity of SHANK3 causing aut...2014] [Two knockdown models of the autism genes SYNGAP1 and SHANK3 in zebrafish produce similar behavioral phenotypes associated with embryonic disruption...2015] [Phenotypic and functional analysis of SHANK3 stop mutations identified in individuals with ASD and/or ID.2015] [De novo SHANK3 mutation causes Rett syndrome-like phenotype in a female patient.2015] [Autism-Associated Insertion Mutation (InsG) of Shank3 Exon 21 Causes Impaired Synaptic Transmission and Behavioral Deficits.2015] [SHANK3 mutations identified in autism lead to modification of dendritic spine morphology via an actin-dependent mechanism.2011] [Case report: an unexpected link between partial deletion of the SHANK3 gene and Heller's dementia infantilis, a rare subtype of autism spectrum dis...2015] [Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Autism-associated SHANK3 haploinsufficiency causes Ih channelopathy in human neurons.2016]1/1/2016
Score remained at 1S
Description
SHANK3 is part of a multi-genic region that is deleted in Phelan-McDermid syndrome, which is accompanied by ASD. A total of eight de novo loss-of-function variants in SHANK3 have been identified in simplex ASD cases (one in PMID 18615476, seven in PMID 25188300); in contrast, no truncating variants in SHANK3 were observed in 1,031 controls. Individuals with truncating SHANK3 variants display ASD with moderate to severe/profound intellectual disability (mean IQ of 31 ± 8) (PMID 25188300). Furthermore, in a recent screen and meta-analysis of SHANK copy number variants in ASD, SHANK3 deletions were shown to be statistically enriched in ASD cases compared to controls [10/5,657 cases (0.18%) vs. 2/19,163 controls (0.01); P=0.019, OR=4.05 (1.26-13.01)] (PMID 25188300). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Multiple inconsistent associations have been reported with idiopathic ASD in other studies (PMIDs: 19566951, 19384346, 18615476, 17999366, 17173049). De novo mutations in schizophrenia have also been reported. (PMID: 20385823).
Reports Added
[22q13.3 deletion syndrome: clinical and molecular analysis using array CGH.2010] [Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders.2006] [Contribution of SHANK3 mutations to autism spectrum disorder.2007] [Novel de novo SHANK3 mutation in autistic patients.2008] [Copy number variation and association analysis of SHANK3 as a candidate gene for autism in the IMGSAC collection.2009] [Association study of SHANK3 gene polymorphisms with autism in Chinese Han population.2009] [Analysis of a purported SHANK3 mutation in a boy with autism: clinical impact of rare variant research in neurodevelopmental disabilities.2010] [Novel variants of the SHANK3 gene in Japanese autistic patients with severe delayed speech development.2011] [Association study of the CNS patterning genes and autism in Han Chinese in Taiwan.2011] [Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders.2011] [Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders.2012] [Lack of association between NLGN3, NLGN4, SHANK2 and SHANK3 gene variants and autism spectrum disorder in a Chinese population.2013] [Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency.2013] [SHANK3 gene mutations associated with autism facilitate ligand binding to the Shank3 ankyrin repeat region.2013] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [A commonly carried genetic variant, rs9616915, in SHANK3 gene is associated with a reduced risk of autism spectrum disorder: replication in a Chine...2014] [Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments.2014] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Whole-genome sequencing of quartet families with autism spectrum disorder.2015] [Refining analyses of copy number variation identifies specific genes associated with developmental delay.2014] [Whole genome sequencing reveals a de novo SHANK3 mutation in familial autism spectrum disorder.2015] [Direct measure of the de novo mutation rate in autism and schizophrenia cohorts.2010] [Bipolar affective disorder and early dementia onset in a male patient with SHANK3 deletion.2012] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.2014] [Chromosome 22q13.3 deletion syndrome with a de novo interstitial 22q13.3 cryptic deletion disrupting SHANK3.2009] [High-throughput sequencing of mGluR signaling pathway genes reveals enrichment of rare variants in autism.2012] [De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia.2010] [Proline-rich synapse-associated proteins ProSAP1 and ProSAP2 interact with synaptic proteins of the SAPAP/GKAP family.1999] [An architectural framework that may lie at the core of the postsynaptic density.2006] [Smaller dendritic spines, weaker synaptic transmission, but enhanced spatial learning in mice lacking Shank1.2008] [Heterogeneous dysregulation of microRNAs across the autism