De novo SCN2A splice site mutation in a boy with Autism spectrum disorder

Tavassoli, Teresa; Kolevzon, Alexander; Wang, A Ting; Curchack-Lichtin, Jocelyn; Halpern, Danielle; Schwartz, Lily; Soffes, Sarah; Bush, Lauren; Grodberg, David; Cai, Guiqing; Buxbaum, Joseph D.

doi:10.1186/1471-2350-15-35

Cited by 49 publications

(43 citation statements)

References 34 publications

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“…Dougherty and colleagues have shown that this circuit is enriched for autism candidate genes (AutDb) but not necessarily genes implicated early in development by de novo LGD events (Xu et al, 2014). Indeed, an examination of the 22 striatal genes implicated in this study with other recently published exomes/genomes (n=3,505) (De Rubeis et al, 2014; Hashimoto et al, 2016; Iossifov et al, 2014; Jiang et al, 2013; Krumm et al, 2015; Lee et al, 2014; Moreno-Ramos et al, 2015; Tavassoli et al, 2014) showed that only one of the genes ( CACNA2D3 ) with evidence for a de novo LGD mutation in an autism proband. Our findings provide further support for this striatal circuit and suggest that multiple de novo regulatory mutations may be an important risk factor for identification of such autism risk genes.…”

Section: Discussionmentioning

confidence: 61%

Genomic Patterns of De Novo Mutation in Simplex Autism

Turner

Coe

Dickel

et al. 2017

Cell

316

351

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SUMMARY To further our understanding of the genetic etiology of autism, we generated and analyzed genome sequence data from 516 idiopathic autism families (2,064 individuals). This resource includes >59 million single-nucleotide variants (SNVs) and 9,212 private copy number variants (CNVs), of which 133,992 and 88 are de novo mutations (DNMs), respectively. We estimate a mutation rate of ~1.5×10−8 SNVs per site per generation with a significantly higher mutation rate in repetitive DNA. Comparing probands and unaffected siblings, we observe several DNM trends. Probands carry more gene-disruptive CNVs and SNVs resulting in severe missense mutations and mapping to predicted fetal brain promoters and embryonic stem cell enhancers. These differences become more pronounced for autism genes (p=1.8×10−3, OR=2.2). Patients are more likely to carry multiple coding and noncoding DNMs in different genes, which are enriched for expression in striatal neurons (p=3×10−3), suggesting a path forward for characterizing genetically more complex cases of autism.

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Section: Discussionmentioning

confidence: 61%

Genomic Patterns of De Novo Mutation in Simplex Autism

Turner

Coe

Dickel

et al. 2017

Cell

316

351

View full text Add to dashboard Cite

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“…[21][22][23] The expanded phenotypic spectrum of SCN2A mutations parallels that seen with KCNQ2 and SCN1A and may be broader than currently appreciated. [34][35][36] As yet, no clear genotype-phenotype correlation explains the phenotypic heterogeneity.…”

Section: -Ax T-ap E-hv/t/ht I Gi-c Sf T2-wm T1-bg T-s T-ests Usmentioning

confidence: 96%

“…phenotypes exist: the self-limited autosomal dominant syndrome of BFNIS (with excellent outcome and seizure resolution) and moderate to severe intellectual disability without epilepsy 2,3,[21][22][23]32,33 ; autism may be present. [21][22][23] The expanded phenotypic spectrum of SCN2A mutations parallels that seen with KCNQ2 and SCN1A and may be broader than currently appreciated.…”

Section: -Ax T-ap E-hv/t/ht I Gi-c Sf T2-wm T1-bg T-s T-ests Usmentioning

confidence: 99%

SCN2A encephalopathy

et al. 2015

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Objective: De novo SCN2A mutations have recently been associated with severe infantile-onset epilepsies. Herein, we define the phenotypic spectrum of SCN2A encephalopathy.Methods: Twelve patients with an SCN2A epileptic encephalopathy underwent electroclinical phenotyping.Results: Patients were aged 0.7 to 22 years; 3 were deceased. Seizures commenced on day 1-4 in 8, week 2-6 in 2, and after 1 year in 2. Characteristic features included clusters of brief focal seizures with multiple hourly (9 patients), multiple daily (2), or multiple weekly (1) seizures, peaking at maximal frequency within 3 months of onset. Multifocal interictal epileptiform discharges were seen in all. Three of 12 patients had infantile spasms. The epileptic syndrome at presentation was epilepsy of infancy with migrating focal seizures (EIMFS) in 7 and Ohtahara syndrome in 2. Nine patients had improved seizure control with sodium channel blockers including supratherapeutic or high therapeutic phenytoin levels in 5. Eight had severe to profound developmental impairment. Other features included movement disorders (10), axial hypotonia (11) with intermittent or persistent appendicular spasticity, early handedness, and severe gastrointestinal symptoms. Mutations arose de novo in 11 patients; paternal DNA was unavailable in one.Conclusions: Review of our 12 and 34 other reported cases of SCN2A encephalopathy suggests 3 phenotypes: neonatal-infantile-onset groups with severe and intermediate outcomes, and a childhood-onset group. Here, we show that SCN2A is the second most common cause of EIMFS and, importantly, does not always have a poor developmental outcome. Sodium channel blockers, particularly phenytoin, may improve seizure control. Neurology ® 2015;85:958-966 GLOSSARY BFNIS 5 benign familial neonatal infantile seizures; EE 5 epileptic encephalopathy; EIMFS 5 epilepsy of infancy with migrating focal seizures; MIP 5 molecular inversion probe; SUDEP 5 sudden unexpected death in epilepsy; WES 5 whole-exome sequencing.

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“…(2014) using whole‐exome sequencing found a de novo splice site variation in SCN2A gene in one patient with ASD. This variation (c.476+1G>A) that occurs at exon 4 of SCNA2A gene generates a truncated protein (Tavassoli et al., 2014; Table 2). In addition, the α subunit 8 gene of a Na + channel was associated with ASD and identified by whole‐genome sequencing in a family with ASD.…”

Section: Reviewmentioning

confidence: 99%

Autism throughout genetics: Perusal of the implication of ion channels

et al. 2018

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BackgroundAutism spectrum disorder (ASD) comprises a group of neurodevelopmental psychiatric disorders characterized by deficits in social interactions, interpersonal communication, repetitive and stereotyped behaviors and may be associated with intellectual disabilities. The description of ASD as a synaptopathology highlights the importance of the synapse and the implication of ion channels in the etiology of these disorders.MethodsA narrative and critical review of the relevant papers from 1982 to 2017 known by the authors was conducted.ResultsGenome‐wide linkages, association studies, and genetic analyses of patients with ASD have led to the identification of several candidate genes and mutations linked to ASD. Many of the candidate genes encode for proteins involved in neuronal development and regulation of synaptic function including ion channels and actors implicated in synapse formation. The involvement of ion channels in ASD is of great interest as they represent attractive therapeutic targets. In agreement with this view, recent findings have shown that drugs modulating ion channel function are effective for the treatment of certain types of patients with ASD.ConclusionThis review describes the genetic aspects of ASD with a focus on genes encoding ion channels and highlights the therapeutic implications of ion channels in the treatment of ASD.

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De novo SCN2A splice site mutation in a boy with Autism spectrum disorder

Cited by 49 publications

References 34 publications

Genomic Patterns of De Novo Mutation in Simplex Autism

Genomic Patterns of De Novo Mutation in Simplex Autism

SCN2A encephalopathy

Autism throughout genetics: Perusal of the implication of ion channels

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