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  • Title: [Study on mosaicism of SCN1A gene mutation in parents of children with Dravet syndrome].
    Author: Liu AJ, Yang XX, Xu XJ, Wu QX, Tian XJ, Yang XL, Wu XR, Wei LP, Zhang YH.
    Journal: Zhonghua Er Ke Za Zhi; 2017 Nov 02; 55(11):818-823. PubMed ID: 29141311.
    Abstract:
    Objective: To investigate the clinical phenotypes and the mutant allele proportion of parents with SCN1A gene mutation mosaicism of Dravet syndrome (DS) children, thus to provide guidance for family reproduction and prenatal diagnosis. Method: The clinical data and peripheral blood DNA samples of DS patients with a SCN1A gene mutation proved by Sanger sequencing were collected prospectively from February 2005 to November 2016 in Department of Pediatrics, Peking University First Hospital. The same mutation was searched in parents and other available relatives. Parental somatic mosaicism was confirmed and quantified by Ion Torrent Personal Genome Machine (PGM) and Raindrop droplet digital PCR (ddPCR). The families were followed up and prenatal diagnosis was provided. Result: Mosaicisms of SCN1A gene mutation in parents were identified in 5.2% (30 out of 575) DS families. Seventeen were fathers and thirteen were mothers. The mutant allele proportion ranged from 1.7% to 32.9% by PGM and from 0.82% to 34.51% by ddPCR, respectively. In 30 parents with somatic mosaicism, thirteen were asymptomatic, ten had a history of febrile seizures (FS), five with epilepsy, one with febrile seizure plus and one had a history of afebrile seizure. Four families had two children with DS. Three siblings of the probands were confirmed genetically with the same pathogenic mutation. One deceased sister of the proband was assumed to have the same pathogenic mutation because she matched DS diagnosis after medical history review despite no blood sample. Two families received prenatal diagnosis. One second pregnancy was terminated because the fetus inherited the mutation as the mother's wish. Conclusion: Sanger sequencing detects parents of some children with DS are SCN1A mutation mosaics. PGM and ddPCR can be used for accurate quantification of mutant mosaics, which can provide accurate guidance for family genetic counseling. 目的： 分析Dravet综合征（DS）患儿父母一方为SCN1A基因突变嵌合体的临床表型及突变等位基因占比，为家庭再生育及产前诊断提供指导。 方法： 前瞻性收集2005年2月至2016年11月在北京大学第一医院儿科经Sanger测序发现SCN1A基因突变阳性的DS患儿的临床资料及外周血DNA，对患儿父母及其他家系成员靶向检测突变位点。以Sanger测序发现患儿父母一方疑为突变嵌合体的家系为研究对象，采用Ion Torrent个体化基因组测序仪（PGM）和RainDrop微滴数字聚合酶链反应（ddPCR）技术进行突变验证及定量分析，并对嵌合体家系进行随访和产前诊断。 结果： 在575个DS家系中，共发现30例（5.2%）父母一方为SCN1A突变嵌合体，其中父亲17例，母亲13例。PGM和ddPCR测序分别证实突变等位基因占比范围为1.7%~32.9%和0.82%~34.51%。30例亲代嵌合体中，13例无症状，10例为热性惊厥（FS），5例为癫痫，1例为热性惊厥附加症，1例仅有一次无热惊厥史。有4个家庭已生育2例DS患儿，3例先证者同胞已证实携带相同致病突变，1例先证者同胞姐姐已死亡未获得其外周血DNA，但回顾其病史符合DS诊断。2个家庭进行再生育产前诊断，发现1例胎儿携带家系遗传性突变，母亲自愿终止妊娠。 结论： Sanger测序可以发现部分DS患儿父母一方为SCN1A基因突变嵌合体，采用PGM或ddPCR可对突变嵌合体进行精确定量，为家庭遗传咨询提供更准确的指导。.
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