Human Gene Module / Chromosome X / KDM5C

KDM5Clysine demethylase 5C

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
12 / 46
Rare Variants / Common Variants
64 / 0
Aliases
KDM5C, RP11-258C19.2,  DXS1272E,  JARID1C,  MRXJ,  MRXSCJ,  MRXSJ,  SMCX,  XE169
Associated Syndromes
-
Chromosome Band
Xp11.22
Associated Disorders
DD/NDD, ASD, EP, EPS
Relevance to Autism

A missense mutation in the KDM5C gene was detected in a nondysmorphic patient with developmental delay and autism spectrum disorder (Adegbola et al., 2008).

Molecular Function

This gene is a member of the SMCY homolog family and encodes a protein with one ARID domain, one JmjC domain, one JmjN domain and two PHD-type zinc fingers. The DNA-binding motifs suggest this protein is involved in the regulation of transcription and chromatin remodeling. Mutations in this gene have been associated with X-linked cognitive disability.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to KDM5C (46 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Mutations in the JARID1C gene, which is involved in transcriptional regulation and chromatin remodeling, cause X-linked mental retardation Jensen LR , et al. (2004) No -
2 Support A novel mutation in JARID1C gene associated with mental retardation Santos C , et al. (2006) No -
3 Support Novel JARID1C/SMCX mutations in patients with X-linked mental retardation Tzschach A , et al. (2006) No Epilepsy
4 Primary A novel mutation in JARID1C/SMCX in a patient with autism spectrum disorder (ASD) Adegbola A , et al. (2008) Yes DD
5 Support Mutations in JARID1C are associated with X-linked mental retardation, short stature and hyperreflexia Abidi FE , et al. (2008) No -
6 Support Identification and characterization of two novel JARID1C mutations: suggestion of an emerging genotype-phenotype correlation Rujirabanjerd S , et al. (2009) No -
7 Support A de novo paradigm for mental retardation Vissers LE , et al. (2010) No -
8 Support Hybridisation-based resequencing of 17 X-linked intellectual disability genes in 135 patients reveals novel mutations in ATRX, SLC6A8 and PQBP1 Jensen LR , et al. (2011) No -
9 Support A novel nonsense mutation in KDM5C/JARID1C gene causing intellectual disability, short stature and speech delay Santos-Rebouas CB , et al. (2011) No -
10 Support A novel c.2T > C mutation of the KDM5C/JARID1C gene in one large family with X-linked intellectual disability Ounap K , et al. (2012) No -
11 Support A regulatory path associated with X-linked intellectual disability and epilepsy links KDM5C to the polyalanine expansions in ARX Poeta L , et al. (2012) No -
12 Support Multilocus loss of DNA methylation in individuals with mutations in the histone H3 lysine 4 demethylase KDM5C Grafodatskaya D , et al. (2013) No -
13 Support Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations Toma C , et al. (2013) Yes -
14 Support Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing Redin C , et al. (2014) No -
15 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
16 Support - Moey C , et al. (2015) No ASD, epilepsy/seizures
17 Recent Recommendation A Mouse Model of X-linked Intellectual Disability Associated with Impaired Removal of Histone Methylation Iwase S , et al. (2016) No -
18 Support Comprehensive molecular testing in patients with high functioning autism spectrum disorder Alvarez-Mora MI , et al. (2016) Yes -
19 Support Patient Mutations of the Intellectual Disability Gene KDM5C Downregulate Netrin G2 and Suppress Neurite Growth in Neuro2a Cells Wei G , et al. (2016) No -
20 Support Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics Loviglio MN , et al. (2016) No Behavioral abnormalities (stereotypic, self-injuri
21 Support Using medical exome sequencing to identify the causes of neurodevelopmental disorders: Experience of 2 clinical units and 216 patients Chrot E , et al. (2017) No Microcephaly
22 Support Altered Gene-Regulatory Function of KDM5C by a Novel Mutation Associated With Autism and Intellectual Disability Vallianatos CN , et al. (2018) Yes Microcephaly, cognitive impairment
