Background

Variants in SCN1A gene, encoding the voltage-gated sodium channel Na_v1.1, are associated with distinct epilepsy syndromes ranging from the relatively benign genetic epilepsy with febrile seizures plus (GEFS+) to Dravet syndrome, a severe developmental and epileptic encephalopathy (DEE). Most SCN1A pathogenic variants are heterozygous changes inherited in a dominant or de novo inheritance and many cause a loss-of-function of one allele. To date, recessive inheritance has been suggested in only two families with affected children harboring homozygous SCN1A missense variants while their heterozygous parents were asymptomatic. The aim of this report is to describe two additional families in which affected individuals have biallelic SCN1A variants possibly explaining their phenotype.

Methods and results

We report two novel homozygous SCN1A missense variants in two patients from related parents. Both patients had fever-sensitive epilepsy beginning in the first months of life, followed by afebrile seizures, without severe cognitive impairment. Parents were asymptomatic. Next generation sequencing excluded a pathogenic variant in other genes involved in DEE. Estimation of pathogenicity scores by in-silico tools suggests that the impact of these SCN1A variants is less damaging than that of dominant pathogenic variants.

Conclusion

This study provides additional evidence that homozygous variants in SCN1A can cause GEFS+. This recessive inheritance would imply that hypomorphic variants may not necessarily cause epilepsy at the heterozygous state but may decrease the seizure threshold when combined.

中文翻译：

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具有隐性遗传的 SCN1A 相关癫痫：另外两个家族

背景

变体在SCN1A基因，编码电压-门控钠通道的Na _v 1.1，都具有不同的癫痫综合征，从热性惊厥加（GEFS +），以Dravet综合征，一个严重的发育和癫痫性脑病（DEE）的相对良性遗传性癫痫有关。大多数SCN1A致病性变异是在显性遗传或从头遗传中遗传的杂合变化，许多导致一个等位基因的功能丧失。迄今为止，仅在两个受影响儿童携带纯合SCN1A 的家庭中提出隐性遗传错义变异，而它们的杂合双亲则无症状。本报告的目的是描述另外两个家族，其中受影响的个体具有双等位基因SCN1A变体，这可能解释了他们的表型。

方法和结果

我们报告了来自相关父母的两名患者的两种新型纯合SCN1A错义变异。两名患者在出生后的头几个月都患有发热敏感性癫痫，随后出现无热性癫痫发作，但没有严重的认知障碍。父母无症状。下一代测序排除了与 DEE 相关的其他基因中的致病性变异。通过计算机工具对致病性评分的估计表明，这些SCN1A变异的影响比显性致病变异的破坏性要小。

结论

这项研究提供了额外的证据，表明SCN1A中的纯合变异可导致 GEFS+。这种隐性遗传意味着亚形变体在杂合子状态下不一定会导致癫痫，但在组合时可能会降低癫痫发作阈值。