Human Gene Module / Chromosome X / CDKL5

CDKL5cyclin-dependent kinase-like 5

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
17 / 62
Rare Variants / Common Variants
126 / 0
Aliases
CDKL5, STK9
Associated Syndromes
Rett syndrome, Rett syndrome, Angelman syndrome
Chromosome Band
Xp22.13
Associated Disorders
DD/NDD, ADHD, ID, EP, EPS, ASD
Relevance to Autism

This gene has been identified with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, studies have found that rare mutations in the CDKL5 gene are identified with Rett syndrome. In addition, CDKL5 mutations have also been identified with epilepsy and Angelman syndrome.

Molecular Function

This gene is a member of Ser/Thr protein kinase family and encodes a phosphorylated protein with protein kinase activity.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CDKL5 (62 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation Weaving LS , et al. (2004) No -
2 Recent Recommendation CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients Archer HL , et al. (2006) No -
3 Recent Recommendation Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes Russo S , et al. (2009) No -
4 Recent Recommendation A novel mutation in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene associated with a severe Rett phenotype Sprovieri T , et al. (2009) No -
5 Recent Recommendation Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression Zweier M , et al. (2010) No -
6 Support Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders Schaaf CP , et al. (2011) Yes -
7 Recent Recommendation A girl with early-onset epileptic encephalopathy associated with microdeletion involving CDKL5 Saitsu H , et al. (2011) No -
8 Recent Recommendation Extrasynaptic N-methyl-D-aspartate (NMDA) receptor stimulation induces cytoplasmic translocation of the CDKL5 kinase and its proteasomal degradation Rusconi L , et al. (2011) No -
9 Support Application of array comparative genomic hybridization in 102 patients with epilepsy and additional neurodevelopmental disorders Bartnik M , et al. (2012) No ASD, DD, ID
10 Support CDKL5 gene status in female patients with epilepsy and Rett-like features: two new mutations in the catalytic domain Maortua H , et al. (2012) No -
11 Recent Recommendation CDKL5 ensures excitatory synapse stability by reinforcing NGL-1-PSD95 interaction in the postsynaptic compartment and is impaired in patient iPSC-derived neurons Ricciardi S , et al. (2012) No -
12 Support Analysis of the effects of rare variants on splicing identifies alterations in GABAA receptor genes in autism spectrum disorder individuals Piton A , et al. (2012) Yes -
13 Support Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1 Carvill GL , et al. (2013) No ID, ASD, DD
14 Positive Association De novo mutations in epileptic encephalopathies Epi4K Consortium , et al. (2013) No IS, LGS, DD, ID, ASD, ADHD
15 Support Clinical features and gene mutational spectrum of CDKL5-related diseases in a cohort of Chinese patients Zhao Y , et al. (2014) No Autistic features
16 Recent Recommendation GluD1 is a common altered player in neuronal differentiation from both MECP2-mutated and CDKL5-mutated iPS cells Livide G , et al. (2014) No -
17 Recent Recommendation Loss of CDKL5 impairs survival and dendritic growth of newborn neurons by altering AKT/GSK-3? signaling Fuchs C , et al. (2014) No -
18 Support Neurodevelopmental and neurobehavioral characteristics in males and females with CDKL5 duplications Szafranski P , et al. (2014) Yes ADHD, OCD, sensory integration disorder
19 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
20 Support Integrated analysis of whole-exome sequencing and transcriptome profiling in males with autism spectrum disorders Codina-Sol M , et al. (2015) Yes -
21 Recent Recommendation Incorporating Functional Information in Tests of Excess De Novo Mutational Load Jiang Y , et al. (2015) No -
22 Support Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities Zhang Y , et al. (2015) No -
23 Support Mutations in HECW2 are associated with intellectual disability and epilepsy Halvardson J , et al. (2016) No -
24 Support Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior Doan RN , et al. (2016) Yes -
25 Support De novo genic mutations among a Chinese autism spectrum disorder cohort Wang T , et al. (2016) Yes -
26 Support The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies Redin C , et al. (2016) No -