23 Support Drosophila Histone Demethylase KDM5 Regulates Social Behavior through Immune Control and Gut Microbiota Maintenance Chen K , et al. (2019) No -
24 Recent Recommendation Histone demethylase KDM5C is a SAHA-sensitive central hub at the crossroads of transcriptional axes involved in multiple neurodevelopmental disorders Poeta L , et al. (2019) No -
25 Support Further delineation of the female phenotype with KDM5C disease causing variants: 19 new individuals and review of the literature Carmignac V et al. (2020) No Behavioral abnormalities
26 Support - Alonso-Gonzalez A et al. (2021) Yes -
27 Support - Taşkıran EZ et al. (2021) No Epilepsy/seizures, autistic features
28 Support - Chen JS et al. (2021) Yes -
29 Support - Mahjani B et al. (2021) Yes -
30 Support - Chen S et al. (2021) Yes Epilepsy/seizures
31 Support - Wang Q et al. (2022) Yes -
32 Support - Brea-Fernández AJ et al. (2022) No -
33 Support - Zhou X et al. (2022) Yes -
34 Support - Shen R et al. (2022) No -
35 Support - Li S et al. (2023) No -
36 Support - Bonefas KM et al. (2023) No -
37 Support - Giovenino C et al. (2023) No -
38 Recent Recommendation - Kundishora AJ et al. (2023) No ASD, DD, epilepsy/seizures
39 Support - Sanchis-Juan A et al. (2023) No -
40 Support - M Cecilia Poli et al. () No -
41 Recent Recommendation - Violetta Karwacki-Neisius et al. (2024) No -
42 Support - Tamam Khalaf et al. (2024) No -
43 Support - Yasser Al-Sarraj et al. (2024) Yes -
44 Support - Matanel Yheskel et al. (2024) No -
45 Support - Axel Schmidt et al. (2024) No -
46 Support - Suhua Chang et al. () Yes -
Rare Variants   (64)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain De novo - Simplex 26059843 Moey C , et al. (2015)
c.2041C>T p.Arg681Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_gain Familial Maternal Simplex 26059843 Moey C , et al. (2015)
c.1827C>T p.Tyr609= synonymous_variant - - - 21267006 Jensen LR , et al. (2011)
c.2080C>T p.Arg694Ter stop_gained Unknown - - 38438125 Tamam Khalaf et al. (2024)
c.2214C>A p.Cys738Ter stop_gained De novo - - 39039281 Axel Schmidt et al. (2024)
c.3533C>A p.Ser1178Ter stop_gained De novo - Simplex 36536324 Shen R et al. (2022)
c.1354G>A p.Gly452Ser missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.-172del - frameshift_variant De novo - Simplex 32279304 Carmignac V et al. (2020)
c.1382+5G>A - splice_site_variant Unknown - Unknown 18697827 Abidi FE , et al. (2008)
c.3068A>G p.Lys1023Arg missense_variant Unknown - - 27799067 Loviglio MN , et al. (2016)
c.2233C>G p.Gln745Glu missense_variant Unknown - Unknown 33753861 Chen JS et al. (2021)
- - copy_number_gain Familial Maternal Extended multiplex 26059843 Moey C , et al. (2015)
c.3745C>T p.Arg1249Cys missense_variant De novo - Simplex 39126614 Suhua Chang et al. ()
c.2152G>C p.Ala718Pro missense_variant De novo - Simplex 25167861 Redin C , et al. (2014)
c.709C>T p.Gln237Ter stop_gained Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.3357G>A p.Met1119Ile missense_variant Unknown - - 26845707 Alvarez-Mora MI , et al. (2016)
c.860C>T p.Ser287Leu missense_variant Familial Maternal - 38177409 M Cecilia Poli et al. ()
c.1866G>T p.Trp622Cys missense_variant De novo - Simplex 32279304 Carmignac V et al. (2020)
c.2482C>T p.Arg828Ter stop_gained Familial Maternal Simplex 28708303 Chrot E , et al. (2017)
c.2092G>A p.Glu698Lys missense_variant Unknown - Multiplex 15586325 Jensen LR , et al. (2004)
c.2296C>T p.Arg766Trp missense_variant Familial Maternal - 18203167 Adegbola A , et al. (2008)
c.845A>G p.Tyr282Cys splice_site_variant De novo - Simplex 32279304 Carmignac V et al. (2020)
c.1837G>A p.Glu613Lys missense_variant Unknown - Multiplex 32279304 Carmignac V et al. (2020)
c.440dup p.Arg148GlufsTer5 frameshift_variant Familial Maternal - 34800434 Chen S et al. (2021)
c.2080C>T p.Arg694Ter stop_gained Familial Maternal Multiplex 15586325 Jensen LR , et al. (2004)