spectrum.2008] [ProSAPiP2, a novel postsynaptic density protein that interacts with ProSAP2/Shank3.2009] [Disruption of glutamate receptors at Shank-postsynaptic platform in Alzheimer's disease.2009] [Synaptic cross-talk between N-methyl-D-aspartate receptors and LAPSER1-beta-catenin at excitatory synapses.2009] [Shank3 mutant mice display autistic-like behaviours and striatal dysfunction.2011] [Shank3-Rich2 interaction regulates AMPA receptor recycling and synaptic long-term potentiation.2013] [Shank3 deficiency induces NMDA receptor hypofunction via an actin-dependent mechanism.2013] [Epigenetic dysregulation of SHANK3 in brain tissues from individuals with autism spectrum disorders.2013] [The PSD protein ProSAP2/Shank3 displays synapto-nuclear shuttling which is deregulated in a schizophrenia-associated mutation.2014] [Transcriptional and functional complexity of Shank3 provides a molecular framework to understand the phenotypic heterogeneity of SHANK3 causing aut...2014] [Two knockdown models of the autism genes SYNGAP1 and SHANK3 in zebrafish produce similar behavioral phenotypes associated with embryonic disruption...2015] [Phenotypic and functional analysis of SHANK3 stop mutations identified in individuals with ASD and/or ID.2015] [De novo SHANK3 mutation causes Rett syndrome-like phenotype in a female patient.2015] [Autism-Associated Insertion Mutation (InsG) of Shank3 Exon 21 Causes Impaired Synaptic Transmission and Behavioral Deficits.2015] [SHANK3 mutations identified in autism lead to modification of dendritic spine morphology via an actin-dependent mechanism.2011] [Case report: an unexpected link between partial deletion of the SHANK3 gene and Heller's dementia infantilis, a rare subtype of autism spectrum dis...2015] [Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015]7/1/2015
Score remained at 1S
Description
SHANK3 is part of a multi-genic region that is deleted in Phelan-McDermid syndrome, which is accompanied by ASD. A total of eight de novo loss-of-function variants in SHANK3 have been identified in simplex ASD cases (one in PMID 18615476, seven in PMID 25188300); in contrast, no truncating variants in SHANK3 were observed in 1,031 controls. Individuals with truncating SHANK3 variants display ASD with moderate to severe/profound intellectual disability (mean IQ of 31 ± 8) (PMID 25188300). Furthermore, in a recent screen and meta-analysis of SHANK copy number variants in ASD, SHANK3 deletions were shown to be statistically enriched in ASD cases compared to controls [10/5,657 cases (0.18%) vs. 2/19,163 controls (0.01); P=0.019, OR=4.05 (1.26-13.01)] (PMID 25188300). Multiple inconsistent associations have been reported with idiopathic ASD in other studies (PMIDs: 19566951, 19384346, 18615476, 17999366, 17173049). De novo mutations in schizophrenia have also been reported. (PMID: 20385823).
Reports Added
[22q13.3 deletion syndrome: clinical and molecular analysis using array CGH.2010] [Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders.2006] [Contribution of SHANK3 mutations to autism spectrum disorder.2007] [Novel de novo SHANK3 mutation in autistic patients.2008] [Copy number variation and association analysis of SHANK3 as a candidate gene for autism in the IMGSAC collection.2009] [Association study of SHANK3 gene polymorphisms with autism in Chinese Han population.2009] [Analysis of a purported SHANK3 mutation in a boy with autism: clinical impact of rare variant research in neurodevelopmental disabilities.2010] [Novel variants of the SHANK3 gene in Japanese autistic patients with severe delayed speech development.2011] [Association study of the CNS patterning genes and autism in Han Chinese in Taiwan.2011] [Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders.2011] [Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders.2012] [Lack of association between NLGN3, NLGN4, SHANK2 and SHANK3 gene variants and autism spectrum disorder in a Chinese population.2013] [Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency.2013] [SHANK3 gene mutations associated with autism facilitate ligand binding to the Shank3 ankyrin repeat region.2013] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [A commonly carried genetic variant, rs9616915, in SHANK3 gene is associated with a reduced risk of autism spectrum disorder: replication in a Chine...2014] [Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments.2014] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Whole-genome sequencing of quartet families with autism spectrum disorder.2015] [Refining analyses of copy number variation identifies specific genes associated with developmental delay.2014] [Whole genome sequencing reveals a de novo SHANK3 mutation in familial autism spectrum disorder.2015] [Direct measure of the de novo mutation rate in autism and schizophrenia cohorts.2010] [Bipolar affective