Human Gene Module / Chromosome 20 / KCNB1

KCNB1potassium voltage-gated channel subfamily B member 1

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
11 / 30
Rare Variants / Common Variants
112 / 0
Aliases
KCNB1, DRK1,  Kv2.1
Associated Syndromes
-
Chromosome Band
20q13.13
Associated Disorders
DD/NDD, ADHD, ASD
Relevance to Autism

Mutations in the KCNB1 gene are associated with epileptic encephalopathy-26 (EIEE26; OMIM 616056). de Kovel et al., 2017 examined the clinical spectrum associated with KCNB1 variation in a cohort of 26 patients. Developmental delay was reported in all patients, with intractable epilepsy (84%) and features of epileptic encephalopathy on EEG (95%) also frequently observed; ASD was reported in 10/20 patients (50%). Among the de novo variants in KCNB1 identified in patients with ASD were three predicted loss-of-function variants and a missense variant that was demonstrated to impair channel sensitivity and cooperativity. Parrini et al., 2017 identified a de novo nonsense variant in KCNB1 in a male patient presenting with West syndrome and autism spectrum disorder. Bar et al., 2019 presented genetic and phenotypic data from a cohort of 64 patients (37 previously unreported and 27 novel) with pathogenic KCNB1 variants and reported that behavioral issues were observed in 37/49 patients with available data, including autism spectrum disorder in 26 cases (53%). Kang et al., 2019 described clinical and functional analysis of KCNB1 variants identified in 32 patients, eight of whom were reported to present with ASD; pathogenic variants were found to display diverse functional effects, including altered current density and shifts in the voltage-dependence of activation and/or inactivaton, as well as reduced total protein expression and/or cell-surface expression. Bar et al., 2021 assessed the adaptive and behavioral features in a series of 25 individuals with a KCNB1 encephalopathy, using the the Social Communication Questionnaire (SCQ) to screen for autism spectrum disorder (ASD); the SCQ was filled by 18/21 caregivers according to the age criteria for this questionnaire (> 4 years), and thirteen out of 18 participants had a score above the threshold of risk for ASD. Five rare and potentially damaging missense variants, as well as two de novo loss-of-function variants, in the KCNB1 gene were reported in ASD proband from the Autism Sequencing Consortium, the MSSNG cohort, and the SPARK cohort in Zhou et al., 2022; a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in this report identified KCNB1 as a gene reaching exome-wide significance (P < 2.5E-06).

Molecular Function

This gene encodes a member of the potassium channel, voltage-gated, shab-related subfamily. The voltage-gated potassium channel encoded by the KCNB1 gene mediates transmembrane potassium transport in excitable membranes, primarily in the brain, but also in the pancreas and cardiovascular system; it also contributes to the regulation of the action potential (AP) repolarization, duration and frequency of repetitive AP firing in neurons, muscle cells and endocrine cells and plays a role in homeostatic attenuation of electrical excitability throughout the brain. Mutations in the KCNB1 gene are associated with epileptic encephalopathy-26 (EIEE26; OMIM 616056).

