Qi Na, Yang Ke, Lei Xingxing, Wang Fengyang, Wu Dong, Gao Yue, Zhang Yuwei, Liao Shixiu
Institute of Medical Genetics, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, China.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2023 Apr 10;40(4):408-412. doi: 10.3760/cma.j.cn511374-20220402-00224.
To explore the clinical features and genetic etiology of two children with intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia (MICPCH).
Two children with MICPCH who were presented at the Henan Provincial People's Hospital between April 2019 and December 2021 were selected as the study subjects. Clinical data of the two children were collected, along with peripheral venous blood samples of them and their parents, and amniotic fluid sample of the mother of child 1. Whole exome sequencing (WES), array-comparative genomic hybridization (aCGH) and real-time quantitative PCR (qPCR) were carried out for the children, their parents and the fetus. The pathogenicity of candidate variants were evaluated.
Child 1 was a 6-year-old girl featuring motor and language delay, whilst child 2 was a 4.5-year-old girl mainly featuring microcephaly and mental retardation. WES revealed that child 2 has harbored a 158.7 kb duplication in Xp11.4 (chrX: 41446160_41604854), which has encompassed exons 4~14 of the CASK gene. The same duplication was not found in either of her parents. aCGH revealed that child 1 has harbored a 29 kb deletion at Xp11.4 (chrX: 41637892_41666665), which encompassed exon 3 of the CASK gene. The same deletion was not found in either of her parents and the fetus. The above results were confirmed by qPCR assay. Above deletion and duplication were not found in the ExAC, 1000 Genomes and gnomAD databases. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were rated as likely pathogenic (PS2+PM2_Supporting).
The deletion of exon 3 and duplication of exons 4~14 of the CASK gene probably underlay the pathogenesis of MICPCH in these two children, respectively.
探讨两名患有智力发育障碍、小头畸形伴脑桥和小脑发育不全（MICPCH）儿童的临床特征及遗传病因。
选取2019年4月至2021年12月在河南省人民医院就诊的两名MICPCH患儿作为研究对象。收集两名患儿的临床资料，以及他们及其父母的外周静脉血样本，和患儿1母亲的羊水样本。对患儿、其父母及胎儿进行全外显子组测序（WES）、阵列比较基因组杂交（aCGH）和实时定量PCR（qPCR）。评估候选变异的致病性。
患儿1为6岁女孩，有运动和语言发育迟缓；患儿2为4.5岁女孩，主要表现为小头畸形和智力障碍。WES显示患儿2在Xp11.4（chrX: 41446160_41604854）存在158.7 kb的重复，该重复包含CASK基因的外显子4至14。其父母均未发现相同重复。aCGH显示患儿1在Xp11.4（chrX: 41637892_41666665）存在29 kb的缺失，该缺失包含CASK基因的外显子3。其父母及胎儿均未发现相同缺失。上述结果经qPCR检测得到证实。在ExAC、千人基因组和gnomAD数据库中均未发现上述缺失和重复。根据美国医学遗传学与基因组学学会（ACMG）的指南，两个变异均被评为可能致病（PS2+PM2_Supporting）。
CASK基因外显子3的缺失和外显子4至14的重复可能分别是这两名儿童MICPCH发病机制的基础。