27 Support Clinical exome sequencing: results from 2819 samples reflecting 1000 families Trujillano D , et al. (2016) No DD, epilepsy/seizures
28 Support Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes Parrini E , et al. (2016) No West syndrome
29 Support Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test Lionel AC , et al. (2017) Yes -
30 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders Li J , et al. (2017) Yes -
31 Support High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies Hamdan FF , et al. (2017) No DD/ID
32 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
33 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 -
34 Support The combination of whole-exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders Jiao Q , et al. (2019) No DD, microcephaly, stereotypies
35 Support Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes Xiong J , et al. (2019) Yes Epilepsy/seizures
36 Support Phenotypic manifestations between male and female children with CDKL5 mutations Liang JS , et al. (2019) No Autistic features, stereotypic hand movements
37 Support Next Generation Sequencing of 134 Children with Autism Spectrum Disorder and Regression Yin J et al. (2020) Yes Developmental regression
38 Support - Brunet T et al. (2021) No -
39 Support - Liu L et al. (2021) No ASD, DD
40 Support - Zou D et al. (2021) No -
41 Support - Mahjani B et al. (2021) Yes -
42 Support - Chen S et al. (2021) Yes Epilepsy/seizures
43 Support - Serrano RJ et al. (2022) No -
44 Support - Quintiliani M et al. (2022) No -
45 Support - Frasca A et al. (2022) No -
46 Support - Hieu NLT et al. (2022) No -
47 Support - Varela T et al. (2022) No -
48 Support - Viglione A et al. (2022) No -
49 Support - Wu W et al. (2022) No -
50 Support - De Rosa R et al. (2022) No -
51 Support - Awad PN et al. (2023) No -
52 Support - Tassinari M et al. (2023) No -
53 Support - Balasar et al. (2023) No -
54 Support - Sanchis-Juan A et al. (2023) No -
55 Support - Ko YJ et al. (2023) No ASD
56 Support - Zi-Ai Zhu et al. (2023) No -
57 Support - Karthika Ajit Valaparambil et al. () Yes -
58 Support - Magdalena Badura-Stronka et al. (2024) No ID
59 Support - Hamid Khan et al. (2024) Yes ID
60 Support - Ruohao Wu et al. (2024) Yes -
61 Support - Alistair T Pagnamenta et al. (2024) No -
62 Support - Laura Simões de Oliveira et al. (2024) No -
Rare Variants   (126)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
C>G - intron_variant - - - 16611748 Archer HL , et al. (2006)
- - translocation De novo - - 27841880 Redin C , et al. (2016)
- - copy_number_loss De novo - - 34800434 Chen S et al. (2021)
- - copy_number_loss De novo - - 31031587 Xiong J , et al. (2019)
A>G - splice_site_variant - - - 16611748 Archer HL , et al. (2006)
- - copy_number_loss De novo - - 22825934 Bartnik M , et al. (2012)
G>A p.? splice_site_variant - - - 16611748 Archer HL , et al. (2006)
G>T p.? splice_site_variant - - - 16611748 Archer HL , et al. (2006)
- - inversion Unknown - - 38776926 Alistair T Pagnamenta et al. (2024)
- - copy_number_loss De novo - Unknown 33619735 Brunet T et al. (2021)
c.175C>T p.Arg59Ter stop_gained - - - 16611748 Archer HL , et al. (2006)
c.100-2A>G - splice_site_variant De novo - - 34800434 Chen S et al. (2021)
c.-163+1863G>A - intron_variant - - Unknown 27667684 Doan RN , et al. (2016)
- - 5_prime_UTR_variant Unknown - Unknown 22867051 Maortua H , et al. (2012)
G>A p.? splice_site_variant De novo - - 15492925 Weaving LS , et al. (2004)
- - copy_number_gain Unknown - Unknown 25315662 Szafranski P , et al. (2014)
c.145+2T>C - splice_site_variant De novo - - 19241098 Russo S , et al. (2009)
c.100-2A>G - splice_site_variant De novo - - 31031587 Xiong J , et al. (2019)
- - copy_number_loss Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
- - inversion De novo - Simplex 38776926 Alistair T Pagnamenta et al. (2024)
c.1375C>T p.Gln459Ter stop_gained De novo - - 24564546 Zhao Y , et al. (2014)
c.2854C>T p.Arg952Ter stop_gained De novo - - 27824329 Wang T , et al. (2016)
c.528G>A p.Trp176Ter stop_gained De novo - - 26544041 Zhang Y , et al. (2015)
c.2376+5G>A - splice_site_variant De novo - - 19241098 Russo S , et al. (2009)
c.464-1G>C - splice_site_variant De novo - - 34615535 Mahjani B et al. (2021)
c.539C>T p.Pro180Leu missense_variant - - - 16611748 Archer HL , et al. (2006)
c.134A>T p.Lys45Met missense_variant Unknown - - 34145886 Zou D et al. (2021)
c.58G>C p.Gly20Arg missense_variant De novo - - 34800434 Chen S et al. (2021)
