Oluwole Oluwafemi G
Biomedical Research Centre, Nuffield Department of Medicine, Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.
Division of Human Genetics, University of Cape Town, Cape Town, South Africa.
Open Med (Wars). 2024 Feb 29;19(1):20240917. doi: 10.1515/med-2024-0917. eCollection 2024.
Causal mutations in the MCPH1 gene have been associated with disorders like microcephaly, and recently congenital hearing impairment. This study examined the MCPH1 DNA repair machinery and identified genetic variations of interest in gnomAD database to discuss the biological roles and effects of rare variants in MCPH1-related diseases. Notably, MCPH1 coordinates two of the seven known mechanisms of DNA repair which confirmed its roles in neurogenesis and chromatin condensation. A pathogenic missense variant in MCPH1 p.Gly753Arg, and two pathogenic frameshifts MCPH1 p.Asn189LysfsTer15 and p.Cys624Ter identified in this study, already had entries in ClinVar and were associated with microcephaly. A pathogenic frameshift in MCPH1 p.Val10SerfsTer5 with a loss-of-function flag and a pathogenic stop gained p.Ser571Ter variants with ultra-rare allele frequency (MAF ≤ 0.001) were identified but have not been linked to any phenotype. The predicted pathogenic ultra-rare variants identified in this study, warranty phenotypic discovery, and also positioned these variants or nearby deleterious variants candidate for screening in MCPH1-associated rare diseases.
MCPH1基因中的致病变异与小头畸形等疾病有关，最近还与先天性听力障碍有关。本研究检测了MCPH1的DNA修复机制，并在gnomAD数据库中鉴定了感兴趣的基因变异，以探讨MCPH1相关疾病中罕见变异的生物学作用和影响。值得注意的是，MCPH1协调了七种已知DNA修复机制中的两种，这证实了其在神经发生和染色质浓缩中的作用。本研究中鉴定出的MCPH1 p.Gly753Arg致病性错义变异以及两个致病性移码突变MCPH1 p.Asn189LysfsTer15和p.Cys624Ter，已在ClinVar中登记，并与小头畸形有关。鉴定出了具有功能丧失标记的MCPH1 p.Val10SerfsTer5致病性移码突变以及具有超罕见等位基因频率（MAF≤0.001）的致病性终止获得性p.Ser571Ter变异，但尚未发现它们与任何表型相关。本研究中鉴定出的预测致病性超罕见变异值得进行表型发现，同时也将这些变异或附近的有害变异定位为MCPH1相关罕见疾病筛查的候选对象。
