Wu Wei, Lu Li, Xu Weijue, Liu Jiangbin, Sun Jun, Zheng Lulu, Sheng Qingfeng, Lv Zhibao
Department of General Surgery, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China.
Front Genet. 2019 Jan 14;9:752. doi: 10.3389/fgene.2018.00752. eCollection 2018.
Hirschsprung disease is a birth defect characterized by complete absence of neuronal ganglion cells from a portion of the intestinal tract. To uncover genetic variants contributing to HSCR, we performed whole exome sequencing on seven members of an HSCR family. With the minor allele frequency (MAF) calculated by gnomAD, we finally filtered a total of 1,059 rare variants in this family (MAF < 0.1%). With the mode of inheritance and pathogenicity scores by bioinformatics tools, we identified an in-frameshift variant p.Phe147del in as the disease-causing variant. Further analysis revealed that the in-frameshift variant may function by disrupting the glycosylation of RET protein. To our knowledge, this is the first study to report the in-frameshift variant p.Phe147del in RET responsible for heritable HSCR.
先天性巨结肠症是一种出生缺陷，其特征是肠道的一部分完全没有神经节细胞。为了发现导致先天性巨结肠症（HSCR）的基因变异，我们对一个HSCR家族的七名成员进行了全外显子组测序。根据gnomAD计算的次要等位基因频率（MAF），我们最终在这个家族中筛选出总共1059个罕见变异（MAF < 0.1%）。通过生物信息学工具的遗传模式和致病性评分，我们确定 RET 基因中的一个框内移码变异p.Phe147del是致病变异。进一步分析表明，该框内移码变异可能通过破坏RET蛋白的糖基化发挥作用。据我们所知，这是第一项报道RET基因中导致遗传性HSCR的框内移码变异p.Phe147del的研究。