c.1648C>T p.Arg550Ter stop_gained De novo - - 19241098 Russo S , et al. (2009)
IVS11-42_50del9 - intron_variant Unknown - - 16611748 Archer HL , et al. (2006)
c.2378T>C p.Val793Ala missense_variant - - - 16611748 Archer HL , et al. (2006)
c.99+2C>A - splice_site_variant De novo - Simplex 33951346 Liu L et al. (2021)
c.119C>G p.Ala40Gly missense_variant De novo - - 34800434 Chen S et al. (2021)
c.1519C>T p.Gln507Ter stop_gained De novo - - 31122804 Liang JS , et al. (2019)
c.1670C>G p.Ser557Ter stop_gained Unknown - - 31122804 Liang JS , et al. (2019)
c.464-2A>G - splice_site_variant De novo - - 23708187 Carvill GL , et al. (2013)
c.403+1G>T - splice_site_variant De novo - Simplex 33951346 Liu L et al. (2021)
c.401G>C p.Arg134Pro missense_variant De novo - - 34800434 Chen S et al. (2021)
c.58G>C p.Gly20Arg missense_variant De novo - - 31031587 Xiong J , et al. (2019)
c.2641C>T p.Gln881Ter stop_gained De novo - - 27864847 Parrini E , et al. (2016)
c.1196A>C p.Asn399Thr missense_variant - - - 19253388 Sprovieri T , et al. (2009)
c.533G>A p.Arg178Gln missense_variant De novo - - 24564546 Zhao Y , et al. (2014)
c.215T>C p.Ile72Thr missense_variant De novo - - 19241098 Russo S , et al. (2009)
c.119C>G p.Ala40Gly missense_variant De novo - - 31031587 Xiong J , et al. (2019)
c.-161del - frameshift_variant Unknown - Unknown 19241098 Russo S , et al. (2009)
c.403+27A>G - intron_variant Unknown - Unknown 22867051 Maortua H , et al. (2012)
c.2564C>G p.Ser855Ter stop_gained De novo - - 23708187 Carvill GL , et al. (2013)
c.1675C>T p.Arg559Ter stop_gained De novo - Simplex 33951346 Liu L et al. (2021)
c.1648C>T p.Arg550Ter stop_gained De novo - Simplex 37645600 Ko YJ et al. (2023)
c.380A>G p.His127Arg missense_variant De novo - - 19241098 Russo S , et al. (2009)
c.401G>C p.Arg134Pro missense_variant De novo - - 31031587 Xiong J , et al. (2019)
c.858C>A p.Tyr286Ter stop_gained De novo - - 27848944 Trujillano D , et al. (2016)
c.2112C>G p.Tyr704Ter stop_gained De novo - Simplex 30564305 Guo H , et al. (2018)
c.80T>C p.Val27Ala missense_variant De novo - Simplex 33951346 Liu L et al. (2021)
c.587C>T p.Ser196Leu missense_variant De novo - - 27864847 Parrini E , et al. (2016)
- - copy_number_gain Familial Maternal Simplex 25315662 Szafranski P , et al. (2014)
- - copy_number_gain Familial Paternal Unknown 25315662 Szafranski P , et al. (2014)
c.849dup p.Asp284Ter frameshift_variant De novo - - 31122804 Liang JS , et al. (2019)
c.868C>T p.Gln290Ter stop_gained De novo - Simplex 38764027 Ruohao Wu et al. (2024)
c.533G>A p.Arg178Gln missense_variant De novo - - 23708187 Carvill GL , et al. (2013)
c.545T>C p.Leu182Pro missense_variant De novo - - 23708187 Carvill GL , et al. (2013)
c.620G>A p.Gly207Glu missense_variant De novo - - 23708187 Carvill GL , et al. (2013)
c.2854C>T p.Arg952Ter stop_gained Familial Maternal - 27824329 Wang T , et al. (2016)
c.1741C>T p.His581Tyr missense_variant Unknown - - 23708187 Carvill GL , et al. (2013)
c.2572C>T p.Arg858Cys missense_variant Unknown - - 23708187 Carvill GL , et al. (2013)
c.183del p.Met63CysfsTer13 frameshift_variant - - - 15492925 Weaving LS , et al. (2004)
- - copy_number_loss De novo - Simplex 38328757 Magdalena Badura-Stronka et al. (2024)
c.1387A>G p.Lys463Glu missense_variant Unknown - Unknown 32722525 Yin J et al. (2020)
c.2854C>T p.Arg952Ter stop_gained Familial Maternal - 30763456 Zhou WZ , et al. (2019)
c.1390C>T p.Gln464Ter stop_gained De novo - - 23934111 Epi4K Consortium , et al. (2013)
c.1939C>A p.Pro647Thr missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.282dup p.Asn95LysfsTer16 frameshift_variant De novo - - 34800434 Chen S et al. (2021)
c.238C>T p.Arg80Cys missense_variant Familial Maternal - 30945278 Jiao Q , et al. (2019)
c.234del p.Arg80ValfsTer33 frameshift_variant De novo - - 24564546 Zhao Y , et al. (2014)
NM_003159.2:ISV13+A>G p.? splice_site_variant De novo - - 24564546 Zhao Y , et al. (2014)
NM_003159.2:ISV6+1A>G p.? splice_site_variant De novo - - 24564546 Zhao Y , et al. (2014)
c.532C>T p.Arg178Trp missense_variant De novo - Simplex 35365919 Hieu NLT et al. (2022)
c.400C>T p.Arg134Ter stop_gained De novo - Simplex 27334371 Halvardson J , et al. (2016)
c.1713dup p.Lys572GlufsTer9 frameshift_variant De novo - - 24564546 Zhao Y , et al. (2014)
c.282dup p.Asn95LysfsTer16 frameshift_variant De novo - - 31031587 Xiong J , et al. (2019)
c.2873C>G p.Thr958Arg missense_variant De novo - Simplex 35280940 Frasca A et al. (2022)
