PDF(Pubmed)
Abstract：
Voltage-gated sodium channels (VGSCs) are responsible for the initiation and propagation of action potentials in the brain and muscle. Pathogenic variants in genes encoding VGSCs have been associated with severe disorders including epileptic encephalopathies and congenital myopathies. In this study, we identified pathogenic variants in genes encoding the α subunit of VGSCs in the fetuses of two unrelated families with the use of trio-based whole exome sequencing, as part of a larger cohort study. Sanger sequencing was performed for variant confirmation as well as parental phasing. The fetus of the first family carried a known de novo heterozygous missense variant in the SCN2A gene (NM_001040143.2:c.751G>A p.(Val251Ile)) and presented intrauterine growth retardation, hand clenching and ventriculomegaly. Neonatally, the proband also exhibited refractory epilepsy, spasms and MRI abnormalities. The fetus of the second family was a compound heterozygote for two parentally inherited novel missense variants in the SCN4A gene (NM_000334.4:c.4340T>C, p.(Phe1447Ser), NM_000334.4:c.3798G>C, p.(Glu1266Asp)) and presented a severe prenatal phenotype including talipes, fetal hypokinesia, hypoplastic lungs, polyhydramnios, ear abnormalities and others. Both probands died soon after birth. In a subsequent pregnancy of the latter family, the fetus was also a compound heterozygote for the same parentally inherited variants. This pregnancy was terminated due to multiple ultrasound abnormalities similar to the first pregnancy. Our results suggest a potentially crucial role of the VGSC gene family in fetal development and early lethality.
摘要：
电压门控钠通道（VGSC）负责在大脑和肌肉中启动和传播动作电位。编码VGSC的基因中的致病变体与包括癫痫性脑病和先天性肌病的严重疾病有关。在这项研究中,我们使用基于三重奏的全外显子组测序，在两个不相关家族的胎儿中鉴定了编码VGSCsα亚基的基因中的致病变异，作为一个更大的队列研究的一部分。进行Sanger测序用于变体确认以及亲本定相。第一个家族的胎儿携带SCN2A基因中已知的从头杂合错义变异（NM_001040143.2：c.751G>Ap。（Val251Ile）），并表现出宫内发育迟缓，手紧握和脑室增大。新生儿,先证者还表现出难治性癫痫，痉挛和MRI异常。第二个家族的胎儿是SCN4A基因中两个亲本遗传的新型错义变体的复合杂合子（NM_000334.4：c.4340T>C，p.(Phe1447Ser)，NM_000334.4：c.3798G>C，p。（Glu1266Asp））并表现出严重的产前表型，包括塔利班，胎儿运动减少,发育不良的肺,羊水过多,耳朵异常和其他。两个先证者出生后不久死亡。在后者家庭的随后怀孕中，胎儿也是相同的亲本遗传变体的复合杂合子。由于类似于第一次妊娠的多次超声异常而终止了该妊娠。我们的结果表明，VGSC基因家族在胎儿发育和早期致死率中具有潜在的关键作用。