c.151-2899dup - frameshift_variant Familial Maternal Multiplex 15586325 Jensen LR , et al. (2004)
c.3864G>A p.Trp1288Ter stop_gained Familial Maternal Multiplex 15586325 Jensen LR , et al. (2004)
- p.Ala241fs frameshift_variant Familial Maternal Unknown 38572415 Yasser Al-Sarraj et al. (2024)
c.1487G>T p.Gly496Val missense_variant De novo - Simplex 33431980 Alonso-Gonzalez A et al. (2021)
c.1251A>C p.Thr418Ala missense_variant Familial Maternal Multiplex 23999528 Toma C , et al. (2013)
c.1296dup p.Glu433Ter frameshift_variant Familial Maternal Simplex 25167861 Redin C , et al. (2014)
c.2T>C p.Met1? initiator_codon_variant Familial Maternal Multiplex 22326837 Ounap K , et al. (2012)
c.589dup p.Leu197ProfsTer23 frameshift_variant De novo - Simplex 32279304 Carmignac V et al. (2020)
c.4259G>A p.Trp1420Ter stop_gained Familial Maternal Multi-generational 36625521 Li S et al. (2023)
c.1353C>G p.Ser451Arg missense_variant Familial Maternal Multiplex 16538222 Santos C , et al. (2006)
c.1919G>A p.Cys640Tyr missense_variant Familial Maternal Simplex 21076407 Vissers LE , et al. (2010)
c.156G>T p.Trp52Cys missense_variant Familial Maternal Multiplex 32279304 Carmignac V et al. (2020)
c.3191_3192del p.Glu1064AlafsTer72 frameshift_variant Unknown - Unknown 33753861 Chen JS et al. (2021)
c.2252A>G p.Tyr751Cys missense_variant Familial Maternal Multiplex 16541399 Tzschach A , et al. (2006)
c.1795C>T p.Arg599Cys missense_variant Familial Maternal Multiplex 32279304 Carmignac V et al. (2020)
c.1204G>A p.Asp402Asn missense_variant Familial Maternal Multiplex 36879111 Giovenino C et al. (2023)
c.1112G>A p.Cys371Tyr missense_variant Familial Maternal - 35322241 Brea-Fernández AJ et al. (2022)
c.1226T>C p.Phe409Ser missense_variant Familial Maternal - 35322241 Brea-Fernández AJ et al. (2022)
c.2517_2622del p.Pro840ValfsTer60 splice_site_variant Unknown - Multiplex 35266334 Wang Q et al. (2022)
c.2383_234del p.Arg795GlyfsTer5 frameshift_variant De novo - Simplex 32279304 Carmignac V et al. (2020)
c.4046+289_4046+290del - frameshift_variant Familial Maternal Multiplex 18697827 Abidi FE , et al. (2008)
c.2172C>A p.Cys724Ter stop_gained Familial Maternal Multiplex 21575681 Santos-Rebouas CB , et al. (2011)
c.994C>T p.Arg332Ter stop_gained Familial Maternal Multi-generational 16541399 Tzschach A , et al. (2006)
c.3344G>A p.Arg1115His missense_variant Familial Maternal Simplex 29670509 Vallianatos CN , et al. (2018)
c.145C>T p.Pro49Ser missense_variant Familial Maternal Multiplex 33739554 Taşkıran EZ et al. (2021)
c.229G>A p.Ala77Thr missense_variant Familial Maternal Multi-generational 18697827 Abidi FE , et al. (2008)
c.1510G>A p.Val504Met missense_variant Familial Maternal Multi-generational 18697827 Abidi FE , et al. (2008)
c.260A>G p.Asp87Gly missense_variant Familial Maternal Multi-generational 16541399 Tzschach A , et al. (2006)
c.260A>G p.Asp87Gly missense_variant Familial Maternal Multi-generational 32279304 Carmignac V et al. (2020)
c.1162G>C p.Ala388Pro missense_variant Familial Maternal Multi-generational 15586325 Jensen LR , et al. (2004)
c.1204G>T p.Asp402Tyr missense_variant Familial Maternal Multi-generational 15586325 Jensen LR , et al. (2004)
c.2191C>T p.Leu731Phe missense_variant Familial Maternal Multi-generational 15586325 Jensen LR , et al. (2004)
c.1924T>C p.Phe642Leu missense_variant Familial Maternal Multi-generational 16541399 Tzschach A , et al. (2006)
c.2248C>T p.Arg750Trp missense_variant Familial Maternal Multi-generational 16541399 Tzschach A , et al. (2006)
c.2228dup p.Leu744AlafsTer11 splice_site_variant Familial Maternal Multiplex 32279304 Carmignac V et al. (2020)
c.1160C>A p.Pro554Thr missense_variant Familial Maternal Multi-generational 19826449 Rujirabanjerd S , et al. (2009)
c.3057dup p.Lys1020GlnfsTer43 frameshift_variant Familial Maternal Multiplex 19826449 Rujirabanjerd S , et al. (2009)
c.658-1G>T - splice_site_variant Familial Maternal Multiplex 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

