Abstract: Objective To analyze the genetic variation characteristics and clinical phenotypes of a family with primary microcephaly (MCPH) caused by RTTN gene variation, and to provide reference for genetic counseling and prenatal diagnosis. Methods Clinical data of the three patients (including2 fetuses and 2-year-old proband, and one fetus with clinical diagnosis) and their parents were collected and analyzed. Two of the children and their parents were tested by trio whole exome sequencing (trio-WES), sanger sequencing validation sites, and the hazard of their compound heterozygous variants was predicted. Literature review was conducted through domestic and international databases to collect reported RTTN gene mutation cases. Results Three patients in this family had anomalies of the septum pellucidum, hypoplasia of the corpus callosum and other brain malformations during fetal period. The proband (G2) and fetus (G3) showed intrauterine growth retardation and MCPH in late pregnancy; besides, G2 was born with global developmental delay. Trio-WES detected a c.2101(exon16)C>T(p.Arg701Ter, 1526) nonsense and a c.2863(exon22)G>A(p.Glu955Lys)missense in the RTTN gene of G2 and G3, which were inherited from their father and mother, forming a compound heterozygous variant. According to the American College of Medical Genetics and Genomics (ACMG) variant classification guidelines, two variants were likely to be pathogenic (LP) and uncertain significance (VUS). Among them, c.2863(exon22)G>A was a newly discovered missense, which was predicted by the software to be harmful to the gene product. Conclusions Complex heterozygous variations of RTTN gene (c.2101C>T and c.2863G>A) are the genetic cause of MCPH in this family. This report has enriched the variation spectrum of RTTN gene, provided guidance for prenatal diagnosis and reproduction of this family, as well as material and reference for further understanding of the diseases caused by this gene mutation.

Key words: RTTN gene, primary microcephaly, whole exome sequencing, genetic analysis

摘要： 目的 分析RTTN基因变异导致原发性小头畸形(MCPH)家系的基因变异特点和临床表型,并为其遗传咨询及产前诊断提供参考。方法 收集并分析一家系3例患儿(包括2例胎儿和2岁的先证者,其中1例胎儿为临床诊断患儿)及其父母的临床资料,对其中2名患儿及其父母采用家系全外显子组测序(trio-WES)检测,Sanger测序验证位点,软件预测其复合杂合变异的危害性。查阅国内外文献数据库,收集已报道的RTTN基因突变病例并进行文献复习。结果 该家系3例患者在胎儿期有透明隔异常,胼胝体发育不良等脑部畸形,先证者(G2)、胎儿(G3)表现有孕晚期宫内发育迟缓和原发性小头畸形,G2出生后全面发育落后。trio-WES检出G2和G3的RTTN基因存在父源性的c.2101(exon16)C>T(p.Arg701Ter,1526)无义变异和母源性的c.2863(exon22)G>A(p.Glu955Lys)错义变异,形成复合杂合变异。根据美国医学遗传学与基因组学学会(ACMG)变异分类指南,两个变异分别为可能致病性的(LP)和不确定的(VUS)。其中,位点c.2863(exon22)G>A为新发现的错义变异,且经过软件预测该变异对基因产物有害。结论 RTTN基因c.2101C>T和c.2863G>A复合杂合变异为该家系患儿小头畸形的遗传学病因。本报道丰富了RTTN基因变异谱,为该家系的产前诊断及再次生育提供了指导,并为进一步了解该基因突变导致的疾病提供素材和参考。

关键词: RTTN基因, 原发性小头畸形, 全外显子测序, 遗传学分析