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to KCNB1 (30 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support De novo KCNB1 mutations in epileptic encephalopathy Torkamani A , et al. (2014) No -
2 Support Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes Parrini E , et al. (2016) Yes -
3 Primary Neurodevelopmental Disorders Caused by De Novo Variants in KCNB1 Genotypes and Phenotypes de Kovel CGF , et al. (2017) No ASD
4 Support Characterization of a KCNB1 variant associated with autism, intellectual disability, and epilepsy Calhoun JD , et al. (2017) No Autistic features, disruptive behavior
5 Support Clinical features and outcome of 6 new patients carrying de novo KCNB1 gene mutations Marini C , et al. (2017) No ASD
6 Support Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder Munnich A , et al. (2019) Yes -
7 Recent Recommendation Expanding the genetic and phenotypic relevance of KCNB1 variants in developmental and epileptic encephalopathies: 27 new patients and overview of the literature Bar C , et al. (2019) No Behavioral disorders (including ASD)
8 Recent Recommendation Spectrum of K V 2.1 Dysfunction in KCNB1-Associated Neurodevelopmental Disorders Kang SK , et al. (2019) No -
9 Support Meta-Analyses Support Previous and Novel Autism Candidate Genes: Outcomes of an Unexplored Brazilian Cohort da Silva Montenegro EM , et al. (2019) Yes -
10 Support Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability Chevarin M et al. (2020) No Marfanoid habitus
11 Support Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures Tang S et al. (2020) No -
12 Support Developmental and epilepsy spectrum of KCNB1 encephalopathy with long-term outcome Bar C et al. (2020) No Autistic features, ADHD
13 Support - Liu L et al. (2021) No ASD, DD
14 Support - Mahjani B et al. (2021) Yes -
15 Recent Recommendation - Bar C et al. (2022) No ASD
16 Support - Xiong J et al. (2022) No Autistic features, stereotypy
17 Support - Brea-Fernández AJ et al. (2022) No Epilepsy/seizures
18 Support - Chuan Z et al. (2022) No DD
19 Support - Levchenko O et al. (2022) No -
20 Recent Recommendation - Zhou X et al. (2022) Yes -
21 Support - Uctepe E et al. (2022) No -
22 Support - Veale EL et al. (2022) No -
23 Negative Association - Liu Z et al. (2023) Yes -
24 Support - Chaves LD et al. (2023) Yes -
25 Support - Sanchis-Juan A et al. (2023) No -
26 Support - Omri Bar et al. (2024) Yes ID, epilepsy/seizures
27 Support - Tamam Khalaf et al. (2024) Yes -
28 Support - Seok Kyu Kang et al. (2024) No -
29 Support - Axel Schmidt et al. (2024) Yes Cognitive impairment
30 Support - Rían W Manville et al. (2024) Yes -
Rare Variants   (112)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1463G>A p.Trp488Ter stop_gained De novo - - 32954514 Bar C et al. (2020)
c.984C>G p.Tyr328Ter stop_gained De novo - - 31513310 Bar C , et al. (2019)
c.1489G>T p.Glu497Ter stop_gained De novo - - 31513310 Bar C , et al. (2019)
c.1297C>T p.Arg433Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_loss Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.629C>T p.Thr210Met missense_variant Unknown - - 32954514 Bar C et al. (2020)
c.916C>T p.Arg306Cys missense_variant De novo - - 32954514 Bar C et al. (2020)
c.935G>A p.Arg312His missense_variant De novo - - 32954514 Bar C et al. (2020)
c.935G>A p.Arg312His missense_variant Unknown - - 32954514 Bar C et al. (2020)
c.956C>T p.Ser319Phe missense_variant De novo - - 32954514 Bar C et al. (2020)
c.128A>G p.Glu43Gly missense_variant De novo - - 31513310 Bar C , et al. (2019)
629C>T p.Thr210Met missense_variant Unknown - - 35071126 Xiong J et al. (2022)
c.1109G>A p.Trp370Ter stop_gained De novo - - 29264397 Marini C , et al. (2017)
c.1747C>T p.Arg583Ter stop_gained De novo - - 29264397 Marini C , et al. (2017)
c.1153C>A p.Pro385Thr missense_variant De novo - - 32954514 Bar C et al. (2020)
c.629C>G p.Thr210Arg missense_variant De novo - - 31513310 Bar C , et al. (2019)
c.916C>T p.Arg306Cys missense_variant De novo - - 31513310 Bar C , et al. (2019)
