Zhang Pingping, Gao Zhijie, Jia Jia, Chen Qian
Department of Neurology, Children's Hospital Affiliated to Capital Institute of Pediatrics, Beijing 100020, China.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2021 Nov 10;38(11):1097-1100. doi: 10.3760/cma.j.cn511374-20200522-00371.
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).
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%).
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.
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.
报告一个家庭，该家庭中有两名患有自闭症谱系障碍/发育迟缓（ASD/DD）的兄弟姐妹，其病因是生殖系嵌合导致的SCN2A突变。
收集了先证者及其父母的临床资料。对先证者及其父母进行了下一代测序（NGS）。通过对先证者、其父母和兄弟进行Sanger测序来验证疑似突变。为检测父母中是否存在低比例的体细胞嵌合，进行了液滴数字PCR。ddPCR结果显示父亲为生殖系嵌合（0.233%）。
NGS在先证者及其兄弟中鉴定出SCN2A基因的一个新生剪接突变，c.605+1G>A。结合其临床表型和遗传模式，判断SCN2A为致病基因。上述发现强烈提示父母生殖系嵌合。
生殖系嵌合导致SCN2A突变的兄弟姐妹出现ASD/DD。对于携带SCN2A突变孩子的父母进行遗传咨询时，应将父系嵌合视为重要的遗传模式之一。ddPCR有助于揭示极低比例的生殖系嵌合。
