Clinical and genetic analysis of two children with intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia
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目的 探讨2例智力障碍和小头畸形伴脑桥和小脑发育不全(MICPCH)患儿的临床特征与遗传学病因。 方法 选取2019年4月至2021年12月期间于河南省人民医院就诊的2例MICPCH患儿为研究对象。收集患儿的临床资料，采集患儿及其父母的外周静脉血样和患儿1母亲的羊水样本，用全外显子组测序(WES)、微阵列比较基因组杂交(aCGH)与荧光定量PCR(qPCR)对2例患儿及其父母、患儿1母亲的胎儿进行检测，对候选变异进行致病性分析。 结果 患儿1为6岁女性，主要临床表现为运动与语言发育迟缓；患儿2为4岁半女性，主要临床表现为小头畸形与智力低下。WES检测结果显示患儿2的CASK基因第4 ~ 14外显子区域(chrX：41446160_41604854)存在158.7 kb重复，其父母均未见该变异，提示为新发变异；aCGH检测结果显示患儿1的CASK基因第3外显子区域(chrX: 41637892_41666665)存在29 kb缺失，其父母和母亲的胎儿均未见该变异，提示为新发变异；qPCR检测结果进一步证实了WES与aCGH的检测结果。CASK基因第3外显子区域(chrX: 41637892_41666665)缺失与第4 ~ 14外显子区域(chrX：41446160_41604854)重复在ExAC、1000 Genomes及gnomAD等数据库中均未见收录，根据美国医学遗传学与基因组学学会(ACMG)相关指南，二者均被评级为可能致病性变异(PS2+PM2_Supporting)。 结论 CASK基因第3外显子区(chrX: 41637892_41666665)的缺失与第4 ~ 14外显子区(chrX：41446160_41604854)的重复可能分别是2例患儿的遗传学病因。上述结果为患儿的确诊提供了依据。 Objective To explore the clinical features and genetic etiology of two children with intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia (MICPCH). Methods 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 quantitative PCR (qPCR) were carried out for the children, their parents and the fetus. The pathogenicity of candidate variants were evaluated. Results 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). Conclusion 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.
Objective To explore the clinical features and genetic etiology of two children with intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia (MICPCH). Methods 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 quantitative PCR (qPCR) were carried out for the children, their parents and the fetus. The pathogenicity of candidate variants were evaluated. Results 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). Conclusion 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.
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