RTTN基因复合杂合变异导致原发性小头畸形家系分析并文献复习

doi:10.11852/zgetbjzz2023-0521

中国儿童保健杂志 ›› 2024, Vol. 32 ›› Issue (2): 212-217.DOI: 10.11852/zgetbjzz2023-0521

RTTN基因复合杂合变异导致原发性小头畸形家系分析并文献复习

赵晨玥¹, 蒋劲嵩¹, 张莉雪¹, 郭敏¹, 高景波², 孙夏瑜², 郭荣², 卢洪涌², 武坚锐², 薛慧琴²

1.山西医科大学儿科医学系,山西太原 030001;
2.山西省儿童医院(山西省妇幼保健院)细胞遗传室,山西太原 030001

收稿日期:2023-05-25 发布日期:2024-02-21 出版日期:2024-02-10
通讯作者: 薛慧琴,E-mail: pyxhq@163.com
作者简介:赵晨玥(1998-),女,山西人,学士学位,硕士研究生在读,主要研究方向为儿童遗传性疾病的诊治及机制研究。
基金资助:
国家人口与生殖健康科学数据中心工程项目(No2005DKA32408);山西省“四个一批”科技兴医创新计划项目——医学遗传学研究委级重点实验室项目(2020SYS24)

Family analysis of primary microcephaly caused by complex heterozygous variants of the RTTN gene and literature review

ZHAO Chenyue¹, JIANG Jinsong¹, ZHANG Lixue¹, GUO Min¹, GAO Jingbo², SUN Xiayu², GUO Rong², LU Hongyong², WU Jianrui², XUE Huiqin²

1. Pediatrics Discipline, Graduate School of Shanxi Medical University, Taiyuan, Shanxi 030001, China;
2. Shanxi Provincial Children's Hospital(Shanxi Maternal and Child Health Care Hospital), Taiyuan, Shanxi 030001, China

Received:2023-05-25 Online:2024-02-10 Published:2024-02-21
Contact: XUE Huiqin,E-mail: pyxhq@163.com

摘要/Abstract

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

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

中图分类号:

R725.9

赵晨玥, 蒋劲嵩, 张莉雪, 郭敏, 高景波, 孙夏瑜, 郭荣, 卢洪涌, 武坚锐, 薛慧琴. RTTN基因复合杂合变异导致原发性小头畸形家系分析并文献复习[J]. 中国儿童保健杂志, 2024, 32(2): 212-217.

ZHAO Chenyue, JIANG Jinsong, ZHANG Lixue, GUO Min, GAO Jingbo, SUN Xiayu, GUO Rong, LU Hongyong, WU Jianrui, XUE Huiqin. Family analysis of primary microcephaly caused by complex heterozygous variants of the RTTN gene and literature review[J]. Chinese Journal of Child Health Care, 2024, 32(2): 212-217.

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RTTN基因复合杂合变异导致原发性小头畸形家系分析并文献复习

Family analysis of primary microcephaly caused by complex heterozygous variants of the RTTN gene and literature review

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