c.1278A>C p.Ser426= synonymous_variant Unknown - Unknown 23169495 Piton A , et al. (2012)
c.1111del p.Ala372LeufsTer121 frameshift_variant De novo - - 34800434 Chen S et al. (2021)
c.1700C>T p.Thr567Met missense_variant Familial Maternal - 30945278 Jiao Q , et al. (2019)
c.2360del p.Lys787ArgfsTer16 frameshift_variant De novo - - 24564546 Zhao Y , et al. (2014)
c.532C>T p.Arg178Trp missense_variant De novo - Simplex 29100083 Hamdan FF , et al. (2017)
c.379C>T p.His127Tyr missense_variant De novo - - 23934111 Epi4K Consortium , et al. (2013)
c.638G>A p.Gly213Glu missense_variant De novo - - 23934111 Epi4K Consortium , et al. (2013)
c.446_447dup p.Lys150Ter frameshift_variant De novo - Simplex 37645600 Ko YJ et al. (2023)
c.163_166del p.Glu55ArgfsTer20 frameshift_variant De novo - - 34800434 Chen S et al. (2021)
c.1111del p.Ala372LeufsTer121 frameshift_variant De novo - - 24564546 Zhao Y , et al. (2014)
c.2372A>C p.Gln791Pro missense_variant Familial Maternal - 19241098 Russo S , et al. (2009)
c.2767C>T p.Arg923Cys missense_variant Familial Maternal - 19241098 Russo S , et al. (2009)
c.2315del p.Lys772ArgfsTer12 frameshift_variant De novo - - 26544041 Zhang Y , et al. (2015)
c.2363_2367del p.Lys788IlefsTer11 frameshift_variant - - - 16611748 Archer HL , et al. (2006)
c.1842T>A p.Tyr614Ter stop_gained Unknown - - 37943464 Karthika Ajit Valaparambil et al. ()
c.1111del p.Ala372LeufsTer121 frameshift_variant De novo - - 31031587 Xiong J , et al. (2019)
c.119C>A p.Ala40Glu missense_variant De novo - Simplex 27848944 Trujillano D , et al. (2016)
c.163_166del p.Glu55ArgfsTer20 frameshift_variant De novo - - 31031587 Xiong J , et al. (2019)
c.433C>T p.His145Tyr missense_variant Familial Maternal - 23708187 Carvill GL , et al. (2013)
c.1136_1139del p.Leu379ProfsTer113 frameshift_variant Unknown - - 34145886 Zou D et al. (2021)
c.1247_1248del p.Glu416ValfsTer2 frameshift_variant De novo - - 30945278 Jiao Q , et al. (2019)
c.902_903dup p.Leu302AspfsTer49 frameshift_variant De novo - - 19241098 Russo S , et al. (2009)
c.1926del p.Gln643AsnfsTer15 frameshift_variant De novo - - 23708187 Carvill GL , et al. (2013)
c.1926del p.Gln643AsnfsTer15 frameshift_variant Unknown - - 23708187 Carvill GL , et al. (2013)
- - copy_number_gain Familial Maternal Extended multiplex 25315662 Szafranski P , et al. (2014)
c.2635_2636del p.Leu879GlufsTer30 frameshift_variant De novo - - 31122804 Liang JS , et al. (2019)
c.1247_1248del p.Glu416ValfsTer2 frameshift_variant Unknown - - 27864847 Parrini E , et al. (2016)
c.747del p.Pro250GlnfsTer17 copy_number_loss De novo - Simplex 22867051 Maortua H , et al. (2012)
c.1449_1452dup p.Lys485AspfsTer11 frameshift_variant De novo - - 27864847 Parrini E , et al. (2016)
c.2635_2636del p.Leu879GlufsTer30 frameshift_variant Unknown - - 28771251 Lionel AC , et al. (2017)
c.1731_1732del p.Met577IlefsTer3 frameshift_variant De novo - Simplex 33951346 Liu L et al. (2021)
c.950A>G p.His317Arg missense_variant Familial Maternal Simplex 21624971 Schaaf CP , et al. (2011)
c.2389G>A p.Asp797Asn missense_variant Familial Paternal Unknown 22867051 Maortua H , et al. (2012)
c.2626A>G p.Ile876Val missense_variant Familial Maternal Simplex 38649688 Hamid Khan et al. (2024)
c.890_891dup p.Gln298PhefsTer53 frameshift_variant De novo - Multiplex 24564546 Zhao Y , et al. (2014)
c.1834_1838del p.Ser612ValfsTer5 frameshift_variant Unknown - Simplex 37524782 Balasar et al. (2023)
c.510_511dup p.Tyr171CysfsTer58 frameshift_variant Unknown - Simplex 22867051 Maortua H , et al. (2012)
c.1940C>T p.Pro647Leu missense_variant Familial Maternal Simplex 25969726 Codina-Sol M , et al. (2015)
c.1292_1293del p.Thr431LysfsTer31 frameshift_variant De novo - Simplex 29100083 Hamdan FF , et al. (2017)
c.1455_1460del p.Ala486_Lys487del inframe_deletion Familial Maternal Simplex 22867051 Maortua H , et al. (2012)
c.104C>T p.Thr35Ile missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.del678_691ins683_673 p.Gly228_Pro231delinsAlaProSer inframe_indel Unknown - - 16611748 Archer HL , et al. (2006)
c.532C>T p.Arg178Trp missense_variant Familial Maternal Simplex 38328757 Magdalena Badura-Stronka et al. (2024)
c.-163+1683_-163+1684insGTAGAGCT - 2KB_upstream_variant Familial Both parents Unknown 27667684 Doan RN , et al. (2016)
c.2009_2012dup p.Thr672ArgfsTer12 frameshift_variant Unknown - Simplex 38328757 Magdalena Badura-Stronka et al. (2024)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
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.