c.934C>T p.Arg312Cys missense_variant De novo - - 31513310 Bar C , et al. (2019)
c.935G>A p.Arg312His missense_variant De novo - - 31513310 Bar C , et al. (2019)
c.968C>T p.Thr323Ile missense_variant De novo - - 31513310 Bar C , et al. (2019)
c.916C>T p.Arg306Cys missense_variant De novo - - 32469098 Tang S et al. (2020)
c.597C>G p.Ile199Met missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.935G>A p.Arg312His missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.49C>A p.Pro17Thr missense_variant De novo - - 36618935 Veale EL et al. (2022)
c.1109G>A p.Trp370Ter stop_gained De novo - - 27864847 Parrini E , et al. (2016)
c.1001T>C p.Leu334Pro missense_variant De novo - - 31513310 Bar C , et al. (2019)
c.1041C>G p.Ser347Arg missense_variant De novo - - 31513310 Bar C , et al. (2019)
c.1045G>T p.Val349Phe missense_variant De novo - - 31513310 Bar C , et al. (2019)
c.1105T>C p.Trp369Arg missense_variant De novo - - 31513310 Bar C , et al. (2019)
c.1115C>A p.Thr372Asn missense_variant De novo - - 31513310 Bar C , et al. (2019)
c.1115C>T p.Thr372Ile missense_variant De novo - - 31513310 Bar C , et al. (2019)
c.1130C>A p.Thr377Asn missense_variant De novo - - 31513310 Bar C , et al. (2019)
c.1132G>T p.Val378Phe missense_variant De novo - - 31513310 Bar C , et al. (2019)
c.1139A>G p.Tyr380Cys missense_variant De novo - - 31513310 Bar C , et al. (2019)
c.1144G>A p.Asp382Asn missense_variant De novo - - 31513310 Bar C , et al. (2019)
c.1180G>A p.Gly394Arg missense_variant De novo - - 31513310 Bar C , et al. (2019)
c.1183G>A p.Gly395Arg missense_variant De novo - - 31513310 Bar C , et al. (2019)
c.1183G>A p.Gly395Arg missense_variant Unknown - - 31513310 Bar C , et al. (2019)
c.1201G>A p.Gly401Arg missense_variant De novo - - 31513310 Bar C , et al. (2019)
c.1226T>C p.Ile409Thr missense_variant De novo - - 31513310 Bar C , et al. (2019)
c.1248C>A p.Phe416Leu missense_variant Unknown - - 31513310 Bar C , et al. (2019)
c.814C>T p.Pro272Ser missense_variant Unknown - - 35071126 Xiong J et al. (2022)
c.940T>C p.Ser314Pro missense_variant Unknown - - 35071126 Xiong J et al. (2022)
c.954G>T p.Gln318His missense_variant Unknown - - 35071126 Xiong J et al. (2022)
c.990G>T p.Glu330Asp missense_variant Unknown - - 35071126 Xiong J et al. (2022)
c.1747C>T p.Arg583Ter stop_gained De novo - Simplex 33951346 Liu L et al. (2021)
c.1130C>T p.Thr377Ile missense_variant Unknown - - 35071126 Xiong J et al. (2022)
c.1136G>T p.Gly379Val missense_variant Unknown - - 35071126 Xiong J et al. (2022)
c.1222G>A p.Pro408Ser missense_variant Unknown - - 35071126 Xiong J et al. (2022)
c.1141G>A p.Gly381Arg missense_variant Unknown - - 35571021 Chuan Z et al. (2022)
c.629C>T p.Thr210Met missense_variant De novo - - 31600826 Kang SK , et al. (2019)
c.916C>T p.Arg306Cys missense_variant De novo - - 31600826 Kang SK , et al. (2019)
c.934C>T p.Arg312Cys missense_variant De novo - - 31600826 Kang SK , et al. (2019)
c.973C>T p.Arg325Trp missense_variant De novo - - 31600826 Kang SK , et al. (2019)
c.990G>C p.Glu330Asp missense_variant De novo - - 31600826 Kang SK , et al. (2019)
c.682C>T p.Gln228Ter stop_gained De novo - - 28806457 de Kovel CGF , et al. (2017)
c.1108T>C p.Trp370Arg missense_variant De novo - - 31600826 Kang SK , et al. (2019)
c.1133T>C p.Val378Ala missense_variant De novo - - 31600826 Kang SK , et al. (2019)
c.1153C>A p.Pro385Thr missense_variant De novo - - 31600826 Kang SK , et al. (2019)
c.1246T>C p.Phe416Leu missense_variant De novo - - 31600826 Kang SK , et al. (2019)
c.586A>T p.Ile196Phe missense_variant De novo - - 29264397 Marini C , et al. (2017)
c.629C>T p.Thr210Met missense_variant De novo - - 29264397 Marini C , et al. (2017)
c.916C>T p.Arg306Cys missense_variant De novo - - 29264397 Marini C , et al. (2017)
c.980G>C p.Ser327Thr missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.1107G>A p.Trp369Ter stop_gained De novo - - 28806457 de Kovel CGF , et al. (2017)
c.1599C>A p.Tyr533Ter stop_gained De novo - - 28806457 de Kovel CGF , et al. (2017)
c.1747C>T p.Arg583Ter stop_gained De novo - - 28806457 de Kovel CGF , et al. (2017)
