title: De novo SCN2A splice site mutation in a boy with Autism spectrum disorder.
abstract: BACKGROUND
  SCN2A is a gene that codes for the alpha subunit of voltage-gated, type II sodium channels, and is highly expressed in the brain. Sodium channel disruptions, such as mutations in SCN2A, may play an important role in psychiatric disorders. Recently, de novo SCN2A mutations in autism spectrum disorder (ASD) have been identified. The current study characterizes a de novo splice site mutation in SCN2A that alters mRNA and protein products.
  
  
  METHODS
  We describe results from clinical and genetic characterizations of a seven-year-old boy with ASD. Psychiatric interview and gold standard autism diagnostic instruments (ADOS and ADI-R) were used to confirm ASD diagnosis, in addition to performing standardized cognitive and adaptive functioning assessments (Leiter-R and Vineland Adaptive Behavior Scale), and sensory reactivity assessments (Sensory Profile and Sensory Processing Scales). Genetic testing by whole exome sequencing revealed four de novo events, including a splice site mutation c.476 + 1G > A in SCN2A, a missense mutation (c.2263G > A) causing a p.V755I change in the TLE1 gene, and two synonymous mutations (c.2943A > G in the BUB1 gene, and c.1254 T > A in C10orf68 gene). The de novo SCN2A splice site mutation produced a stop codon 10 amino acids downstream, possibly resulting in a truncated protein and/or a nonsense-mediated mRNA decay. The participant met new DSM-5 criteria for ASD, presenting with social and communication impairment, repetitive behaviors, and sensory reactivity issues. The participant's adaptive and cognitive skills fell in the low range of functioning.
  
  
  CONCLUSIONS
  This report indicates that a splice site mutation in SCN2A might be contributing to the risk of ASD. Describing the specific phenotype associated with SCN2A mutations might help to reduce heterogeneity seen in ASD.
authors.affiliation: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA. teresa.tavassoli@mssm.edu.
authors.forename: Teresa
authors.initials: T
authors.lastname: Tavassoli
authors.forename: Alexander
authors.initials: A
authors.lastname: Kolevzon
authors.forename: A Ting
authors.initials: AT
authors.lastname: Wang
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Curchack-Lichtin
authors.forename: Danielle
authors.initials: D
authors.lastname: Halpern
authors.forename: Lily
authors.initials: L
authors.lastname: Schwartz
authors.forename: Sarah
authors.initials: S
authors.lastname: Soffes
authors.forename: Lauren
authors.initials: L
authors.lastname: Bush
authors.forename: David
authors.initials: D
authors.lastname: Grodberg
authors.forename: Guiqing
authors.initials: G
authors.lastname: Cai
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000175:diagnosis* / Q000235:genetics / Q000523:psychology; D056970:Co-Repressor Proteins; D004252:DNA Mutational Analysis; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D025202:Molecular Diagnostic Techniques; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D062551:NAV1.2 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D022821:RNA Splice Sites; D012097:Repressor Proteins / Q000235:genetics
chemical_list: D056970:Co-Repressor Proteins; D062551:NAV1.2 Voltage-Gated Sodium Channel; D020033:Protein Isoforms; D022821:RNA Splice Sites; D012097:Repressor Proteins; C568251:SCN2A protein, human; C499043:TLE1 protein, human