Human Gene Module / Chromosome 20 / KCNQ2

KCNQ2potassium voltage-gated channel subfamily Q member 2

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
14 / 63
Rare Variants / Common Variants
122 / 2
Aliases
KCNQ2, RP11-261N11.2,  BFNC,  BFNS1,  EBN,  EBN1,  EIEE7,  ENB1,  HNSPC,  KCNA11,  KV7.2,  KVEBN1
Associated Syndromes
-
Chromosome Band
20q13.33
Associated Disorders
DD/NDD, ADHD, ID, ASD
Relevance to Autism

A paternally-inherited splice-site variant in KCNQ2 was identified in a male ASD proband; this variant was inherited from a father with Asperger disorder and was also observed in the proband's sister, who was reported to exhibit autistic-like behavior (Jiang et al., 2013). A de novo frameshift variant in the KCNQ2 gene was identified in a male ASD proband from the Simons Simplex Collection (PMID 25284784). Mutations in the KCNQ2 gene are responsible for early infantile epileptic encephalopathy-7 (EIEE7; OMIM 613720) and benign familial neonatal seizures-1 (BFNS1; OMIM 121200). Miceli et al. 2022 provided detailed clinical information on fifteen patients (14 novels and 1 previously published) with KCNQ2 p.Arg144 missense variants; all patients had developmental delay with prominent language impairment, and ten of these patients (67%) presented with autistic features. Furthermore, functional analysis of KCNQ2 p.Arg144 missense variants by whole-cell patch-clamp recordings in this report demonstrated that activation gating of homomeric mutant channels was left-shifted, suggesting gain-of-function effects.

Molecular Function

The M channel is a slowly activating and deactivating potassium channel that plays a critical role in the regulation of neuronal excitability. The M channel is formed by the association of the protein encoded by this gene and a related protein encoded by the KCNQ3 gene, both integral membrane proteins. M channel currents are inhibited by M1 muscarinic acetylcholine receptors and activated by retigabine, a novel anti-convulsant drug. Defects in this gene are a cause of benign familial neonatal convulsions type 1 (BFNC), also known as epilepsy, benign neonatal type 1 (EBN1).

