Human Gene Module / Chromosome X / CDKL5

CDKL5cyclin-dependent kinase-like 5

Score
S
Syndromic Syndromic
Autism Reports / Total Reports
8 / 31
Rare Variants / Common Variants
81 / 0
Aliases
CDKL5, STK9
Associated Syndromes
Rett syndrome, Rett syndrome, Angelman syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
Xp22.13
Associated Disorders
ADHD, ID, ASD, DD/NDD, EPS
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.

Reports related to CDKL5 (31 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 ... 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-d... 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 -
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 (2/4 cases)
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
Rare Variants   (81)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.183delT p.Met63CysfsTer13 frameshift_variant - - - 15492925 Weaving LS , et al. (2004)
G to A N/A splice_site_variant De novo - - 15492925 Weaving LS , et al. (2004)
C to G N/A intron_variant - - - 16611748 Archer HL , et al. (2006)
c.2378T>C p.Val793Ala missense_variant - - - 16611748 Archer HL , et al. (2006)
c.IVS1142_50del9 - intron_variant Unknown - - 16611748 Archer HL , et al. (2006)
G to T N/A splice_site_variant - - - 16611748 Archer HL , et al. (2006)
A to G - splice_site_variant - - - 16611748 Archer HL , et al. (2006)
G to A N/A splice_site_variant - - - 16611748 Archer HL , et al. (2006)
c.2363_2367delAGAAA p.Lys788IlefsTer11 frameshift_variant - - - 16611748 Archer HL , et al. (2006)
c.del678_691ins683_673 p.Gly228_Pro231delinsAlaProSer inframe_variant Unknown - - 16611748 Archer HL , et al. (2006)
c.175C>T p.Arg59Ter stop_gained - - - 16611748 Archer HL , et al. (2006)
c.539C>T p.Pro180Leu missense_variant - - - 16611748 Archer HL , et al. (2006)
c.145+2T>C p.Glu34LysfsTer60 splice_site_variant De novo - - 19241098 Russo S , et al. (2009)
c.215T>C p.Ile72Thr missense_variant De novo - - 19241098 Russo S , et al. (2009)
c.1648C>T p.Arg550Ter stop_gained De novo - - 19241098 Russo S , et al. (2009)
c.-162-?_99+?del p.Met1? frameshift_variant Unknown - Unknown 19241098 Russo S , et al. (2009)
c.902_903dupGA p.Leu302AspfsTer49 frameshift_variant De novo - - 19241098 Russo S , et al. (2009)
c.380A>G p.His127Arg missense_variant De novo - - 19241098 Russo S , et al. (2009)
c.2376+5G>A - splice_site_variant De novo - - 19241098 Russo S , et al. (2009)
c.2767C>T p.Arg923Cys missense_variant Familial Maternal - 19241098 Russo S , et al. (2009)
c.2372A>C p.Gln791Pro missense_variant Familial Maternal - 19241098 Russo S , et al. (2009)
c.1196A>C p.Asn399Thr missense_variant - - - 19253388 Sprovieri T , et al. (2009)
c.950A>G p.His950Gly missense_variant Familial Maternal Simplex 21624971 Schaaf CP , et al. (2011)
- - copy_number_loss De novo - - 22825934 Bartnik M , et al. (2012)
- - copy_number_loss De novo - - 22825934 Bartnik M , et al. (2012)
c.509_510insGT p.Glu170GlyfsTer36 frameshift_variant Unknown - Simplex 22867051 Maortua H , et al. (2012)
c.745-?_825+?del p.Phe249_Lys275del copy_number_loss De novo - Simplex 22867051 Maortua H , et al. (2012)
c.1455_1460delGGCCAA p.Ala486_Lys487del inframe_deletion Familial Maternal Simplex 22867051 Maortua H , et al. (2012)
c.2389G>A p.Asp797Asn missense_variant Familial Paternal Unknown 22867051 Maortua H , et al. (2012)
c.-426C>G - 5_prime_UTR_variant Unknown - Unknown 22867051 Maortua H , et al. (2012)
c.403+27A>G - intron_variant Unknown - Unknown 22867051 Maortua H , et al. (2012)
c.1278A>C p.(=) synonymous_variant Unknown - Unknown 23169495 Piton A , et al. (2012)
c.464-2A>G - splice_site_variant De novo - - 23708187 Carvill GL , et al. (2013)
c.433C>T p.His145Tyr missense_variant Familial Maternal - 23708187 Carvill GL , et al. (2013)
c.545T>C p.Leu182Pro missense_variant De novo - - 23708187 Carvill GL , et al. (2013)
c.2564C>G p.Ser855Ter stop_gained De novo - - 23708187 Carvill GL , et al. (2013)
c.1926delT p.Leu642ArgfsTer16 frameshift_variant De novo - - 23708187 Carvill GL , et al. (2013)
c.533G>A p.Arg178Gln 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.1926delT p.Leu642ArgfsTer16 frameshift_variant Unknown - - 23708187 Carvill GL , et al. (2013)
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.1390C>T p.Gln464Ter stop_gained De novo - - 23934111 Epi4K Consortium , et al. (2013)
c.638G>A p.Gly213Glu missense_variant De novo - - 23934111 Epi4K Consortium , et al. (2013)
c.379C>T p.His127Tyr missense_variant De novo - - 23934111 Epi4K Consortium , et al. (2013)