disorder and early dementia onset in a male patient with SHANK3 deletion.2012] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.2014] [Chromosome 22q13.3 deletion syndrome with a de novo interstitial 22q13.3 cryptic deletion disrupting SHANK3.2009] [High-throughput sequencing of mGluR signaling pathway genes reveals enrichment of rare variants in autism.2012] [De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia.2010] [Proline-rich synapse-associated proteins ProSAP1 and ProSAP2 interact with synaptic proteins of the SAPAP/GKAP family.1999] [An architectural framework that may lie at the core of the postsynaptic density.2006] [Smaller dendritic spines, weaker synaptic transmission, but enhanced spatial learning in mice lacking Shank1.2008] [Heterogeneous dysregulation of microRNAs across the autism spectrum.2008] [ProSAPiP2, a novel postsynaptic density protein that interacts with ProSAP2/Shank3.2009] [Disruption of glutamate receptors at Shank-postsynaptic platform in Alzheimer's disease.2009] [Synaptic cross-talk between N-methyl-D-aspartate receptors and LAPSER1-beta-catenin at excitatory synapses.2009] [Shank3 mutant mice display autistic-like behaviours and striatal dysfunction.2011] [Shank3-Rich2 interaction regulates AMPA receptor recycling and synaptic long-term potentiation.2013] [Shank3 deficiency induces NMDA receptor hypofunction via an actin-dependent mechanism.2013] [Epigenetic dysregulation of SHANK3 in brain tissues from individuals with autism spectrum disorders.2013] [The PSD protein ProSAP2/Shank3 displays synapto-nuclear shuttling which is deregulated in a schizophrenia-associated mutation.2014] [Transcriptional and functional complexity of Shank3 provides a molecular framework to understand the phenotypic heterogeneity of SHANK3 causing aut...2014] [Two knockdown models of the autism genes SYNGAP1 and SHANK3 in zebrafish produce similar behavioral phenotypes associated with embryonic disruption...2015] [Phenotypic and functional analysis of SHANK3 stop mutations identified in individuals with ASD and/or ID.2015] [De novo SHANK3 mutation causes Rett syndrome-like phenotype in a female patient.2015] [Autism-Associated Insertion Mutation (InsG) of Shank3 Exon 21 Causes Impaired Synaptic Transmission and Behavioral Deficits.2015] [SHANK3 mutations identified in autism lead to modification of dendritic spine morphology via an actin-dependent mechanism.2011]4/1/2015
Score remained at 1S
Description
SHANK3 is part of a multi-genic region that is deleted in Phelan-McDermid syndrome, which is accompanied by ASD. A total of eight de novo loss-of-function variants in SHANK3 have been identified in simplex ASD cases (one in PMID 18615476, seven in PMID 25188300); in contrast, no truncating variants in SHANK3 were observed in 1,031 controls. Individuals with truncating SHANK3 variants display ASD with moderate to severe/profound intellectual disability (mean IQ of 31 ± 8) (PMID 25188300). Furthermore, in a recent screen and meta-analysis of SHANK copy number variants in ASD, SHANK3 deletions were shown to be statistically enriched in ASD cases compared to controls [10/5,657 cases (0.18%) vs. 2/19,163 controls (0.01); P=0.019, OR=4.05 (1.26-13.01)] (PMID 25188300). Multiple inconsistent associations have been reported with idiopathic ASD in other studies (PMIDs: 19566951, 19384346, 18615476, 17999366, 17173049). De novo mutations in schizophrenia have also been reported. (PMID: 20385823).
Reports Added
[Two knockdown models of the autism genes SYNGAP1 and SHANK3 in zebrafish produce similar behavioral phenotypes associated with embryonic disruption...2015] [Phenotypic and functional analysis of SHANK3 stop mutations identified in individuals with ASD and/or ID.2015] [De novo SHANK3 mutation causes Rett syndrome-like phenotype in a female patient.2015]1/1/2015
Score remained at 1S
Description
SHANK3 is part of a multi-genic region that is deleted in Phelan-McDermid syndrome, which is accompanied by ASD. A total of eight de novo loss-of-function variants in SHANK3 have been identified in simplex ASD cases (one in PMID 18615476, seven in PMID 25188300); in contrast, no truncating variants in SHANK3 were observed in 1,031 controls. Individuals with truncating SHANK3 variants display ASD with moderate to severe/profound intellectual disability (mean IQ of 31 ± 8) (PMID 25188300). Furthermore, in a recent screen and meta-analysis of SHANK copy number variants in ASD, SHANK3 deletions were shown to be statistically enriched in ASD cases compared to controls [10/5,657 cases (0.18%) vs. 2/19,163 controls (0.01); P=0.019, OR=4.05 (1.26-13.01)] (PMID 25188300). Multiple inconsistent associations have been reported with idiopathic ASD in other studies (PMIDs: 19566951, 19384346, 18615476, 17999366, 17173049). De novo mutations in schizophrenia have also been reported. (PMID: 20385823).
