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ORIGINAL RESEARCH article

Front. Genet.
Sec. Genetics of Common and Rare Diseases
Volume 15 - 2024 | doi: 10.3389/fgene.2024.1405644

Identification of biallelic mutations in MCM3AP and comprehensive literature analysis

Provisionally accepted
Chan Liu Chan Liu 1*Qingfeng Xie Qingfeng Xie 1*Quan Hu Quan Hu 1*Bingwu Xiang Bingwu Xiang 1*Kaiyi Zhao Kaiyi Zhao 1*Xiang Chen Xiang Chen 1*Feixia Zheng Feixia Zheng 2*
  • 1 Department of Physical Medicine and Rehabilitation Center, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, wenzhou, China
  • 2 Department of Pediatrics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China

The final, formatted version of the article will be published soon.

    Background: Minichromosome maintenance complex component 3 associated protein (MCM3AP) is a gene in which mutations can result in autosomal recessive peripheral neuropathy with or without impaired intellectual development. The MCM3AP genotype-phenotype correlation and prognosis remain unclear. The aim of this study was to explore the genotype-phenotype correlations pertaining toMethods: Whole-exome sequencing (WES) combined with copy number variation sequencing (CNV-seq) were performed on the genomic DNA isolated from four members of a Chinese family, and quantitative PCR and cDNA analyses were performed to examine the mutations. The retrospective study was conducted on 28 individuals with biallelic MCM3AP mutation-related diseases, including features such as mutations, motor development impairment, intellectual disability, weakness/atrophy, and cerebral magnetic resonance imaging abnormalities.Results: Sequencing identified novel compound heterozygous mutations in MCM3AP, 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 MCM3AP: 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 MCM3AP and highlight the genotype-phenotype associations. Additionally, we elaborate on the importance of rehabilitation intervention.

    Keywords: peripheral neuropathy, Intellectual Disability, MCM3AP, GaNP, biallelic mutations

    Received: 23 Mar 2024; Accepted: 31 Jul 2024.

    Copyright: © 2024 Liu, Xie, Hu, Xiang, Zhao, Chen and Zheng. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Chan Liu, Department of Physical Medicine and Rehabilitation Center, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, wenzhou, China
    Qingfeng Xie, Department of Physical Medicine and Rehabilitation Center, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, wenzhou, China
    Quan Hu, Department of Physical Medicine and Rehabilitation Center, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, wenzhou, China
    Bingwu Xiang, Department of Physical Medicine and Rehabilitation Center, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, wenzhou, China
    Kaiyi Zhao, Department of Physical Medicine and Rehabilitation Center, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, wenzhou, China
    Xiang Chen, Department of Physical Medicine and Rehabilitation Center, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, wenzhou, China
    Feixia Zheng, Department of Pediatrics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325027, Zhejiang Province, China

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