S

Syndromic

See all Category S Genes

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

Rare variant (frameshift) seen in three siblings from single family: identical twin girls showed Rett Syndrome and Autistic Disorder, respectively, and male sib presented with MR and seizures. Splice site mutation likewise observed in screen of 44 additional individuals with Rett and demonstrated to result in premature truncation of cDNA (no controls evaluated here; Weaving LS et al.). Likely pathogenic mutations observed in girls with autistic features, intellectual disability, and infantile spasms, with Rett-like features seen only in 1/7 carriers (Archer HL et al.). Additional putative mutations seen in additional Rett-like as well as Angelman-like individuals (Russo S et al.).

Reports Added
[Confirming the contribution and genetic spectrum of de novo mutation in infantile spasms: Evidence from a Chinese cohort2021]
1/1/2021
1
icon
1

Score remained at 1

Description

Rare variant (frameshift) seen in three siblings from single family: identical twin girls showed Rett Syndrome and Autistic Disorder, respectively, and male sib presented with MR and seizures. Splice site mutation likewise observed in screen of 44 additional individuals with Rett and demonstrated to result in premature truncation of cDNA (no controls evaluated here; Weaving LS et al.). Likely pathogenic mutations observed in girls with autistic features, intellectual disability, and infantile spasms, with Rett-like features seen only in 1/7 carriers (Archer HL et al.). Additional putative mutations seen in additional Rett-like as well as Angelman-like individuals (Russo S et al.).

Reports Added
[De novo variants in neurodevelopmental disorders-experiences from a tertiary care center2021]
7/1/2020
1
icon
1

Score remained at 1

Description

Rare variant (frameshift) seen in three siblings from single family: identical twin girls showed Rett Syndrome and Autistic Disorder, respectively, and male sib presented with MR and seizures. Splice site mutation likewise observed in screen of 44 additional individuals with Rett and demonstrated to result in premature truncation of cDNA (no controls evaluated here; Weaving LS et al.). Likely pathogenic mutations observed in girls with autistic features, intellectual disability, and infantile spasms, with Rett-like features seen only in 1/7 carriers (Archer HL et al.). Additional putative mutations seen in additional Rett-like as well as Angelman-like individuals (Russo S et al.).

Reports Added
[Next Generation Sequencing of 134 Children with Autism Spectrum Disorder and Regression2020]
10/1/2019
S
icon
1

Increased from S to 1

New Scoring Scheme
Description

Rare variant (frameshift) seen in three siblings from single family: identical twin girls showed Rett Syndrome and Autistic Disorder, respectively, and male sib presented with MR and seizures. Splice site mutation likewise observed in screen of 44 additional individuals with Rett and demonstrated to result in premature truncation of cDNA (no controls evaluated here; Weaving LS et al.). Likely pathogenic mutations observed in girls with autistic features, intellectual disability, and infantile spasms, with Rett-like features seen only in 1/7 carriers (Archer HL et al.). Additional putative mutations seen in additional Rett-like as well as Angelman-like individuals (Russo S et al.).

Reports Added
[New Scoring Scheme]
7/1/2019
S
icon
S

Increased from S to S

Description

Rare variant (frameshift) seen in three siblings from single family: identical twin girls showed Rett Syndrome and Autistic Disorder, respectively, and male sib presented with MR and seizures. Splice site mutation likewise observed in screen of 44 additional individuals with Rett and demonstrated to result in premature truncation of cDNA (no controls evaluated here; Weaving LS et al.). Likely pathogenic mutations observed in girls with autistic features, intellectual disability, and infantile spasms, with Rett-like features seen only in 1/7 carriers (Archer HL et al.). Additional putative mutations seen in additional Rett-like as well as Angelman-like individuals (Russo S et al.).

Reports Added
[Phenotypic manifestations between male and female children with CDKL5 mutations.2019]
4/1/2019
S
icon
S

Increased from S to S

Description

Rare variant (frameshift) seen in three siblings from single family: identical twin girls showed Rett Syndrome and Autistic Disorder, respectively, and male sib presented with MR and seizures. Splice site mutation likewise observed in screen of 44 additional individuals with Rett and demonstrated to result in premature truncation of cDNA (no controls evaluated here; Weaving LS et al.). Likely pathogenic mutations observed in girls with autistic features, intellectual disability, and infantile spasms, with Rett-like features seen only in 1/7 carriers (Archer HL et al.). Additional putative mutations seen in additional Rett-like as well as Angelman-like individuals (Russo S et al.).

