title: Association of rare missense variants in the second intracellular loop of NaV1.7 sodium channels with familial autism.
abstract: Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder often accompanied by intellectual disability, language impairment and medical co-morbidities. The heritability of autism is high and multiple genes have been implicated as causal. However, most of these genes have been identified in de novo cases. To further the understanding of familial autism, we performed whole-exome sequencing on five families in which second- and third-degree relatives were affected. By focusing on novel and protein-altering variants, we identified a small set of candidate genes. Among these, a novel private missense C1143F variant in the second intracellular loop of the voltage-gated sodium channel NaV1.7, encoded by the SCN9A gene, was identified in one family. Through electrophysiological analysis, we show that NaV1.7C1143Fexhibits partial loss-of-function effects, resulting in slower recovery from inactivation and decreased excitability in cultured cortical neurons. Furthermore, for the same intracellular loop of NaV1.7, we found an excess of rare variants in a case-control variant-burden study. Functional analysis of one of these variants, M932L/V991L, also demonstrated reduced firing in cortical neurons. However, although this variant is rare in Caucasians, it is frequent in Latino population, suggesting that genetic background can alter its effects on phenotype. Although the involvement of the SCN1A and SCN2A genes encoding NaV1.1 and NaV1.2 channels in de novo ASD has previously been demonstrated, our study indicates the involvement of inherited SCN9A variants and partial loss-of-function of NaV1.7 channels in the etiology of rare familial ASD.
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Rubinstein
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Patowary
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA, USA.
authors.forename: I B
authors.initials: IB
authors.lastname: Stanaway
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA, USA.
authors.forename: E
authors.initials: E
authors.lastname: McCord
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
authors.forename: R R
authors.initials: RR
authors.lastname: Nesbitt
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Archer
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Scheuer
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Nickerson
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.|Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: W H
authors.initials: WH
authors.lastname: Raskind
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA, USA.|Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.|Department of Biostatistics, University of Washington, Seattle, WA, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Wijsman
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Bernier
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA, USA.
authors.forename: W A
authors.initials: WA
authors.lastname: Catterall
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Brkanac
mesh_terms: D000067877:Autism Spectrum Disorder / Q000235:genetics; D001321:Autistic Disorder / Q000235:genetics*; D016022:Case-Control Studies; D005190:Family; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D009154:Mutation; D020125:Mutation, Missense / Q000235:genetics; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D010641:Phenotype; D015222:Sodium Channels / Q000235:genetics; D000073359:Exome Sequencing
chemical_list: D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D015222:Sodium Channels