c.1045G>T p.Val349Phe missense_variant De novo - - 29264397 Marini C , et al. (2017)
c.1222C>T p.Pro408Ser missense_variant Unknown - - 36943625 Chaves LD et al. (2023)
T>TA p.Lys502fs frameshift_variant De novo - - 28806457 de Kovel CGF , et al. (2017)
c.595A>T p.Ile199Phe missense_variant De novo - - 29264390 Calhoun JD , et al. (2017)
c.629C>T p.Thr210Met missense_variant De novo - Simplex 33951346 Liu L et al. (2021)
c.1237G>A p.Val413Ile missense_variant De novo - - 35887114 Levchenko O et al. (2022)
c.916C>T p.Arg306Cys missense_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.934C>T p.Arg312Cys missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.955T>C p.Ser319Pro missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1183G>A p.Gly395Arg missense_variant Unknown - - 38438125 Tamam Khalaf et al. (2024)
c.605C>T p.Ser202Phe missense_variant De novo - - 28806457 de Kovel CGF , et al. (2017)
c.629C>A p.Thr210Lys missense_variant De novo - - 28806457 de Kovel CGF , et al. (2017)
c.629C>T p.Thr210Met missense_variant De novo - - 28806457 de Kovel CGF , et al. (2017)
c.632T>C p.Leu211Pro missense_variant De novo - - 28806457 de Kovel CGF , et al. (2017)
c.916C>T p.Arg306Cys missense_variant De novo - - 28806457 de Kovel CGF , et al. (2017)
c.935G>A p.Arg312His missense_variant De novo - - 28806457 de Kovel CGF , et al. (2017)
c.935G>A p.Arg312His missense_variant Unknown - - 28806457 de Kovel CGF , et al. (2017)
c.1083C>G p.Phe361Leu missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1041C>A p.Ser347Arg missense_variant De novo - - 28806457 de Kovel CGF , et al. (2017)
c.1121C>T p.Thr374Ile missense_variant De novo - - 28806457 de Kovel CGF , et al. (2017)
c.1133T>C p.Val378Ala missense_variant De novo - - 28806457 de Kovel CGF , et al. (2017)
c.1135G>A p.Gly379Arg missense_variant De novo - - 28806457 de Kovel CGF , et al. (2017)
c.1141G>A p.Gly381Arg missense_variant De novo - - 28806457 de Kovel CGF , et al. (2017)
c.1153C>A p.Pro385Thr missense_variant De novo - - 28806457 de Kovel CGF , et al. (2017)
c.1173A>C p.Lys391Asn missense_variant De novo - - 28806457 de Kovel CGF , et al. (2017)
c.1193G>T p.Cys398Phe missense_variant De novo - - 28806457 de Kovel CGF , et al. (2017)
c.1201G>A p.Gly401Arg missense_variant De novo - - 28806457 de Kovel CGF , et al. (2017)
c.1248C>G p.Phe416Leu missense_variant De novo - - 28806457 de Kovel CGF , et al. (2017)
c.857del p.Val286GlyfsTer58 frameshift_variant De novo - - 31513310 Bar C , et al. (2019)
c.660C>T p.Phe220%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.571del p.Ala192ProfsTer2 frameshift_variant Unknown - - 35071126 Xiong J et al. (2022)
c.934C>T p.Arg312Cys missense_variant De novo - Simplex 38256266 Omri Bar et al. (2024)
c.128A>G p.Glu43Gly missense_variant De novo - Simplex 31406558 Munnich A , et al. (2019)
c.1579C>T p.Gln527Ter stop_gained De novo - - 35322241 Brea-Fernández AJ et al. (2022)
c.817dup p.Tyr273LeufsTer37 frameshift_variant De novo - - 31600826 Kang SK , et al. (2019)
c.1371C>G p.Ser457Arg missense_variant Familial - Simplex 31600826 Kang SK , et al. (2019)
c.643_644del p.Gln215GlufsTer4 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.1747C>T p.Arg583Ter stop_gained Familial Maternal Simplex 31513310 Bar C , et al. (2019)
c.1240A>G p.Asn414Asp missense_variant De novo - Simplex 32277047 Chevarin M et al. (2020)
c.916C>T p.Arg306Cys missense_variant De novo - - 35322241 Brea-Fernández AJ et al. (2022)
c.916C>T p.Arg306Cys missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.1088del p.Ser363ThrfsTer13 frameshift_variant De novo - - 28806457 de Kovel CGF , et al. (2017)
c.522del p.Lys174AsnfsTer20 frameshift_variant Familial Maternal - 36457583 Uctepe E et al. (2022)
c.916C>T p.Arg306Cys missense_variant De novo - Simplex 31696658 da Silva Montenegro EM , et al. (2019)
c.342C>A p.Ser114Arg missense_variant Unknown Not maternal Multiplex 39135902 Rían W Manville et al. (2024)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2021
1
icon
1