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 KCNQ2 (63 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Positive Association PP2A-Bgamma subunit and KCNQ2 K+ channels in bipolar disorder Borsotto M , et al. (2006) No -
2 Recent Recommendation Similar early characteristics but variable neurological outcome of patients with a de novo mutation of KCNQ2 Milh M , et al. (2013) No DD, ID
3 Recent Recommendation Converging Evidence for Epistasis between ANK3 and Potassium Channel Gene KCNQ2 in Bipolar Disorder Judy JT , et al. (2013) No -
4 Primary Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing Jiang YH , et al. (2013) Yes -
5 Positive Association De novo mutations in epileptic encephalopathies Epi4K Consortium , et al. (2013) No IS, LGS, DD, ID, ASD, ADHD
6 Support Dominant-negative effects of KCNQ2 mutations are associated with epileptic encephalopathy Orhan G , et al. (2013) No -
7 Support De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies EuroEPINOMICS-RES Consortium , et al. (2014) No -
8 Support De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder Dong S , et al. (2014) No -
9 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No DD, ID
10 Support Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities Zhang Y , et al. (2015) No -
11 Support Mutations in HECW2 are associated with intellectual disability and epilepsy Halvardson J , et al. (2016) No -
12 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability Lelieveld SH et al. (2016) No -
13 Support Clinical exome sequencing: results from 2819 samples reflecting 1000 families Trujillano D , et al. (2016) No -
14 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 -
15 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
16 Support Genomic diagnosis for children with intellectual disability and/or developmental delay Bowling KM , et al. (2017) No Hypotonia
17 Support High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies Hamdan FF , et al. (2017) No DD/ID
18 Support Exome Pool-Seq in neurodevelopmental disorders Popp B , et al. (2017) No Hypotonia
19 Support Diagnostic exome sequencing of syndromic epilepsy patients in clinical practice Tumien B , et al. (2017) No -
20 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 -
21 Support Variant recurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense variants Lecoquierre F , et al. (2019) No -
22 Support The Clinical and Genetic Features of Co-occurring Epilepsy and Autism Spectrum Disorder in Chinese Children Long S , et al. (2019) Yes -
23 Support Clinical utility of multigene panel testing in adults with epilepsy and intellectual disability Borlot F , et al. (2019) No -
24 Support Overrepresentation of genetic variation in the AnkyrinG interactome is related to a range of neurodevelopmental disorders van der Werf IM et al. (2020) No ASD
25 Support - Yap CX et al. (2021) Yes -
26 Support - Chen JS et al. (2021) No -
27 Support - Mary L et al. (2021) No Autistic features
28 Support - Liu L et al. (2021) No ASD, DD
29 Support - Zou D et al. (2021) No -
30 Support - Pode-Shakked B et al. (2021) No -
31 Support - Mahjani B et al. (2021) Yes -
32 Support - Kim EC et al. (2021) No -
33 Support - Bruno LP et al. (2021) Yes -
34 Support - Verberne EA et al. (2022) No -
35 Support - Hieu NLT et al. (2022) No -
36 Support - Chuan Z et al. (2022) No ID
37 Support - Siracusano M et al. (2022) Yes DD, ID
38 Recent Recommendation - Miceli F et al. (2022) No Autistic features, stereotypy, epilepsy/seizures
39 Support - Krgovic D et al. (2022) Yes Epilepsy/seizures
40 Support - Levchenko O et al. (2022) No -
41 Support - Stenshorne I et al. (2022) No ID
42 Support - Zhou X et al. (2022) Yes -
43 Support - Yang GM et al. (2023) No Afs
44 Support - Spataro N et al. (2023) No Stereotypy
45 Support - Cossu A et al. (2023) No ASD
46 Support - Hou B et al. (2023) No -
47 Support - Sanchis-Juan A et al. (2023) No DD
