Targeted sequencing identifies a novel SH2D1A pathogenic variant in a Chinese family: Carrier screening and prenatal genetic testing.
Targeted sequencing identifies a novel SH2D1A pathogenic variant in a Chinese family: Carrier screening and prenatal genetic testing.
复制标题
靶向测序在中国家庭中发现一种新的SH2D1A致病性变异：携带者筛查和产前基因检测
DOI：
10.1371/journal.pone.0172173
复制
发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Xu CM
中科院分区：
文献类型：
--
作者：
Zhang JY;Chen SC;Chen YY;Li SY;Zhang LL;Shen YH;Chang CX;Xiang YQ;Huang HF;Xu CM
X-连锁淋巴组织增生性疾病1型（XLP 1）是一种罕见的原发性免疫缺陷，其特征是由严重的EBV诱导的噬血细胞性淋巴组织细胞增多症、B细胞淋巴瘤和异常丙种球蛋白血症组成的临床三联征。SH 2D 1A基因突变已被揭示为XLP 1的原因。在这项研究中，一名孕妇与分娩免疫缺陷复发史进行了筛查致病性变异，因为先证者样本不可用。我们的目的是澄清基因诊断，并提供产前检查的家庭。采用基于下一代测序（NGS）的多基因板对孕妇进行携带者筛查。免疫缺陷相关基因的变异进行了分析和优先级。通过使用桑格测序验证候选变体。通过RNA测定来评估所鉴定的变体的可能影响。进行羊膜穿刺术、染色体核型分析和桑格测序进行产前检查。我们发现了一种新的从头移码SH 2D 1A致病性变异（c.251_255delTTTCA）在怀孕的载体。外周血RNA检测表明，突变体转录本能逃避无义介导的mRNA衰变（NMD），可能编码一个C端截短的蛋白。该变异的信息导致成功的胎儿产前诊断。总之，我们的研究阐明了XLP 1妊娠携带者的基因诊断和改变疾病预防。
X-linked lymphoproliferative disease type 1 (XLP1) is a rare primary immunodeficiency characterized by a clinical triad consisting of severe EBV-induced hemophagocytic lymphohistiocytosis, B-cell lymphoma, and dysgammaglobulinemia. Mutations in SH2D1A gene have been revealed as the cause of XLP1. In this study, a pregnant woman with recurrence history of birthing immunodeficiency was screened for pathogenic variant because the proband sample was unavailable. We aimed to clarify the genetic diagnosis and provide prenatal testing for the family. Next-generation sequencing (NGS)-based multigene panel was used in carrier screening of the pregnant woman. Variants of immunodeficiency related genes were analyzed and prioritized. Candidate variant was verified by using Sanger sequencing. The possible influence of the identified variant was evaluated through RNA assay. Amniocentesis, karyotyping, and Sanger sequencing were performed for prenatal testing. We identified a novel de novo frameshift SH2D1A pathogenic variant (c.251_255delTTTCA) in the pregnant carrier. Peripheral blood RNA assay indicated that the mutant transcript could escape nonsense-mediated mRNA decay (NMD) and might encode a C-terminal truncated protein. Information of the variant led to success prenatal diagnosis of the fetus. In conclusion, our study clarified the genetic diagnosis and altered disease prevention for a pregnant carrier of XLP1.