Score Delta: Score remained at 1

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.

4/1/2022
2
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1

Decreased from 2 to 1

4/1/2021
2
icon
2

Decreased from 2 to 2

Description

Maternally-inherited, possibly damaging missense variants in KDM5C have been identified in ASD cases in two studies (PMIDs 18203167, 23999528); a maternally-inherited frameshift variant in this gene was also identified in a male patient with intellectual disability and a diagnosis of pervasive developmental disorder (PMID 25167861). Mutations in the KDM5C gene are responsible for a syndromic form of X-linked intellectual disability (Mental retardation, X-linked, syndromic, Claes-Jensen type; OMIM 300534); behavioral abnormalities such as aggression and autistic features have been noted in some patients (PMIDs 15586325). Disruption of the KDM5C gene in mice was recently shown to result in impaired social behavior, memory deficits, and aggression (PMID 26804915). Several missense variants in KDM5C identified in patients with intellectual disability were shown to suppress retinoic acid-induced neurite growth in transfected Neuro2a cells (Wei et al., 2016).

Reports Added
[Diagnostic yield of whole-exome sequencing in non-syndromic intellectual disability2021] [Comorbidities associated with genetic abnormalities in children with intellectual disability2021]
1/1/2021
2
icon
2

Decreased from 2 to 2

Description

Maternally-inherited, possibly damaging missense variants in KDM5C have been identified in ASD cases in two studies (PMIDs 18203167, 23999528); a maternally-inherited frameshift variant in this gene was also identified in a male patient with intellectual disability and a diagnosis of pervasive developmental disorder (PMID 25167861). Mutations in the KDM5C gene are responsible for a syndromic form of X-linked intellectual disability (Mental retardation, X-linked, syndromic, Claes-Jensen type; OMIM 300534); behavioral abnormalities such as aggression and autistic features have been noted in some patients (PMIDs 15586325). Disruption of the KDM5C gene in mice was recently shown to result in impaired social behavior, memory deficits, and aggression (PMID 26804915). Several missense variants in KDM5C identified in patients with intellectual disability were shown to suppress retinoic acid-induced neurite growth in transfected Neuro2a cells (Wei et al., 2016).