48 Support - Sheth F et al. (2023) Yes DD, ID, epilepsy/seizures
49 Support - Varghese N et al. (2023) Yes -
50 Support - Ko YJ et al. (2023) No ASD
51 Support - Amerh S Alqahtani et al. (2023) No -
52 Support - Anton Iftimovici et al. (2024) Yes -
53 Support - Emily A Innes et al. (2024) No ASD, ADHD, DD
54 Support - Magdalena Badura-Stronka et al. (2024) No DD
55 Support - Purvi Majethia et al. (2024) No DD
56 Recent Recommendation - Bianca Graziano et al. (2024) Yes -
57 Support - Ruohao Wu et al. (2024) No -
58 Support - Karen Lob et al. () Yes Epilepsy/seizures
59 Support - Liene Thys et al. (2024) No DD, ID, epilepsy/seizures
60 Support - Hosneara Akter et al. () No -
61 Support - Chengyan Li et al. (2024) No -
62 Support - Mario Nappi et al. (2024) No ASD, ID, epilepsy/seizures
63 Highly Cited A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns Singh NA , et al. (1998) No -
Rare Variants   (122)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.471G>A p.Trp157Ter stop_gained De novo - - 23692823 Milh M , et al. (2013)
c.1709+2C>T - splice_site_variant Unknown - - 35571021 Chuan Z et al. (2022)
c.1632-5T>A - splice_region_variant Unknown - - 35571021 Chuan Z et al. (2022)
c.953T>C p.Leu318Pro missense_variant Unknown - - 34145886 Zou D et al. (2021)
c.1817+759G>T - intron_variant De novo - Simplex 35982159 Zhou X et al. (2022)
- - copy_number_loss Familial Maternal Multiplex 33568206 Yap CX et al. (2021)
c.1678C>T p.Arg560Trp missense_variant Unknown - - 39136901 Karen Lob et al. ()
c.430C>T p.Arg144Trp missense_variant De novo - - 33754465 Mary L et al. (2021)
c.431G>A p.Arg144Gln missense_variant De novo - - 33754465 Mary L et al. (2021)
c.254T>C p.Leu85Pro missense_variant Unknown - - 35571021 Chuan Z et al. (2022)
c.1004C>T p.Pro335Leu missense_variant De novo - - 33754465 Mary L et al. (2021)
c.1667G>A p.Gly556Asp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1984T>C p.Tyr662His missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.523G>T p.Val175Leu missense_variant De novo - - 23692823 Milh M , et al. (2013)
c.566G>T p.Gly189Val missense_variant De novo - - 23692823 Milh M , et al. (2013)
c.715G>C p.Gly239Arg missense_variant De novo - - 23692823 Milh M , et al. (2013)
c.793G>A p.Ala265Thr missense_variant De novo - - 23692823 Milh M , et al. (2013)
c.821C>T p.Thr274Met missense_variant De novo - - 23692823 Milh M , et al. (2013)
c.860C>A p.Thr287Asn missense_variant De novo - - 23692823 Milh M , et al. (2013)
c.868G>A p.Gly290Ser missense_variant De novo - - 23692823 Milh M , et al. (2013)
c.881C>T p.Ala294Val missense_variant De novo - - 23692823 Milh M , et al. (2013)
c.886A>C p.Thr296Pro missense_variant De novo - - 23692823 Milh M , et al. (2013)
c.911T>C p.Phe304Ser missense_variant De novo - - 23692823 Milh M , et al. (2013)
c.926C>T p.Ala309Val missense_variant De novo - - 23692823 Milh M , et al. (2013)
c.997C>T p.Arg333Trp missense_variant De novo - - 23692823 Milh M , et al. (2013)
c.902G>A p.Gly301Asp missense_variant De novo - - 29158550 Popp B , et al. (2017)
c.365C>T p.Ser122Leu missense_variant De novo - - 35571021 Chuan Z et al. (2022)
c.373G>T p.Ala125Ser missense_variant Unknown - - 35571021 Chuan Z et al. (2022)
c.838T>C p.Tyr280His missense_variant Unknown - - 35571021 Chuan Z et al. (2022)
c.749T>C p.Val250Ala missense_variant De novo - - 36932231 Yang GM et al. (2023)
c.772A>T p.Asn258Tyr missense_variant De novo - - 36932231 Yang GM et al. (2023)
c.779A>C p.His260Pro missense_variant De novo - - 36932231 Yang GM et al. (2023)
c.793G>A p.Ala265Thr missense_variant De novo - - 36932231 Yang GM et al. (2023)
c.868G>A p.Gly290Ser missense_variant De novo - - 36932231 Yang GM et al. (2023)
c.851A>G p.Tyr284Cys missense_variant Familial - - 9425895 Singh NA , et al. (1998)
c.916G>A p.Ala306Thr missense_variant Familial - - 9425895 Singh NA , et al. (1998)