Reports Added
[The combination of whole-exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders.2019] [Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes.2019]
1/1/2019
S
icon
S

Increased from S to S

Description

Rare variant (frameshift) seen in three siblings from single family: identical twin girls showed Rett Syndrome and Autistic Disorder, respectively, and male sib presented with MR and seizures. Splice site mutation likewise observed in screen of 44 additional individuals with Rett and demonstrated to result in premature truncation of cDNA (no controls evaluated here; Weaving LS et al.). Likely pathogenic mutations observed in girls with autistic features, intellectual disability, and infantile spasms, with Rett-like features seen only in 1/7 carriers (Archer HL et al.). Additional putative mutations seen in additional Rett-like as well as Angelman-like individuals (Russo S et al.).

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018] [Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype c...2019]
10/1/2017
S
icon
S

Increased from S to S

Description

Rare variant (frameshift) seen in three siblings from single family: identical twin girls showed Rett Syndrome and Autistic Disorder, respectively, and male sib presented with MR and seizures. Splice site mutation likewise observed in screen of 44 additional individuals with Rett and demonstrated to result in premature truncation of cDNA (no controls evaluated here; Weaving LS et al.). Likely pathogenic mutations observed in girls with autistic features, intellectual disability, and infantile spasms, with Rett-like features seen only in 1/7 carriers (Archer HL et al.). Additional putative mutations seen in additional Rett-like as well as Angelman-like individuals (Russo S et al.).

Reports Added
[Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders.2017] [High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.2017]
7/1/2017
S
icon
S

Increased from S to S

Description

Rare variant (frameshift) seen in three siblings from single family: identical twin girls showed Rett Syndrome and Autistic Disorder, respectively, and male sib presented with MR and seizures. Splice site mutation likewise observed in screen of 44 additional individuals with Rett and demonstrated to result in premature truncation of cDNA (no controls evaluated here; Weaving LS et al.). Likely pathogenic mutations observed in girls with autistic features, intellectual disability, and infantile spasms, with Rett-like features seen only in 1/7 carriers (Archer HL et al.). Additional putative mutations seen in additional Rett-like as well as Angelman-like individuals (Russo S et al.).

Reports Added
[Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test.2017]
1/1/2017
S
icon
S

Increased from S to S

Description

Rare variant (frameshift) seen in three siblings from single family: identical twin girls showed Rett Syndrome and Autistic Disorder, respectively, and male sib presented with MR and seizures. Splice site mutation likewise observed in screen of 44 additional individuals with Rett and demonstrated to result in premature truncation of cDNA (no controls evaluated here; Weaving LS et al.). Likely pathogenic mutations observed in girls with autistic features, intellectual disability, and infantile spasms, with Rett-like features seen only in 1/7 carriers (Archer HL et al.). Additional putative mutations seen in additional Rett-like as well as Angelman-like individuals (Russo S et al.).

Reports Added
[Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes.2016]
10/1/2016
S
icon
S

Increased from S to S

Description

Rare variant (frameshift) seen in three siblings from single family: identical twin girls showed Rett Syndrome and Autistic Disorder, respectively, and male sib presented with MR and seizures. Splice site mutation likewise observed in screen of 44 additional individuals with Rett and demonstrated to result in premature truncation of cDNA (no controls evaluated here; Weaving LS et al.). Likely pathogenic mutations observed in girls with autistic features, intellectual disability, and infantile spasms, with Rett-like features seen only in 1/7 carriers (Archer HL et al.). Additional putative mutations seen in additional Rett-like as well as Angelman-like individuals (Russo S et al.).

Reports Added
[Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.2016] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016]
7/1/2016
S
icon
S

Increased from S to S

Description

Rare variant (frameshift) seen in three siblings from single family: identical twin girls showed Rett Syndrome and Autistic Disorder, respectively, and male sib presented with MR and seizures. Splice site mutation likewise observed in screen of 44 additional individuals with Rett and demonstrated to result in premature truncation of cDNA (no controls evaluated here; Weaving LS et al.). Likely pathogenic mutations observed in girls with autistic features, intellectual disability, and infantile spasms, with Rett-like features seen only in 1/7 carriers (Archer HL et al.). Additional putative mutations seen in additional Rett-like as well as Angelman-like individuals (Russo S et al.).

Reports Added
[Mutations in HECW2 are associated with intellectual disability and epilepsy.2016]
1/1/2016
S
icon
S

Increased from S to S

Description

Rare variant (frameshift) seen in three siblings from single family: identical twin girls showed Rett Syndrome and Autistic Disorder, respectively, and male sib presented with MR and seizures. Splice site mutation likewise observed in screen of 44 additional individuals with Rett and demonstrated to result in premature truncation of cDNA (no controls evaluated here; Weaving LS et al.). Likely pathogenic mutations observed in girls with autistic features, intellectual disability, and infantile spasms, with Rett-like features seen only in 1/7 carriers (Archer HL et al.). Additional putative mutations seen in additional Rett-like as well as Angelman-like individuals (Russo S et al.).

