Human Gene Module / Chromosome 22 / SHANK3

SHANK3SH3 and multiple ankyrin repeat domains 3

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
81 / 146
Rare Variants / Common Variants
340 / 9
EAGLE Score
74.85
Strong Learn More
Aliases
SHANK3, PSAP2,  PROSAP2,  SPANK-2,  KIAA1650
Associated Syndromes
Phelan-McDermid syndrome, Rett syndrome-like phenotype, Pediatric Acute-Onset Neuropsychiatric Syndrome (P, Phelan-McDermid syndrome, ASD
Chromosome Band
22q13.33
Associated Disorders
DD/NDD, BPD, ID, EPS, ASD
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association, Functional
Relevance 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.

SFARI Genomic Platforms
Reports related to SHANK3 (146 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 - et al. () Yes -
144 Support - et al. () Yes -
145 Support - et al. () Yes Epilepsy/seizures
146 Support - et al. () No -
Rare Variants   (340)
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)
c.*74C>A - stop_gained Unknown - - 37943464 et al. ()
- - 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)
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.3368del p.Gly1123AlafsTer17 frameshift_variant De novo - - 38008000 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.3459C>T p.Pro1166Ser stop_gained De novo - - 31209962 Aspromonte MC , et al. (2019)
c.3470_3479del p.His1157ProfsTer97 frameshift_variant Unknown - - 37943464 et al. ()
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.3730dup p.Arg1244ProfsTer114 frameshift_variant Unknown - Unknown 37799141 et al. ()
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.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.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.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.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.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.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.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.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.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.1987G>A p.Arg675His missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1302+46_1302+47insGGGGGGGGG - intron_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
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.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.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.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.3679dup p.Ala1227GlyfsTer69 frameshift_variant Familial Maternal Simplex 34737294 Loureiro LO et al. (2021)
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.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
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

1

High Confidence

See all Category 1 Genes

We 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
1
icon
1

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
1
icon
1

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
1
icon
1

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
1
icon
1

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
1
icon
1

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).

1/1/2020
1
icon
1

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).

10/1/2019
1S
icon
1

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).

7/1/2019
1S
icon
1S

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).

1/1/2019
1S
icon
1S

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).

10/1/2018
1S
icon
1S

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
1S
icon
1S

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
1S
icon
1S

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
1S
icon
1S

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
1S
icon
1S

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).

4/1/2016
1S
icon
1S

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
1S
icon
1S

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
1S
icon
1S

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
1S
icon
1S

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).

1/1/2015
1S
icon
1S

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).

10/1/2014
1S
icon
1S

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
No data
icon
1S

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]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
ExAC Score

Score 0.99983961998191

Ranking 753/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Iossifov Probability Score

Score 0.9

Ranking 139/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Sanders TADA Score

Score 0.0009855281567879

Ranking 19/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Larsen Cumulative Evidence Score

Score 350

Ranking 1/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score 0.44970025156365

Ranking 924/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
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
Submit New Gene

Report an Error