c.1035A>C p.Arg345Ser missense_variant Unknown - - 35571021 Chuan Z et al. (2022)
c.1849C>T p.Pro617Ser missense_variant Unknown - - 35571021 Chuan Z et al. (2022)
c.430C>T p.Arg144Trp missense_variant De novo - - 35780567 Miceli F et al. (2022)
c.431G>A p.Arg144Gln missense_variant De novo - - 35780567 Miceli F et al. (2022)
c.543G>A p.Ala181= splice_site_variant Familial - - 9425895 Singh NA , et al. (1998)
c.821C>T p.Thr274Met missense_variant De novo - - 31273778 Borlot F , et al. (2019)
c.504C>G p.Phe168Leu missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.593G>A p.Arg198Gln missense_variant De novo - - 36980980 Spataro N et al. (2023)
c.1342C>T p.Arg448Ter stop_gained De novo - - 27848944 Trujillano D , et al. (2016)
c.1067T>G p.Leu356Arg missense_variant De novo - - 29286531 Tumien B , et al. (2017)
c.1997C>T p.Pro666Leu missense_variant Unknown - - 35813072 Krgovic D et al. (2022)
c.798T>A p.Asp266Glu missense_variant De novo - - 27864847 Parrini E , et al. (2016)
c.802C>T p.Leu268Phe missense_variant De novo - - 27864847 Parrini E , et al. (2016)
c.873G>T p.Arg291Ser missense_variant De novo - - 27864847 Parrini E , et al. (2016)
c.881C>T p.Ala294Val missense_variant De novo - - 27864847 Parrini E , et al. (2016)
c.901G>A p.Gly301Ser missense_variant De novo - - 27864847 Parrini E , et al. (2016)
c.881C>T p.Ala294Val missense_variant De novo - - 39213953 Liene Thys et al. (2024)
c.1742G>A p.Arg581Gln missense_variant De novo - - 27864847 Parrini E , et al. (2016)
c.2105C>T p.Ser702Leu missense_variant Unknown - - 39342494 Hosneara Akter et al. ()
c.2204A>C p.Asp735Ala missense_variant Unknown - - 39342494 Hosneara Akter et al. ()
c.620G>A p.Arg207Gln missense_variant Unknown - - 35253369 Verberne EA et al. (2022)
c.949G>A p.Ala317Thr missense_variant De novo - - 39602259 Mario Nappi et al. (2024)
c.952C>G p.Leu318Val missense_variant De novo - - 39602259 Mario Nappi et al. (2024)
c.34C>G p.Pro12Ala missense_variant Familial Maternal - 34145886 Zou D et al. (2021)
c.593G>A p.Arg198Gln missense_variant De novo - Simplex 33951346 Liu L et al. (2021)
c.430C>T p.Arg144Trp missense_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.902G>A p.Gly301Asp missense_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.602G>A p.Arg201His missense_variant De novo - - 35979408 Stenshorne I et al. (2022)
c.997C>T p.Arg333Trp missense_variant De novo - - 35979408 Stenshorne I et al. (2022)
c.1078T>G p.Trp360Gly missense_variant De novo - Simplex 37645600 Ko YJ et al. (2023)
c.881C>T p.Ala294Val missense_variant Unknown - Unknown 33753861 Chen JS et al. (2021)
c.868G>T p.Gly290Cys missense_variant De novo - Simplex 37543562 Sheth F et al. (2023)
c.1744A>T p.Ile582Phe missense_variant De novo - - 27848944 Trujillano D , et al. (2016)
c.794C>T p.Ala265Val missense_variant De novo - - 31036916 Lecoquierre F , et al. (2019)
c.833T>C p.Ile278Thr missense_variant De novo - - 38374498 Purvi Majethia et al. (2024)
c.365C>T p.Ser122Leu missense_variant De novo - Simplex 26544041 Zhang Y , et al. (2015)
c.830C>T p.Thr277Ile missense_variant De novo - Simplex 26544041 Zhang Y , et al. (2015)
c.956A>C p.Lys319Thr missense_variant De novo - Simplex 26544041 Zhang Y , et al. (2015)
c.628C>T p.Arg210Cys missense_variant De novo - Simplex 34948243 Bruno LP et al. (2021)
c.868G>A p.Gly290Ser missense_variant De novo - Simplex 35365919 Hieu NLT et al. (2022)
c.2412G>A p.Thr804%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1655A>C p.Lys552Thr missense_variant De novo - Simplex 26544041 Zhang Y , et al. (2015)
c.765G>T p.Lys255Asn missense_variant De novo - Simplex 38764027 Ruohao Wu et al. (2024)
c.523del p.Val175CysfsTer34 frameshift_variant Familial - - 9425895 Singh NA , et al. (1998)
c.1048A>C p.Asn350His missense_variant Familial Maternal - 30945278 Jiao Q , et al. (2019)
c.2234dup p.Cys746LeufsTer91 frameshift_variant De novo - - 23692823 Milh M , et al. (2013)