Reports Added
[Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders.2011] [Neurodevelopmental and neurobehavioral characteristics in males and females with CDKL5 duplications.2014] [Analysis of the effects of rare variants on splicing identifies alterations in GABAA receptor genes in autism spectrum disorder individuals.2012] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Clinical features and gene mutational spectrum of CDKL5-related diseases in a cohort of Chinese patients.2014] [CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients.2006] [Application of array comparative genomic hybridization in 102 patients with epilepsy and additional neurodevelopmental disorders.2012] [CDKL5 gene status in female patients with epilepsy and Rett-like features: two new mutations in the catalytic domain.2012] [Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.2013] [De novo mutations in epileptic encephalopathies.2013] [Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation.2004] [A novel mutation in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene associated with a severe Rett phenotype.2009] [Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes.2009] [Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 ...2010] [A girl with early-onset epileptic encephalopathy associated with microdeletion involving CDKL5.2011] [Extrasynaptic N-methyl-D-aspartate (NMDA) receptor stimulation induces cytoplasmic translocation of the CDKL5 kinase and its proteasomal degradation.2011] [CDKL5 ensures excitatory synapse stability by reinforcing NGL-1-PSD95 interaction in the postsynaptic compartment and is impaired in patient iPSC-d...2012] [GluD1 is a common altered player in neuronal differentiation from both MECP2-mutated and CDKL5-mutated iPS cells.2014] [Loss of CDKL5 impairs survival and dendritic growth of newborn neurons by altering AKT/GSK-3 signaling.2014] [Integrated analysis of whole-exome sequencing and transcriptome profiling in males with autism spectrum disorders.2015] [Incorporating Functional Information in Tests of Excess De Novo Mutational Load.2015] [Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.2015]
7/1/2015
S
icon
S

Increased from S to S

Description

Rare variant (frameshift) seen in three siblings from single family: identical twin girls showed Rett Syndrome and Autistic Disorder, respectively, and male sib presented with MR and seizures. Splice site mutation likewise observed in screen of 44 additional individuals with Rett and demonstrated to result in premature truncation of cDNA (no controls evaluated here; Weaving LS et al.). Likely pathogenic mutations observed in girls with autistic features, intellectual disability, and infantile spasms, with Rett-like features seen only in 1/7 carriers (Archer HL et al.). Additional putative mutations seen in additional Rett-like as well as Angelman-like individuals (Russo S et al.).

Reports Added
[Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders.2011] [Neurodevelopmental and neurobehavioral characteristics in males and females with CDKL5 duplications.2014] [Analysis of the effects of rare variants on splicing identifies alterations in GABAA receptor genes in autism spectrum disorder individuals.2012] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Clinical features and gene mutational spectrum of CDKL5-related diseases in a cohort of Chinese patients.2014] [CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients.2006] [Application of array comparative genomic hybridization in 102 patients with epilepsy and additional neurodevelopmental disorders.2012] [CDKL5 gene status in female patients with epilepsy and Rett-like features: two new mutations in the catalytic domain.2012] [Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.2013] [De novo mutations in epileptic encephalopathies.2013] [Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation.2004] [A novel mutation in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene associated with a severe Rett phenotype.2009] [Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes.2009] [Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 ...2010] [A girl with early-onset epileptic encephalopathy associated with microdeletion involving CDKL5.2011] [Extrasynaptic N-methyl-D-aspartate (NMDA) receptor stimulation induces cytoplasmic translocation of the CDKL5 kinase and its proteasomal degradation.2011] [CDKL5 ensures excitatory synapse stability by reinforcing NGL-1-PSD95 interaction in the postsynaptic compartment and is impaired in patient iPSC-d...2012] [GluD1 is a common altered player in neuronal differentiation from both MECP2-mutated and CDKL5-mutated iPS cells.2014] [Loss of CDKL5 impairs survival and dendritic growth of newborn neurons by altering AKT/GSK-3 signaling.2014] [Integrated analysis of whole-exome sequencing and transcriptome profiling in males with autism spectrum disorders.2015] [Incorporating Functional Information in Tests of Excess De Novo Mutational Load.2015]
4/1/2015
S
icon
S

Increased from S to S

Description

Rare variant (frameshift) seen in three siblings from single family: identical twin girls showed Rett Syndrome and Autistic Disorder, respectively, and male sib presented with MR and seizures. Splice site mutation likewise observed in screen of 44 additional individuals with Rett and demonstrated to result in premature truncation of cDNA (no controls evaluated here; Weaving LS et al.). Likely pathogenic mutations observed in girls with autistic features, intellectual disability, and infantile spasms, with Rett-like features seen only in 1/7 carriers (Archer HL et al.). Additional putative mutations seen in additional Rett-like as well as Angelman-like individuals (Russo S et al.).

