Whole gene duplication of <i>SCN2A</i> and <i>SCN3A</i> is associated with neonatal seizures and a normal intellectual development

Thuresson, Ann‐Charlotte; Buggenhout, Griet Van; Sheth, Frenny; Kamate, Mahesh; Andrieux, Joris; Smith, Jill; Zander, Cecilia

doi:10.1111/cge.12797

Cited by 15 publications

(11 citation statements)

References 14 publications

(21 reference statements)

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“…Moreover, in the SCN CNV cohort, we observed that patients with duplications presented with significantly earlier seizure onset and responded better to SCBs compared to patients with deletions. This early seizure onset is likely caused by duplication of the SCN2A/SCN3A genes, which are the earliest SCN s expressed during development, resulting in GoF effects due to SCN2A/SCN3A protein overexpression …”

Section: Discussionmentioning

confidence: 99%

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Biological concepts in human sodium channel epilepsies and their relevance in clinical practice

Brunklaus

Steckler

et al. 2020

Epilepsia

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Objective Voltage‐gated sodium channels (SCNs) share similar amino acid sequence, structure, and function. Genetic variants in the four human brain‐expressed SCN genes SCN1A/2A/3A/8A have been associated with heterogeneous epilepsy phenotypes and neurodevelopmental disorders. To better understand the biology of seizure susceptibility in SCN‐related epilepsies, our aim was to determine similarities and differences between sodium channel disorders, allowing us to develop a broader perspective on precision treatment than on an individual gene level alone. Methods We analyzed genotype‐phenotype correlations in large SCN‐patient cohorts and applied variant constraint analysis to identify severe sodium channel disease. We examined temporal patterns of human SCN expression and correlated functional data from in vitro studies with clinical phenotypes across different sodium channel disorders. Results Comparing 865 epilepsy patients (504 SCN1A, 140 SCN2A, 171 SCN8A, four SCN3A, 46 copy number variation [CNV] cases) and analysis of 114 functional studies allowed us to identify common patterns of presentation. All four epilepsy‐associated SCN genes demonstrated significant constraint in both protein truncating and missense variation when compared to other SCN genes. We observed that age at seizure onset is related to SCN gene expression over time. Individuals with gain‐of‐function SCN2A/3A/8A missense variants or CNV duplications share similar characteristics, most frequently present with early onset epilepsy (<3 months), and demonstrate good response to sodium channel blockers (SCBs). Direct comparison of corresponding SCN variants across different SCN subtypes illustrates that the functional effects of variants in corresponding channel locations are similar; however, their clinical manifestation differs, depending on their role in different types of neurons in which they are expressed. Significance Variant function and location within one channel can serve as a surrogate for variant effects across related sodium channels. Taking a broader view on precision treatment suggests that in those patients with a suspected underlying genetic epilepsy presenting with neonatal or early onset seizures (<3 months), SCBs should be considered.

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Section: Discussionmentioning

confidence: 99%

“…This early seizure onset is likely caused by duplication of the SCN2A/SCN3A genes, which are the earliest SCNs expressed during development, resulting in GoF effects due to SCN2A/SCN3A protein overexpression. 41…”

Section: Discussionmentioning

confidence: 99%

Biological concepts in human sodium channel epilepsies and their relevance in clinical practice

Brunklaus

Steckler

et al. 2020

Epilepsia

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“…Yoshitomi et al (127) reported 3 patients manifesting focal seizures and infantile spasms having microduplication mutation on the 2q24.3 chromosomal loci. Eight additional duplications were reported by Thuresson et al (128). The region duplicated was overlapped and the spanned range approximately between 0.05 and 7.63 Mb in size.…”

Section: Deletion Regionsmentioning

confidence: 90%

Voltage Gated Sodium Channel Genes in Epilepsy: Mutations, Functional Studies, and Treatment Dimensions

et al. 2021

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Genetic epilepsy occurs as a result of mutations in either a single gene or an interplay of different genes. These mutations have been detected in ion channel and non-ion channel genes. A noteworthy class of ion channel genes are the voltage gated sodium channels (VGSCs) that play key roles in the depolarization phase of action potentials in neurons. Of huge significance are SCN1A, SCN1B, SCN2A, SCN3A, and SCN8A genes that are highly expressed in the brain. Genomic studies have revealed inherited and de novo mutations in sodium channels that are linked to different forms of epilepsies. Due to the high frequency of sodium channel mutations in epilepsy, this review discusses the pathogenic mutations in the sodium channel genes that lead to epilepsy. In addition, it explores the functional studies on some known mutations and the clinical significance of VGSC mutations in the medical management of epilepsy. The understanding of these channel mutations may serve as a strong guide in making effective treatment decisions in patient management.

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“…Table 1 summarizes the patients reported to have EIEE due to either heterozygous or de novo mutations within the SCN2A gene. 7,12…”

Section: Discussionmentioning

confidence: 99%

Biallelic SCN2A Gene Mutation Causing Early Infantile Epileptic Encephalopathy: Case Report and Review

AlSaif

Umair

Alfadhel

2019

J Cent Nerv Syst Dis

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The voltage-gated sodium channel neuronal type 2 alpha subunit (Na v α1.2) encoded by the SCN2A gene causes early infantile epileptic encephalopathy (EIEE) inherited in an autosomal dominant manner. Clinically, it has variable presentations, ranging from benign familial infantile seizures (BFIS) to severe EIEE. Diagnosis is achieved through molecular DNA testing of the SCN2A gene. Herein, we report on a 30-month-old Saudi girl who presented on the fourth day of life with EIEE, normal brain magnetic resonance imaging (MRI), normal electroencephalography (EEG), and well-controlled seizures. Genetic investigation revealed a novel homozygous missense mutation (c.5242A > G; p.Asn1748Asp) in the SCN2A gene (NM_001040142.1). This is the first reported autosomal recessive inheritance of a disease allele in the SCN2A and therefore expands the molecular and inheritance spectrum of the SCN2A gene defects.

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Whole gene duplication of SCN2A and SCN3A is associated with neonatal seizures and a normal intellectual development

Cited by 15 publications

References 14 publications

Biological concepts in human sodium channel epilepsies and their relevance in clinical practice

Biological concepts in human sodium channel epilepsies and their relevance in clinical practice

Voltage Gated Sodium Channel Genes in Epilepsy: Mutations, Functional Studies, and Treatment Dimensions

Biallelic SCN2A Gene Mutation Causing Early Infantile Epileptic Encephalopathy: Case Report and Review

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