c.1341del p.Ser448HisfsTer63 frameshift_variant De novo - - 35571021 Chuan Z et al. (2022)
c.928-26_928-1del p.? frameshift_variant De novo - Simplex 25284784 Dong S , et al. (2014)
c.859A>G p.Thr287Ala missense_variant De novo - Simplex 29100083 Hamdan FF , et al. (2017)
c.431G>A p.Arg144Gln missense_variant De novo - - 23934111 Epi4K Consortium , et al. (2013)
c.2327del p.Gly776AlafsTer126 frameshift_variant De novo - - 31139143 Long S , et al. (2019)
c.916del p.Ala306ArgfsTer13 inframe_deletion De novo - - 28554332 Bowling KM , et al. (2017)
c.793G>A p.Ala265Thr missense_variant Unknown - Unknown 35887114 Levchenko O et al. (2022)
c.812G>A p.Gly271Asp missense_variant De novo - Simplex 35645364 Siracusano M et al. (2022)
c.431G>A p.Arg144Gln missense_variant Unknown Not maternal - 35780567 Miceli F et al. (2022)
c.1525G>T p.Glu509Ter stop_gained Unknown - Unknown 37799141 Amerh S Alqahtani et al. (2023)
c.1010C>G p.Ala337Gly missense_variant De novo - Multiplex 39528574 Chengyan Li et al. (2024)
c.1687G>T p.Asp563Tyr missense_variant De novo - Simplex 27334371 Halvardson J , et al. (2016)
c.629G>A p.Arg210His missense_variant De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.878T>C p.Leu293Pro missense_variant De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.590T>C p.Leu197Pro missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.845A>T p.Asp282Val missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.915C>G p.Phe305Leu missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.1678C>T p.Arg560Trp missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.1790C>A p.Pro597Gln missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.749T>G p.Val250Gly missense_variant De novo - Simplex 32651551 van der Werf IM et al. (2020)
c.1687G>A p.Asp563Asn missense_variant De novo - Simplex 32651551 van der Werf IM et al. (2020)
c.470G>A p.Trp157Ter stop_gained Unknown - Extended multiplex 38160512 Emily A Innes et al. (2024)
c.1054_1055del p.Ser352AlafsTer48 frameshift_variant De novo - Simplex 37645600 Ko YJ et al. (2023)
c.1750_1751dup p.His585GlyfsTer54 frameshift_variant Familial Paternal - 34145886 Zou D et al. (2021)
c.569A>G p.Asn190Ser missense_variant Familial Paternal Simplex 38160512 Emily A Innes et al. (2024)
c.587C>T p.Ala196Val missense_variant De novo - Simplex 38328757 Magdalena Badura-Stronka et al. (2024)
c.1764A>T p.Arg588Ser missense_variant Unknown - Multi-generational 38160512 Emily A Innes et al. (2024)
c.2126dup p.Ser710LeufsTer173 frameshift_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.2404_2405insA p.Val802AspfsTer35 frameshift_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.402del p.Ile134MetfsTer37 frameshift_variant Familial Paternal - 38108335 Anton Iftimovici et al. (2024)
c.430C>T p.Arg144Trp missense_variant De novo - Multiplex (monozygotic twins) 35780567 Miceli F et al. (2022)
NM_172109.1:c.1247+1G>A p.? splice_site_variant Familial Paternal Multiplex 23849776 Jiang YH , et al. (2013)
c.1764-6C>A - splice_region_variant Familial Paternal Multi-generational 38160512 Emily A Innes et al. (2024)
c.1741C>G p.Arg581Gly missense_variant De novo - Simplex 25262651 EuroEPINOMICS-RES Consortium , et al. (2014)
c.283insGT - frameshift_variant Familial Maternal and paternal Multi-generational 9425895 Singh NA , et al. (1998)
c.793G>A p.Ala265Thr missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.841G>A p.Gly281Arg missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.846C>G p.Asp282Glu missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.1004C>T p.Pro335Leu missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.788C>T p.Thr263Ile missense_variant De novo - Multi-generational 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
A/G - intron_variant - - - 16733521 Borsotto M , et al. (2006)
C/T - intron_variant - - - 16733521 Borsotto M , et al. (2006)
SFARI Gene score
2

