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

ZHAO Chenyue; JIANG Jinsong; ZHANG Lixue; GUO Min; GAO Jingbo; SUN Xiayu; GUO Rong; LU Hongyong; WU Jianrui; XUE Huiqin

doi:10.11852/zgetbjzz2023-0521

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Chinese Journal of Child Health Care ›› 2024, Vol. 32 ›› Issue (2) : 212-217. DOI: 10.11852/zgetbjzz2023-0521

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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

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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

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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 https://doi.org/10.11852/zgetbjzz2023-0521

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