Reports Added
[Exploring the biological role of postzygotic and germinal de novo mutations in ASD2021]
4/1/2020
2
icon
2

Decreased from 2 to 2

Description

Maternally-inherited, possibly damaging missense variants in KDM5C have been identified in ASD cases in two studies (PMIDs 18203167, 23999528); a maternally-inherited frameshift variant in this gene was also identified in a male patient with intellectual disability and a diagnosis of pervasive developmental disorder (PMID 25167861). Mutations in the KDM5C gene are responsible for a syndromic form of X-linked intellectual disability (Mental retardation, X-linked, syndromic, Claes-Jensen type; OMIM 300534); behavioral abnormalities such as aggression and autistic features have been noted in some patients (PMIDs 15586325). Disruption of the KDM5C gene in mice was recently shown to result in impaired social behavior, memory deficits, and aggression (PMID 26804915). Several missense variants in KDM5C identified in patients with intellectual disability were shown to suppress retinoic acid-induced neurite growth in transfected Neuro2a cells (Wei et al., 2016).

Reports Added
[Further delineation of the female phenotype with KDM5C disease causing variants: 19 new individuals and review of the literature2020]
10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Maternally-inherited, possibly damaging missense variants in KDM5C have been identified in ASD cases in two studies (PMIDs 18203167, 23999528); a maternally-inherited frameshift variant in this gene was also identified in a male patient with intellectual disability and a diagnosis of pervasive developmental disorder (PMID 25167861). Mutations in the KDM5C gene are responsible for a syndromic form of X-linked intellectual disability (Mental retardation, X-linked, syndromic, Claes-Jensen type; OMIM 300534); behavioral abnormalities such as aggression and autistic features have been noted in some patients (PMIDs 15586325). Disruption of the KDM5C gene in mice was recently shown to result in impaired social behavior, memory deficits, and aggression (PMID 26804915). Several missense variants in KDM5C identified in patients with intellectual disability were shown to suppress retinoic acid-induced neurite growth in transfected Neuro2a cells (Wei et al., 2016).

Reports Added
[Histone demethylase KDM5C is a SAHA-sensitive central hub at the crossroads of transcriptional axes involved in multiple neurodevelopmental disorders.2019] [New Scoring Scheme]
4/1/2019
3
icon
3

Decreased from 3 to 3

Description

Maternally-inherited, possibly damaging missense variants in KDM5C have been identified in ASD cases in two studies (PMIDs 18203167, 23999528); a maternally-inherited frameshift variant in this gene was also identified in a male patient with intellectual disability and a diagnosis of pervasive developmental disorder (PMID 25167861). Mutations in the KDM5C gene are responsible for a syndromic form of X-linked intellectual disability (Mental retardation, X-linked, syndromic, Claes-Jensen type; OMIM 300534); behavioral abnormalities such as aggression and autistic features have been noted in some patients (PMIDs 15586325). Disruption of the KDM5C gene in mice was recently shown to result in impaired social behavior, memory deficits, and aggression (PMID 26804915). Several missense variants in KDM5C identified in patients with intellectual disability were shown to suppress retinoic acid-induced neurite growth in transfected Neuro2a cells (Wei et al., 2016).

Reports Added
[Drosophila Histone Demethylase KDM5 Regulates Social Behavior through Immune Control and Gut Microbiota Maintenance.2019]
7/1/2017
3
icon
3

Decreased from 3 to 3

Description

Maternally-inherited, possibly damaging missense variants in KDM5C have been identified in ASD cases in two studies (PMIDs 18203167, 23999528); a maternally-inherited frameshift variant in this gene was also identified in a male patient with intellectual disability and a diagnosis of pervasive developmental disorder (PMID 25167861). Mutations in the KDM5C gene are responsible for a syndromic form of X-linked intellectual disability (Mental retardation, X-linked, syndromic, Claes-Jensen type; OMIM 300534); behavioral abnormalities such as aggression and autistic features have been noted in some patients (PMIDs 15586325). Disruption of the KDM5C gene in mice was recently shown to result in impaired social behavior, memory deficits, and aggression (PMID 26804915). Several missense variants in KDM5C identified in patients with intellectual disability were shown to suppress retinoic acid-induced neurite growth in transfected Neuro2a cells (Wei et al., 2016).