Reports Added
[Integrated analysis of whole-exome sequencing and transcriptome profiling in males with autism spectrum disorders.2015]
1/1/2015
S
icon
S

Increased from S to S

Description

Rare variant (frameshift) seen in three siblings from single family: identical twin girls showed Rett Syndrome and Autistic Disorder, respectively, and male sib presented with MR and seizures. Splice site mutation likewise observed in screen of 44 additional individuals with Rett and demonstrated to result in premature truncation of cDNA (no controls evaluated here; Weaving LS et al.). Likely pathogenic mutations observed in girls with autistic features, intellectual disability, and infantile spasms, with Rett-like features seen only in 1/7 carriers (Archer HL et al.). Additional putative mutations seen in additional Rett-like as well as Angelman-like individuals (Russo S et al.).

Reports Added
[Large-scale discovery of novel genetic causes of developmental disorders.2014]
10/1/2014
S
icon
S

Increased from S to S

Description

Rare variant (frameshift) seen in three siblings from single family: identical twin girls showed Rett Syndrome and Autistic Disorder, respectively, and male sib presented with MR and seizures. Splice site mutation likewise observed in screen of 44 additional individuals with Rett and demonstrated to result in premature truncation of cDNA (no controls evaluated here; Weaving LS et al.). Likely pathogenic mutations observed in girls with autistic features, intellectual disability, and infantile spasms, with Rett-like features seen only in 1/7 carriers (Archer HL et al.). Additional putative mutations seen in additional Rett-like as well as Angelman-like individuals (Russo S et al.).

Reports Added
[Neurodevelopmental and neurobehavioral characteristics in males and females with CDKL5 duplications.2014]
7/1/2014
No data
icon
S

Increased from No data to S

Description

Rare variant (frameshift) seen in three siblings from single family: identical twin girls showed Rett Syndrome and Autistic Disorder, respectively, and male sib presented with MR and seizures. Splice site mutation likewise observed in screen of 44 additional individuals with Rett and demonstrated to result in premature truncation of cDNA (no controls evaluated here; Weaving LS et al.). Likely pathogenic mutations observed in girls with autistic features, intellectual disability, and infantile spasms, with Rett-like features seen only in 1/7 carriers (Archer HL et al.). Additional putative mutations seen in additional Rett-like as well as Angelman-like individuals (Russo S et al.).

Reports Added
[Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation.2004] [CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients.2006] [Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes.2009] [A novel mutation in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene associated with a severe Rett phenotype.2009] [Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 ...2010] [Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders.2011] [A girl with early-onset epileptic encephalopathy associated with microdeletion involving CDKL5.2011] [Extrasynaptic N-methyl-D-aspartate (NMDA) receptor stimulation induces cytoplasmic translocation of the CDKL5 kinase and its proteasomal degradation.2011] [Application of array comparative genomic hybridization in 102 patients with epilepsy and additional neurodevelopmental disorders.2012] [CDKL5 gene status in female patients with epilepsy and Rett-like features: two new mutations in the catalytic domain.2012] [CDKL5 ensures excitatory synapse stability by reinforcing NGL-1-PSD95 interaction in the postsynaptic compartment and is impaired in patient iPSC-d...2012] [Analysis of the effects of rare variants on splicing identifies alterations in GABAA receptor genes in autism spectrum disorder individuals.2012] [Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.2013] [De novo mutations in epileptic encephalopathies.2013] [Clinical features and gene mutational spectrum of CDKL5-related diseases in a cohort of Chinese patients.2014] [Loss of CDKL5 impairs survival and dendritic growth of newborn neurons by altering AKT/GSK-3 signaling.2014] [GluD1 is a common altered player in neuronal differentiation from both MECP2-mutated and CDKL5-mutated iPS cells.2014]
Krishnan Probability Score

Score 0.4961308341067

Ranking 2680/25841 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.
Original Source
ExAC Score

Score 0.99779005480533

Ranking 1286/18225 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
Original Source
Sanders TADA Score

Score 0.94306394223125

Ranking 15544/18665 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).
Original Source
External PIN Data
BioGRIDHuman Protein Reference Database
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
C9ORF86 RAB, member RAS oncogene family-like 6 Human Protein Binding 55684 Q3YEC7
CDKL5 cyclin-dependent kinase-like 5 Human Autoregulation 6792 O76039
DHX16 DEAH (Asp-Glu-Ala-His) box polypeptide 16 Human Protein Binding 8449 O60231
DHX38 DEAH (Asp-Glu-Ala-His) box polypeptide 38 Human Protein Binding 9785 Q92620
Dnmt1 DNA methyltransferase (cytosine-5) 1 Mouse Protein Modification 13433 P13864
HDGFRP3 Hepatoma-derived growth factor-related protein 3 Human Protein Binding 50810 Q9Y3E1
KIAA1704 KIAA1704 Human Protein Binding 55425 Q8IXQ4
MEF2C myocyte enhancer factor 2C Human DNA Binding 4208 C9JMZ0
MLH1 mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) Human Protein Binding 4292 P40692
NFY Nuclear transcription factor Y subunit alpha Mouse DNA Binding 18044 P23708
NLGN1 neuroligin 1 Human Protein Modification 22871 Q8N2Q7
PP1 Serine/threonine-protein phosphatase PP1-gamma catalytic subunit Mouse Protein Modification 19047 P63087
SERPINB8 Serpin B8 Human Protein Binding 5271 P50452
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