Score remained at 1

Description

Mutations in the KCNB1 gene are associated with epileptic encephalopathy-26 (EIEE26; OMIM 616056). de Kovel et al., 2017 examined the clinical spectrum associated with KCNB1 variation in a cohort of 26 patients. Developmental delay was reported in all patients, with intractable epilepsy (84%) and features of epileptic encephalopathy on EEG (95%) also frequently observed; ASD was reported in 10/20 patients (50%). Among the de novo variants in KCNB1 identified in patients with ASD were three predicted loss-of-function variants and a missense variant that was demonstrated to impair channel sensitivity and cooperativity. Parrini et al., 2017 identified a de novo nonsense variant in KCNB1 in a male patient presenting with West syndrome and autism spectrum disorder. Bar et al., 2019 presented genetic and phenotypic data from a cohort of 64 patients (37 previously unreported and 27 novel) with pathogenic KCNB1 variants and reported that behavioral issues were observed in 37/49 patients with available data, including autism spectrum disorder in 26 cases (53%). Kang et al., 2019 described clinical and functional analysis of KCNB1 variants identified in 32 patients, eight of whom were reported to present with ASD; pathogenic variants were found to display diverse functional effects, including altered current density and shifts in the voltage-dependence of activation and/or inactivaton, as well as reduced total protein expression and/or cell-surface expression.

Reports Added
[Confirming the contribution and genetic spectrum of de novo mutation in infantile spasms: Evidence from a Chinese cohort2021]
10/1/2020
1
icon
1

Score remained at 1

Description

Mutations in the KCNB1 gene are associated with epileptic encephalopathy-26 (EIEE26; OMIM 616056). de Kovel et al., 2017 examined the clinical spectrum associated with KCNB1 variation in a cohort of 26 patients. Developmental delay was reported in all patients, with intractable epilepsy (84%) and features of epileptic encephalopathy on EEG (95%) also frequently observed; ASD was reported in 10/20 patients (50%). Among the de novo variants in KCNB1 identified in patients with ASD were three predicted loss-of-function variants and a missense variant that was demonstrated to impair channel sensitivity and cooperativity. Parrini et al., 2017 identified a de novo nonsense variant in KCNB1 in a male patient presenting with West syndrome and autism spectrum disorder. Bar et al., 2019 presented genetic and phenotypic data from a cohort of 64 patients (37 previously unreported and 27 novel) with pathogenic KCNB1 variants and reported that behavioral issues were observed in 37/49 patients with available data, including autism spectrum disorder in 26 cases (53%). Kang et al., 2019 described clinical and functional analysis of KCNB1 variants identified in 32 patients, eight of whom were reported to present with ASD; pathogenic variants were found to display diverse functional effects, including altered current density and shifts in the voltage-dependence of activation and/or inactivaton, as well as reduced total protein expression and/or cell-surface expression.

