Liu Chan, Xie Qingfeng, Hu Quan, Xiang Bingwu, Zhao Kaiyi, Chen Xiang, Zheng Feixia
Department of Physical Medicine and Rehabilitation Center, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Department of Pediatrics Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Front Genet. 2024 Aug 20;15:1405644. doi: 10.3389/fgene.2024.1405644. eCollection 2024.
Minichromosome maintenance complex component 3 associated protein () is a gene in which mutations can result in autosomal recessive peripheral neuropathy with or without impaired intellectual development. The genotype-phenotype correlation and prognosis remain unclear. The aim of this study was to explore the genotype-phenotype correlations pertaining to .
Whole-exome sequencing (WES) combined with copy number variation sequencing (CNV-seq) were performed on the genomic DNA isolated from a Chinese family, and Sanger sequencing, quantitative PCR and cDNA analyses were performed to examine the mutations. The retrospective study was conducted on 28 individuals with biallelic mutation-related diseases, including features such as mutations, motor development impairment, intellectual disability, weakness/atrophy, and cerebral magnetic resonance imaging abnormalities.
Sequencing identified novel compound heterozygous mutations in , namely, a paternal variant c.1_5426del (loss of exons 1-25) and a maternal splicing variant c.1858 + 3A>G. Functional studies revealed that the variant c.1858 + 3A>G resulted in the heterozygous deletion of exon 5, thereby affecting splicing functionality. Furthermore, the compound heterozygous mutation may affect the functionality of the protein domain. Retrospective analysis revealed different genotype-phenotype correlations for the pathogenic variants in biallelic : all individuals (100%) with mutations outside the Sac3 domain exhibited early-onset symptoms, motor developmental delays, and cognitive abnormalities, conversely, the proportions of individuals carrying mutations within the domain were 26.7% (motor delays) and 46.7% (cognitive abnormalities).
Our findings further expand the genetic mutation spectrum of biallelic and highlight the genotype-phenotype associations. Additionally, we elaborate on the importance of rehabilitation intervention.
微小染色体维持复合体组分3相关蛋白（）是一种基因，其突变可导致常染色体隐性周围神经病，伴或不伴有智力发育受损。该基因的基因型-表型相关性及预后仍不明确。本研究旨在探索与该基因相关的基因型-表型相关性。
对来自一个中国家庭的基因组DNA进行全外显子组测序（WES）联合拷贝数变异测序（CNV-seq），并进行桑格测序、定量PCR及cDNA分析以检测突变。对28例双等位基因突变相关疾病患者进行回顾性研究，这些患者具有突变、运动发育障碍、智力残疾、肌无力/萎缩及脑磁共振成像异常等特征。
测序鉴定出该基因新的复合杂合突变，即父源变异c.1_5426del（外显子1-25缺失）和母源剪接变异c.1858 + 3A>G。功能研究显示，变异c.1858 + 3A>G导致外显子5杂合缺失，从而影响剪接功能。此外，复合杂合突变可能影响蛋白结构域的功能。回顾性分析揭示双等位基因致病变异的不同基因型-表型相关性：所有（100%）Sac3结构域以外有突变的个体均表现为早发症状、运动发育迟缓及认知异常，相反，结构域内有突变的个体中，运动发育迟缓的比例为（26.7%），认知异常的比例为（46.7%）。
我们的研究结果进一步扩展了双等位基因的基因突变谱，并突出了基因型-表型关联。此外，我们阐述了康复干预的重要性。