Reports Added
[Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients.2017]
4/1/2017
3
icon
3

Decreased from 3 to 3

Description

Maternally-inherited, possibly damaging missense variants in KDM5C have been identified in ASD cases in two studies (PMIDs 18203167, 23999528); a maternally-inherited frameshift variant in this gene was also identified in a male patient with intellectual disability and a diagnosis of pervasive developmental disorder (PMID 25167861). Mutations in the KDM5C gene are responsible for a syndromic form of X-linked intellectual disability (Mental retardation, X-linked, syndromic, Claes-Jensen type; OMIM 300534); behavioral abnormalities such as aggression and autistic features have been noted in some patients (PMIDs 15586325). Disruption of the KDM5C gene in mice was recently shown to result in impaired social behavior, memory deficits, and aggression (PMID 26804915). Several missense variants in KDM5C identified in patients with intellectual disability were shown to suppress retinoic acid-induced neurite growth in transfected Neuro2a cells (Wei et al., 2016).

Reports Added
[A novel mutation in JARID1C/SMCX in a patient with autism spectrum disorder (ASD).2008] [Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations.2013] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [A de novo paradigm for mental retardation.2010] [Hybridisation-based resequencing of 17 X-linked intellectual disability genes in 135 patients reveals novel mutations in ATRX, SLC6A8 and PQBP1.2011] [A novel nonsense mutation in KDM5C/JARID1C gene causing intellectual disability, short stature and speech delay.2011] [A novel c.2T>C mutation of the KDM5C/JARID1C gene in one large family with X-linked intellectual disability.2012] [Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.2014] [Mutations in the JARID1C gene, which is involved in transcriptional regulation and chromatin remodeling, cause X-linked mental retardation.2004] [A novel mutation in JARID1C gene associated with mental retardation.2006] [Novel JARID1C/SMCX mutations in patients with X-linked mental retardation.2006] [Mutations in JARID1C are associated with X-linked mental retardation, short stature and hyperreflexia.2008] [Identification and characterization of two novel JARID1C mutations: suggestion of an emerging genotype-phenotype correlation.2009] [A regulatory path associated with X-linked intellectual disability and epilepsy links KDM5C to the polyalanine expansions in ARX.2012] [Multilocus loss of DNA methylation in individuals with mutations in the histone H3 lysine 4 demethylase KDM5C.2013] [A Mouse Model of X-linked Intellectual Disability Associated with Impaired Removal of Histone Methylation.2016] [Comprehensive molecular testing in patients with high functioning autism spectrum disorder.2016] [Patient Mutations of the Intellectual Disability Gene KDM5C Downregulate Netrin G2 and Suppress Neurite Growth in Neuro2a Cells.2016] [Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics.2016]
10/1/2016
3
icon
3

Decreased from 3 to 3

Description

Maternally-inherited, possibly damaging missense variants in KDM5C have been identified in ASD cases in two studies (PMIDs 18203167, 23999528); a maternally-inherited frameshift variant in this gene was also identified in a male patient with intellectual disability and a diagnosis of pervasive developmental disorder (PMID 25167861). Mutations in the KDM5C gene are responsible for a syndromic form of X-linked intellectual disability (Mental retardation, X-linked, syndromic, Claes-Jensen type; OMIM 300534); behavioral abnormalities such as aggression and autistic features have been noted in some patients (PMIDs 15586325). Disruption of the KDM5C gene in mice was recently shown to result in impaired social behavior, memory deficits, and aggression (PMID 26804915). Several missense variants in KDM5C identified in patients with intellectual disability were shown to suppress retinoic acid-induced neurite growth in transfected Neuro2a cells (Wei et al., 2016).