Reports Added
[Whole-genome sequencing of quartet families with autism spectrum disorder.2015] [Whole genome sequencing reveals a de novo SHANK3 mutation in familial autism spectrum disorder.2015] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.2014]10/1/2014
Score remained at 1S
Description
SHANK3 is part of a multi-genic region that is deleted in Phelan-McDermid syndrome, which is accompanied by ASD. A total of eight de novo loss-of-function variants in SHANK3 have been identified in simplex ASD cases (one in PMID 18615476, seven in PMID 25188300); in contrast, no truncating variants in SHANK3 were observed in 1,031 controls. Individuals with truncating SHANK3 variants display ASD with moderate to severe/profound intellectual disability (mean IQ of 31 ± 8) (PMID 25188300). Furthermore, in a recent screen and meta-analysis of SHANK copy number variants in ASD, SHANK3 deletions were shown to be statistically enriched in ASD cases compared to controls [10/5,657 cases (0.18%) vs. 2/19,163 controls (0.01); P=0.019, OR=4.05 (1.26-13.01)] (PMID 25188300). Multiple inconsistent associations have been reported with idiopathic ASD in other studies (PMIDs: 19566951, 19384346, 18615476, 17999366, 17173049). De novo mutations in schizophrenia have also been reported. (PMID: 20385823).
7/1/2014
Increased from No data to 1S
Description
SHANK3 is part of a multi-genic region that is deleted in Phelan-McDermid syndrome, which is accompanied by ASD. A total of eight de novo loss-of-function variants in SHANK3 have been identified in simplex ASD cases (one in PMID 18615476, seven in PMID 25188300); in contrast, no truncating variants in SHANK3 were observed in 1,031 controls. Individuals with truncating SHANK3 variants display ASD with moderate to severe/profound intellectual disability (mean IQ of 31 ± 8) (PMID 25188300). Furthermore, in a recent screen and meta-analysis of SHANK copy number variants in ASD, SHANK3 deletions were shown to be statistically enriched in ASD cases compared to controls [10/5,657 cases (0.18%) vs. 2/19,163 controls (0.01); P=0.019, OR=4.05 (1.26-13.01)] (PMID 25188300). Multiple inconsistent associations have been reported with idiopathic ASD in other studies (PMIDs: 19566951, 19384346, 18615476, 17999366, 17173049). De novo mutations in schizophrenia have also been reported. (PMID: 20385823).
Reports Added
[Proline-rich synapse-associated proteins ProSAP1 and ProSAP2 interact with synaptic proteins of the SAPAP/GKAP family.1999] [An architectural framework that may lie at the core of the postsynaptic density.2006] [Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders.2006] [Contribution of SHANK3 mutations to autism spectrum disorder.2007] [Smaller dendritic spines, weaker synaptic transmission, but enhanced spatial learning in mice lacking Shank1.2008] [Heterogeneous dysregulation of microRNAs across the autism spectrum.2008] [Novel de novo SHANK3 mutation in autistic patients.2008] [Copy number variation and association analysis of SHANK3 as a candidate gene for autism in the IMGSAC collection.2009] [Chromosome 22q13.3 deletion syndrome with a de novo interstitial 22q13.3 cryptic deletion disrupting SHANK3.2009] [ProSAPiP2, a novel postsynaptic density protein that interacts with ProSAP2/Shank3.2009] [Association study of SHANK3 gene polymorphisms with autism in Chinese Han population.2009] [Disruption of glutamate receptors at Shank-postsynaptic platform in Alzheimer's disease.2009] [Synaptic cross-talk between N-methyl-D-aspartate receptors and LAPSER1-beta-catenin at excitatory synapses.2009] [22q13.3 deletion syndrome: clinical and molecular analysis using array CGH.2010] [De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia.2010] [Direct measure of the de novo mutation rate in autism and schizophrenia cohorts.2010] [Analysis of a purported SHANK3 mutation in a boy with autism: clinical impact of rare variant research in neurodevelopmental disabilities.2010] [Novel variants of the SHANK3 gene in Japanese autistic patients with severe delayed speech development.2011] [Shank3 mutant mice display autistic-like behaviours and striatal