Strong Candidate

A paternally-inherited splice-site variant in KCNQ2 was identified in a male ASD proband; this variant was inherited from a father with Asperger disorder and was also observed in the proband's sister, who was reported to exhibit autistic-like behavior (Jiang et al., 2013). A de novo frameshift variant in the KCNQ2 gene was identified in a male ASD proband from the Simons Simplex Collection (PMID 25284784). Mutations in the KCNQ2 gene are responsible for early infantile epileptic encephalopathy-7 (EIEE7; OMIM 613720) and benign familial neonatal seizures-1 (BFNS1; OMIM 121200).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 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.

4/1/2021
2
icon
2

Score remained at 2

Description

A paternally-inherited splice-site variant in KCNQ2 was identified in a male ASD proband; this variant was inherited from a father with Asperger disorder and was also observed in the proband's sister, who was reported to exhibit autistic-like behavior (Jiang et al., 2013). A de novo frameshift variant in the KCNQ2 gene was identified in a male ASD proband from the Simons Simplex Collection (PMID 25284784). Mutations in the KCNQ2 gene are responsible for early infantile epileptic encephalopathy-7 (EIEE7; OMIM 613720) and benign familial neonatal seizures-1 (BFNS1; OMIM 121200).

Reports Added
[Comorbidities associated with genetic abnormalities in children with intellectual disability2021] [Pathogenic variants in KCNQ2 cause intellectual deficiency without epilepsy: Broadening the phenotypic spectrum of a potassium channelopathy2021] [Confirming the contribution and genetic spectrum of de novo mutation in infantile spasms: Evidence from a Chinese cohort2021]
1/1/2021
2
icon
2

Score remained at 2

Description

A paternally-inherited splice-site variant in KCNQ2 was identified in a male ASD proband; this variant was inherited from a father with Asperger disorder and was also observed in the proband's sister, who was reported to exhibit autistic-like behavior (Jiang et al., 2013). A de novo frameshift variant in the KCNQ2 gene was identified in a male ASD proband from the Simons Simplex Collection (PMID 25284784). Mutations in the KCNQ2 gene are responsible for early infantile epileptic encephalopathy-7 (EIEE7; OMIM 613720) and benign familial neonatal seizures-1 (BFNS1; OMIM 121200).

Reports Added
[Analysis of common genetic variation and rare CNVs in the Australian Autism Biobank2021]
7/1/2020
2
icon
2

Score remained at 2

Description

A paternally-inherited splice-site variant in KCNQ2 was identified in a male ASD proband; this variant was inherited from a father with Asperger disorder and was also observed in the proband's sister, who was reported to exhibit autistic-like behavior (Jiang et al., 2013). A de novo frameshift variant in the KCNQ2 gene was identified in a male ASD proband from the Simons Simplex Collection (PMID 25284784). Mutations in the KCNQ2 gene are responsible for early infantile epileptic encephalopathy-7 (EIEE7; OMIM 613720) and benign familial neonatal seizures-1 (BFNS1; OMIM 121200).

Reports Added
[Overrepresentation of genetic variation in the AnkyrinG interactome is related to a range of neurodevelopmental disorders2020]
10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

A paternally-inherited splice-site variant in KCNQ2 was identified in a male ASD proband; this variant was inherited from a father with Asperger disorder and was also observed in the proband's sister, who was reported to exhibit autistic-like behavior (Jiang et al., 2013). A de novo frameshift variant in the KCNQ2 gene was identified in a male ASD proband from the Simons Simplex Collection (PMID 25284784). Mutations in the KCNQ2 gene are responsible for early infantile epileptic encephalopathy-7 (EIEE7; OMIM 613720) and benign familial neonatal seizures-1 (BFNS1; OMIM 121200).