Reports Added
[Developmental and epilepsy spectrum of KCNB1 encephalopathy with long-term outcome2020]
4/1/2020
1
icon
1

Score remained at 1

Description

Mutations in the KCNB1 gene are associated with epileptic encephalopathy-26 (EIEE26; OMIM 616056). de Kovel et al., 2017 examined the clinical spectrum associated with KCNB1 variation in a cohort of 26 patients. Developmental delay was reported in all patients, with intractable epilepsy (84%) and features of epileptic encephalopathy on EEG (95%) also frequently observed; ASD was reported in 10/20 patients (50%). Among the de novo variants in KCNB1 identified in patients with ASD were three predicted loss-of-function variants and a missense variant that was demonstrated to impair channel sensitivity and cooperativity. Parrini et al., 2017 identified a de novo nonsense variant in KCNB1 in a male patient presenting with West syndrome and autism spectrum disorder. Bar et al., 2019 presented genetic and phenotypic data from a cohort of 64 patients (37 previously unreported and 27 novel) with pathogenic KCNB1 variants and reported that behavioral issues were observed in 37/49 patients with available data, including autism spectrum disorder in 26 cases (53%). Kang et al., 2019 described clinical and functional analysis of KCNB1 variants identified in 32 patients, eight of whom were reported to present with ASD; pathogenic variants were found to display diverse functional effects, including altered current density and shifts in the voltage-dependence of activation and/or inactivaton, as well as reduced total protein expression and/or cell-surface expression.

Reports Added
[Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability2020] [Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures2020]
10/1/2019
S
icon
1

Increased from S to 1

New Scoring Scheme
Description

Mutations in the KCNB1 gene are associated with epileptic encephalopathy-26 (EIEE26; OMIM 616056). de Kovel et al., 2017 examined the clinical spectrum associated with KCNB1 variation in a cohort of 26 patients. Developmental delay was reported in all patients, with intractable epilepsy (84%) and features of epileptic encephalopathy on EEG (95%) also frequently observed; ASD was reported in 10/20 patients (50%). Among the de novo variants in KCNB1 identified in patients with ASD were three predicted loss-of-function variants and a missense variant that was demonstrated to impair channel sensitivity and cooperativity. Parrini et al., 2017 identified a de novo nonsense variant in KCNB1 in a male patient presenting with West syndrome and autism spectrum disorder. Bar et al., 2019 presented genetic and phenotypic data from a cohort of 64 patients (37 previously unreported and 27 novel) with pathogenic KCNB1 variants and reported that behavioral issues were observed in 37/49 patients with available data, including autism spectrum disorder in 26 cases (53%). Kang et al., 2019 described clinical and functional analysis of KCNB1 variants identified in 32 patients, eight of whom were reported to present with ASD; pathogenic variants were found to display diverse functional effects, including altered current density and shifts in the voltage-dependence of activation and/or inactivaton, as well as reduced total protein expression and/or cell-surface expression.

Reports Added
[De novo KCNB1 mutations in epileptic encephalopathy.2014] [Expanding the genetic and phenotypic relevance of KCNB1 variants in developmental and epileptic encephalopathies: 27 new patients and overview of t...2019] [Spectrum of KV 2.1 Dysfunction in KCNB1-Associated Neurodevelopmental Disorders.2019] [Meta-Analyses Support Previous and Novel Autism Candidate Genes: Outcomes of an Unexplored Brazilian Cohort.2019] [New Scoring Scheme]
7/1/2019
S
icon
S

Increased from S to S

Description

Mutations in the KCNB1 gene are associated with epileptic encephalopathy-26 (EIEE26; OMIM 616056). de Kovel et al., 2017 examined the clinical spectrum associated with KCNB1 variation in a cohort of 26 patients. Developmental delay was reported in all patients, with intractable epilepsy (84%) and features of epileptic encephalopathy on EEG (95%) also frequently observed; ASD was reported in 10/20 patients (50%). Among the de novo variants in KCNB1 identified in patients with ASD were three predicted loss-of-function variants and a missense variant that was demonstrated to impair channel sensitivity and cooperativity. Parrini et al., 2017 identified a de novo nonsense variant in KCNB1 in a male patient presenting with West syndrome and autism spectrum disorder.

Reports Added
[Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder.2019]
Krishnan Probability Score

Score 0.61320358740483

Ranking 145/25841 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 0.98258786978003

Ranking 2059/18225 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
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Sanders TADA Score

Score 0.94118105282845

Ranking 14838/18665 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
Zhang D Score

Score 0.23545503937706

Ranking 3681/20870 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.
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