c.1111delC p.Ala372LeufsTer121 frameshift_variant De novo - - 24564546 Zhao Y , et al. (2014)
ISV13+A>G - splice_site_variant De novo - - 24564546 Zhao Y , et al. (2014)
c.1791insG - frameshift_variant De novo - - 24564546 Zhao Y , et al. (2014)
ISV6+1A>G - splice_site_variant De novo - - 24564546 Zhao Y , et al. (2014)
c.1375C>T p.Gln459Ter stop_gained De novo - - 24564546 Zhao Y , et al. (2014)
c.891_892insTT p.Gln298PhefsTer53 frameshift_variant De novo - Multiplex 24564546 Zhao Y , et al. (2014)
c.533G>A p.Arg178Gln missense_variant De novo - - 24564546 Zhao Y , et al. (2014)
c.2360delA p.Lys787ArgfsTer16 frameshift_variant De novo - - 24564546 Zhao Y , et al. (2014)
c.234delA p.Arg80ValfsTer33 frameshift_variant De novo - - 24564546 Zhao Y , et al. (2014)
- - copy_number_gain Familial Maternal Possible multi-generational 25315662 Szafranski P , et al. (2014)
- - copy_number_gain Familial Paternal Unknown 25315662 Szafranski P , et al. (2014)
- - copy_number_gain Familial Maternal Multi-generational 25315662 Szafranski P , et al. (2014)
- - copy_number_gain Unknown - Unknown 25315662 Szafranski P , et al. (2014)
- - copy_number_gain Unknown - Unknown 25315662 Szafranski P , et al. (2014)
- - copy_number_gain Unknown - Unknown 25315662 Szafranski P , et al. (2014)
- - copy_number_gain Familial Maternal Extended multiplex 25315662 Szafranski P , et al. (2014)
c.104C>T p.Thr35Ile missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.1940C>T p.Pro647Leu missense_variant Familial Maternal Simplex 25969726 Codina-Sol M , et al. (2015)
c.2314delA p.Lys772ArgfsTer12 frameshift_variant De novo - - 26544041 Zhang Y , et al. (2015)
c.528G>A p.Trp176Ter stop_gained De novo - - 26544041 Zhang Y , et al. (2015)
c.400C>T p.Arg134Ter stop_gained De novo - Simplex 27334371 Halvardson J , et al. (2016)
G>GAGCTGTAG - 2KB_upstream_variant Familial Both parents Unknown 27667684 Doan RN , et al. (2016)
G>A - intron_variant - - Unknown 27667684 Doan RN , et al. (2016)
c.2854C>T p.Arg952Ter stop_gained De novo - - 27824329 Wang T , et al. (2016)
c.2854C>T p.Arg952Ter stop_gained Familial Maternal - 27824329 Wang T , et al. (2016)
- - translocation De novo - - 27841880 Redin C , et al. (2016)
c.119C>A p.Ala40Glu missense_variant De novo - Simplex 27848944 Trujillano D , et al. (2016)
c.858C>A p.Tyr286Ter stop_gained De novo - - 27848944 Trujillano D , et al. (2016)
c.2641C>T p.Gln881Ter stop_gained De novo - - 27864847 Parrini E , et al. (2016)
c.587C>T p.Ser196Leu missense_variant De novo - - 27864847 Parrini E , et al. (2016)
c.1449_1452dup p.Lys485AspfsTer11 frameshift_variant De novo - - 27864847 Parrini E , et al. (2016)
c.1247_1248del p.Glu416ValfsTer2 frameshift_variant Unknown - - 27864847 Parrini E , et al. (2016)
c.2635_2636delCT p.Leu879GlufsTer30 frameshift_variant Unknown - - 28771251 Lionel AC , et al. (2017)
c.1939C>A p.Pro647Thr missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.1291_1292del p.Thr431fs frameshift_variant De novo - Simplex 29100083 Hamdan FF , et al. (2017)
c.532C>T p.Arg178Trp missense_variant De novo - Simplex 29100083 Hamdan FF , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

S

Score Delta: Increased from S to 4S

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."

4/1/2018
S
icon
4S

Increased from S to 4S

Description

S

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.).

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.).

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.).

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.).

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.).

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

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.).

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
[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] [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] [Clinical features and gene mutational spectrum of CDKL5-related diseases in a cohort of Chinese patients.2014] [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]
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.
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
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).
CNVs associated with CDKL5(1 CNVs)
Xp22.13 7 Deletion 10  /  20
Animal Models associated with CDKL5(2 Models)
CDKL5_1_KO_HE 1 Genetic Mus musculus
CDKL5_2_KO_HT 1 Genetic Mus musculus
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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