Reports Added
[New Scoring Scheme]
7/1/2019
3
icon
3

Decreased from 3 to 3

Description

A paternally-inherited splice-site variant in KCNQ2 was identified in a male ASD proband; this variant was inherited from a father with Asperger disorder and was also observed in the proband's sister, who was reported to exhibit autistic-like behavior (Jiang et al., 2013). A de novo frameshift variant in the KCNQ2 gene was identified in a male ASD proband from the Simons Simplex Collection (PMID 25284784). Mutations in the KCNQ2 gene are responsible for early infantile epileptic encephalopathy-7 (EIEE7; OMIM 613720) and benign familial neonatal seizures-1 (BFNS1; OMIM 121200).

Reports Added
[Dominant-negative effects of KCNQ2 mutations are associated with epileptic encephalopathy.2013] [Variantrecurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense v...2019] [The Clinical and Genetic Features of Co-occurring Epilepsy and Autism Spectrum Disorder in Chinese Children.2019] [Clinical utility of multigene panel testing in adults with epilepsy and intellectual disability.2019]
4/1/2019
3
icon
3

Decreased from 3 to 3

Description

A paternally-inherited splice-site variant in KCNQ2 was identified in a male ASD proband; this variant was inherited from a father with Asperger disorder and was also observed in the proband's sister, who was reported to exhibit autistic-like behavior (Jiang et al., 2013). A de novo frameshift variant in the KCNQ2 gene was identified in a male ASD proband from the Simons Simplex Collection (PMID 25284784). Mutations in the KCNQ2 gene are responsible for early infantile epileptic encephalopathy-7 (EIEE7; OMIM 613720) and benign familial neonatal seizures-1 (BFNS1; OMIM 121200).

Reports Added
[The combination of whole-exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders.2019]
10/1/2017
3
icon
3

Decreased from 3 to 3

Description

A paternally-inherited splice-site variant in KCNQ2 was identified in a male ASD proband; this variant was inherited from a father with Asperger disorder and was also observed in the proband's sister, who was reported to exhibit autistic-like behavior (Jiang et al., 2013). A de novo frameshift variant in the KCNQ2 gene was identified in a male ASD proband from the Simons Simplex Collection (PMID 25284784). Mutations in the KCNQ2 gene are responsible for early infantile epileptic encephalopathy-7 (EIEE7; OMIM 613720) and benign familial neonatal seizures-1 (BFNS1; OMIM 121200).

Reports Added
[High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.2017] [Exome Pool-Seq in neurodevelopmental disorders.2017]
4/1/2017
3
icon
3

Decreased from 3 to 3

Description

A paternally-inherited splice-site variant in KCNQ2 was identified in a male ASD proband; this variant was inherited from a father with Asperger disorder and was also observed in the proband's sister, who was reported to exhibit autistic-like behavior (Jiang et al., 2013). A de novo frameshift variant in the KCNQ2 gene was identified in a male ASD proband from the Simons Simplex Collection (PMID 25284784). Mutations in the KCNQ2 gene are responsible for early infantile epileptic encephalopathy-7 (EIEE7; OMIM 613720) and benign familial neonatal seizures-1 (BFNS1; OMIM 121200).

Reports Added
[Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.2013] [PP2A-Bgamma subunit and KCNQ2 K channels in bipolar disorder.2006] [A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns.1998] [Similar early characteristics but variable neurological outcome of patients with a de novo mutation of KCNQ2.2013] [De novo mutations in epileptic encephalopathies.2013] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Converging Evidence for Epistasis between ANK3 and Potassium Channel Gene KCNQ2 in Bipolar Disorder.2013] [De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder.2014] [Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.2015] [Mutations in HECW2 are associated with intellectual disability and epilepsy.2016] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016] [Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016] [Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes.2016] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder2017] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017]
1/1/2017
3
icon
3

Decreased from 3 to 3

Description

A paternally-inherited splice-site variant in KCNQ2 was identified in a male ASD proband; this variant was inherited from a father with Asperger disorder and was also observed in the proband's sister, who was reported to exhibit autistic-like behavior (Jiang et al., 2013). A de novo frameshift variant in the KCNQ2 gene was identified in a male ASD proband from the Simons Simplex Collection (PMID 25284784). Mutations in the KCNQ2 gene are responsible for early infantile epileptic encephalopathy-7 (EIEE7; OMIM 613720) and benign familial neonatal seizures-1 (BFNS1; OMIM 121200).