Reports Added
[Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics.2016]
7/1/2016
3
icon
3

Decreased from 3 to 3

Description

Maternally-inherited, possibly damaging missense variants in KDM5C have been identified in ASD cases in two studies (PMIDs 18203167, 23999528); a maternally-inherited frameshift variant in this gene was also identified in a male patient with intellectual disability and a diagnosis of pervasive developmental disorder (PMID 25167861). Mutations in the KDM5C gene are responsible for a syndromic form of X-linked intellectual disability (Mental retardation, X-linked, syndromic, Claes-Jensen type; OMIM 300534); behavioral abnormalities such as aggression and autistic features have been noted in some patients (PMIDs 15586325). Disruption of the KDM5C gene in mice was recently shown to result in impaired social behavior, memory deficits, and aggression (PMID 26804915). Several missense variants in KDM5C identified in patients with intellectual disability were shown to suppress retinoic acid-induced neurite growth in transfected Neuro2a cells (Wei et al., 2016).

Reports Added
[Patient Mutations of the Intellectual Disability Gene KDM5C Downregulate Netrin G2 and Suppress Neurite Growth in Neuro2a Cells.2016]
1/1/2016
icon
3

Increased from to 3

Description

Maternally-inherited, possibly damaging missense variants in KDM5C have been identified in ASD cases in two studies (PMIDs 18203167, 23999528); a maternally-inherited frameshift variant in this gene was also identified in a male patient with intellectual disability and a diagnosis of pervasive developmental disorder (PMID 25167861). Mutations in the KDM5C gene are responsible for a syndromic form of X-linked intellectual disability (Mental retardation, X-linked, syndromic, Claes-Jensen type; OMIM 300534); behavioral abnormalities such as aggression and autistic features have been noted in some patients (PMIDs 15586325). Disruption of the KDM5C gene in mice was recently shown to result in impaired social behavior, memory deficits, and aggression (PMID 26804915).

Reports Added
[A novel mutation in JARID1C/SMCX in a patient with autism spectrum disorder (ASD).2008] [Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations.2013] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Hybridisation-based resequencing of 17 X-linked intellectual disability genes in 135 patients reveals novel mutations in ATRX, SLC6A8 and PQBP1.2011] [A novel nonsense mutation in KDM5C/JARID1C gene causing intellectual disability, short stature and speech delay.2011] [A novel c.2T>C mutation of the KDM5C/JARID1C gene in one large family with X-linked intellectual disability.2012] [Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.2014] [Mutations in the JARID1C gene, which is involved in transcriptional regulation and chromatin remodeling, cause X-linked mental retardation.2004] [A novel mutation in JARID1C gene associated with mental retardation.2006] [Novel JARID1C/SMCX mutations in patients with X-linked mental retardation.2006] [Mutations in JARID1C are associated with X-linked mental retardation, short stature and hyperreflexia.2008] [Identification and characterization of two novel JARID1C mutations: suggestion of an emerging genotype-phenotype correlation.2009] [A regulatory path associated with X-linked intellectual disability and epilepsy links KDM5C to the polyalanine expansions in ARX.2012] [Multilocus loss of DNA methylation in individuals with mutations in the histone H3 lysine 4 demethylase KDM5C.2013] [A Mouse Model of X-linked Intellectual Disability Associated with Impaired Removal of Histone Methylation.2016] [Comprehensive molecular testing in patients with high functioning autism spectrum disorder.2016]
Krishnan Probability Score

Score 0.49236655846734

Ranking 4573/25841 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 0.99784256924102

Ranking 1279/18225 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 0.94706011304186

Ranking 17122/18665 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
Larsen Cumulative Evidence Score

Score 7

Ranking 244/461 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.
Original Source
Zhang D Score

Score 0.57267801902499

Ranking 166/20870 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.
Original Source
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
ARHGAP25 Rho GTPase-activating protein 25 Human Protein Binding 9938 P42331-2
HLA-F HLA class I histocompatibility antigen, alpha chain F Human Protein Binding 3134 P30511-3
OLFM2 Noelin-2 Human Protein Binding 93145 O95897
SCML4 Sex comb on midleg-like protein 4 Human Protein Binding 256380 Q8N228-2
SSH3 Protein phosphatase Slingshot homolog 3 Human Protein Binding 54961 Q8TE77-2
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