生殖细胞嵌合致SCN2A突变的同胞患孤独谱系障碍/发育迟滞

Autism spectrum disorder/development delay in siblings with SCN2A mutations caused by germline mosaicism

目的报告一个生殖细胞嵌合致SCN2A突变的同胞患孤独谱系障碍/发育迟滞的家系。方法收集先证者及其父母的临床资料,进行基于二代测序技术(next generation sequencing,NGS)的全外显子检测,确定致病突变,对先证者及其父母、同胞哥哥进行Sanger测序验证。进一步对父母样本进行数字PCR(droplet digital PCR,ddPCR)检测,验证患儿父母是否存在低比例的生殖细胞嵌合。结果先证者及其同胞哥哥均存在SCN2A c.605+1G>A杂合新生突变,结合其临床表型及遗传方式,判断SCN2A为其致病基因,强烈提示亲代生殖细胞嵌合,ddPCR检测结果证实父亲为表型正常的生殖细胞低比例嵌合(0.233%)携带者。结论生殖细胞嵌合可导致SCN2A突变的同胞患孤独谱系障碍/发育迟滞。在对生育有SCN2A新生突变的患儿父母进行遗传咨询时,父亲生殖细胞嵌合应该被认为是重要的遗传方式之一。ddPCR检测有助于发现极低比例的生殖细胞嵌合。

Objective To report on a family which has two siblings with SCN2A mutation caused by germline mosaicism suffering from autism spectrum disorder/development delay(ASD/DD).Methods Clinical data was collected for the proband and his parents.Next generation sequencing(NGS)was carried out on the proband and his parents.Suspected mutations were verified by Sanger sequencing of the proband,his parents and brother.To detect whether there is a low proportion of somatic mosaicism in the parents,a droplet digital PCR was conducted.The result of ddPCR showed that the father was germline mosaicism(0.233%).Results NGS has identified a de novo splicing mutation of the SCN2A gene,c.605+1G>A,in the proband and his brother.Combined with its clinical phenotype and inheritance pattern,SCN2A was judged to be the pathogenic gene.Above findings strongly suggested parental germline mosaicism.Conclusion ASD/DD in siblings with SCN2A mutations caused by germline mosaicism.Paternal mosaicism should be considered as one of the important inheritance patterns for counseling parents with a child carrying SCN2A mutation.The ddPCR can help to reveal very low proportion of germline mosaicism.