Reports Added
[Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes.2016]
10/1/2016
3
icon
3

Decreased from 3 to 3

Description

A paternally-inherited splice-site variant in KCNQ2 was identified in a male ASD proband; this variant was inherited from a father with Asperger disorder and was also observed in the proband's sister, who was reported to exhibit autistic-like behavior (Jiang et al., 2013). A de novo frameshift variant in the KCNQ2 gene was identified in a male ASD proband from the Simons Simplex Collection (PMID 25284784). Mutations in the KCNQ2 gene are responsible for early infantile epileptic encephalopathy-7 (EIEE7; OMIM 613720) and benign familial neonatal seizures-1 (BFNS1; OMIM 121200).

Reports Added
[Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016]
7/1/2016
3
icon
3

Decreased from 3 to 3

Description

A paternally-inherited splice-site variant in KCNQ2 was identified in a male ASD proband; this variant was inherited from a father with Asperger disorder and was also observed in the proband's sister, who was reported to exhibit autistic-like behavior (Jiang et al., 2013). A de novo frameshift variant in the KCNQ2 gene was identified in a male ASD proband from the Simons Simplex Collection (PMID 25284784). Mutations in the KCNQ2 gene are responsible for early infantile epileptic encephalopathy-7 (EIEE7; OMIM 613720) and benign familial neonatal seizures-1 (BFNS1; OMIM 121200).

Reports Added
[Mutations in HECW2 are associated with intellectual disability and epilepsy.2016] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016]
1/1/2016
3
icon
3

Decreased from 3 to 3

Description

A paternally-inherited splice-site variant in KCNQ2 was identified in a male ASD proband; this variant was inherited from a father with Asperger disorder and was also observed in the proband's sister, who was reported to exhibit autistic-like behavior (Jiang et al., 2013). A de novo frameshift variant in the KCNQ2 gene was identified in a male ASD proband from the Simons Simplex Collection (PMID 25284784). Mutations in the KCNQ2 gene are responsible for early infantile epileptic encephalopathy-7 (EIEE7; OMIM 613720) and benign familial neonatal seizures-1 (BFNS1; OMIM 121200).

Reports Added
[Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.2013] [PP2A-Bgamma subunit and KCNQ2 K channels in bipolar disorder.2006] [A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns.1998] [Similar early characteristics but variable neurological outcome of patients with a de novo mutation of KCNQ2.2013] [De novo mutations in epileptic encephalopathies.2013] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Converging Evidence for Epistasis between ANK3 and Potassium Channel Gene KCNQ2 in Bipolar Disorder.2013] [De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder.2014] [Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.2015]
7/1/2015
icon
3

Increased from to 3

Description

A paternally-inherited splice-site variant in KCNQ2 was identified in a male ASD proband; this variant was inherited from a father with Asperger disorder and was also observed in the proband's sister, who was reported to exhibit autistic-like behavior (Jiang et al., 2013). A de novo frameshift variant in the KCNQ2 gene was identified in a male ASD proband from the Simons Simplex Collection (PMID 25284784). Mutations in the KCNQ2 gene are responsible for early infantile epileptic encephalopathy-7 (EIEE7; OMIM 613720) and benign familial neonatal seizures-1 (BFNS1; OMIM 121200).

Krishnan Probability Score

Score 0.61544698513644

Ranking 116/25841 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 0.99935609863785

Ranking 983/18225 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 0.35217872398636

Ranking 225/18665 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 15.5

Ranking 126/461 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 0.30659428508961

Ranking 2638/20870 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
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