dysfunction.2011] [Association study of the CNS patterning genes and autism in Han Chinese in Taiwan.2011] [Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders.2011] [High-throughput sequencing of mGluR signaling pathway genes reveals enrichment of rare variants in autism.2012] [Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders.2012] [Bipolar affective disorder and early dementia onset in a male patient with SHANK3 deletion.2012] [Lack of association between NLGN3, NLGN4, SHANK2 and SHANK3 gene variants and autism spectrum disorder in a Chinese population.2013] [Shank3-Rich2 interaction regulates AMPA receptor recycling and synaptic long-term potentiation.2013] [Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency.2013] [SHANK3 gene mutations associated with autism facilitate ligand binding to the Shank3 ankyrin repeat region.2013] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [Shank3 deficiency induces NMDA receptor hypofunction via an actin-dependent mechanism.2013] [Epigenetic dysregulation of SHANK3 in brain tissues from individuals with autism spectrum disorders.2013] [The PSD protein ProSAP2/Shank3 displays synapto-nuclear shuttling which is deregulated in a schizophrenia-associated mutation.2014] [A commonly carried genetic variant, rs9616915, in SHANK3 gene is associated with a reduced risk of autism spectrum disorder: replication in a Chine...2014] [Transcriptional and functional complexity of Shank3 provides a molecular framework to understand the phenotypic heterogeneity of SHANK3 causing aut...2014] [Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments.2014]Krishnan Probability Score
Score 0.49156990996817
Ranking 5402/25841 scored genes
[Show Scoring Methodology]
ExAC Score
Score 0.99983961998191
Ranking 753/18225 scored genes
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Iossifov Probability Score
Score 0.9
Ranking 139/239 scored genes
[Show Scoring Methodology]
Sanders TADA Score
Score 0.0009855281567879
Ranking 19/18665 scored genes
[Show Scoring Methodology]
Larsen Cumulative Evidence Score
Score 350
Ranking 1/461 scored genes
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Zhang D Score
Score 0.44970025156365
Ranking 924/20870 scored genes
[Show Scoring Methodology]
External PIN Data
Interactome
- Protein Binding
- DNA Binding
- RNA Binding
- Protein Modification
- Direct Regulation
- ASD-Linked Genes
Interaction Table
| Interactor Symbol | Interactor Name | Interactor Organism | Interactor Type | Entrez ID | Uniprot ID |
|---|---|---|---|---|---|
| AGAP7 | ArfGAP with GTPase domain, ankyrin repeat and PH domain 7 | Human | Protein Binding | 653268 | Q5VUJ5 |
| C6orf154 | chromosome 6 open reading frame 154 | Human | Protein Binding | 221424 | Q5JTD7 |
| CA10 | carbonic anhydrase X | Human | Protein Binding | 56934 | Q9NS85 |
| FRS3 | fibroblast growth factor receptor substrate 3 | Human | Protein Binding | 10817 | O43559 |
| HECW1 | HECT, C2 and WW domain containing E3 ubiquitin protein ligase 1 | Human | Protein Binding | 23072 | Q76N89 |
| IGSF9 | immunoglobulin superfamily, member 9 | Human | Protein Binding | 57549 | Q9P2J2 |
| ITGBL1 | integrin, beta-like 1 (with EGF-like repeat domains) | Human | Protein Binding | 9358 | O95965 |
| LOC727948 | LOC727948similar to KIAA0454 protein | Human | Protein Binding | 727948 | N/A |
| MEGF11 | multiple EGF-like-domains 11 | Human | Protein Binding | 84465 | A6BM72 |
| N4BP3 | NEDD4 binding protein 3 | Human | Protein Binding | 23138 | O15049 |
| PLEKHA4 | pleckstrin homology domain containing, family A (phosphoinositide binding specific) member 4 | Human | Protein Binding | 57664 | Q9H4M7 |
| PPP2R3B | protein phosphatase 2, regulatory subunit B'', beta | Human | Protein Binding | 28227 | Q9Y5P8 |
| ROA0 | Heterogeneous nuclear ribonucleoprotein A0 | Mouse | Protein Binding | 77134 | Q9CX86 |
| ROA2 | Heterogeneous nuclear ribonucleoproteins A2/B1 | Mouse | Protein Binding | 102642938 | O88569 |
| ROA3 | Heterogeneous nuclear ribonucleoprotein A3 | Mouse | Protein Binding | 229279 | Q8BG05 |
| RUNDC3A | RUN domain containing 3A | Human | Protein Binding | 10900 | Q59EK9 |