Zhang Runfeng, Jia Peng, Yao Yanyi, Zhu Feng
College of Life Sciences, Hubei Normal University, Huangshi, China.
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Front Genet. 2022 Aug 25;13:933785. doi: 10.3389/fgene.2022.933785. eCollection 2022.
Mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH) is a rare genetic disorder that results in varying levels of pontocerebellar hypoplasia, microcephaly, and severe intellectual disabilities. Prior genetic analyses have identified the gene as a driver of MICPCH. Herein, we analyzed a Chinese family with MICPCH. The index patient was an 8-year-old male. He and his 3-year-old brother suffered from microcephaly, pontocerebellar hypoplasia, serious mental retardation, ataxia, gait disorder, and inability to speak. Through a combination of whole-exome sequencing and subsequent Sanger sequencing, a novel X-linked missense mutation, c.1882G>C (p.D628H) in the gene, was identified in two siblings, as well as their mother and grandmother, who exhibited mild mental retardation. Other family members with negative genetic testing were normal. analyses indicated that this missense mutation was predicted to reduce CASK protein stability, disrupt the SRC homology 3 (SH3) domain, and abolish its function. In summary, we identified a novel missense variate in CASK associated with MICPCH. Our work facilitates the diagnosis of the disease in this family and broadens the gene variant spectrum of the in MICPCH patients.
伴有脑桥和小脑发育不全的智力发育迟缓与小头畸形（MICPCH）是一种罕见的遗传性疾病，会导致不同程度的脑桥小脑发育不全、小头畸形和严重智力残疾。先前的基因分析已确定该基因是MICPCH的致病因素。在此，我们分析了一个患有MICPCH的中国家庭。先证者是一名8岁男性。他和他3岁的弟弟患有小头畸形、脑桥小脑发育不全、严重智力发育迟缓、共济失调、步态障碍和无法说话。通过全外显子组测序和随后的桑格测序相结合，在两名患病兄弟姐妹以及他们表现出轻度智力发育迟缓的母亲和祖母中，发现了该基因一个新的X连锁错义突变，即c.1882G>C（p.D628H）。其他基因检测为阴性的家庭成员表现正常。分析表明，该错义突变预计会降低CASK蛋白稳定性，破坏SRC同源3（SH3）结构域并使其功能丧失。总之，我们在CASK基因中鉴定出一个与MICPCH相关的新错义变异。我们的工作有助于该家庭中疾病的诊断，并拓宽了MICPCH患者中该基因变异谱。
