Characterization of genotype–phenotype correlation with MORC2 mutated Axonal Charcot–Marie–Tooth disease in a cohort of Chinese patients

Orphanet Journal of Rare Diseases

Jing Li¹  Yuting Zhang¹  Xiaohui Duan²  Qing Sun²  Ying Hao²  Weihong Gu²  Wei Wang²  Yuanyuan Chen²  Renbin Wang²  Shaojie Sun²  Mingrui Dong²  Xiaoxuan Liu³  Dongsheng Fan³  Yuwei Da⁴  Min Xu⁴  Guochun Wang⁵  Zhenhua Cao⁶ 

[1] Department of Clinical Research Institute, China-Japan Friendship Hospital, 100029, Beijing, People’s Republic of China;Department of Neurology, China-Japan Friendship Hospital, 100029, Beijing, People’s Republic of China;Department of Neurology, Peking University Third Hospital, 100191, Beijing, People’s Republic of China;Department of Neurology, Xuanwu Hospital, Capital Medical University, Chang Chun Street, 100053, Beijing, People’s Republic of China;Department of Rheumatology and Immunology, China-Japan Friendship Hospital, 100029, Beijing, People’s Republic of China;Running Gene Inc., 100191, Beijing, People’s Republic of China;

关键词: Charcot–Marie–Tooth disease;    Spinal muscular atrophy;    MORC2;    Genotype;    Phenotype;    Whole-exome sequencing;   

DOI  :  10.1186/s13023-021-01881-7

来源: Springer

【 摘 要 】

BackgroundCharcot–Marie–Tooth (CMT) disease is an exciting field of study, with a growing number of causal genes and an expanding phenotypic spectrum. The microrchidia family CW-type zinc finger 2 gene (MORC2) was newly identified as a causative gene of CMT2Z in 2016. We aimed to describe the phenotypic-genetic spectrum of MORC2-related diseases in the Chinese population.MethodsWith the use of Sanger sequencing and Next Generation Sequencing (NGS) technologies, we screened a cohort of 284 unrelated Chinese CMT2 families. Pathogenicity assessments of MORC2 variants were interpreted according to the ACMG guidelines. Potential pathogenic variants were confirmed by Sanger sequencing.ResultsWe identified 4 different heterozygous MORC2 mutations in four unrelated families, accounting for 1.4% (4/284). A novel mutation c.1397A>G p. D466G was detected in family 1 and all affected patients presented with later onset axonal CMT with hyperCKemia. The patient in family 2 showed a spinal muscular atrophy (SMA)-like disease with cerebellar hypoplasia and mental retardation, with a hot spot de novo mutation c.260C>T p. S87L. The twin sisters in family 3 were identified as having the most common mutation c.754C>T p. R252W and suffered from axonal motor neuropathy with high variability in disease severity and duration. The patient in family 4 developed an early onset axonal motor and sensory neuropathy, with a reported mutation c.1220G>A p.C407Y. All identified mutations associated with MORC2-related neuropathies are localized in the N-terminal ATPase module.ConclusionsOur study confirmed that MORC2-related neuropathies exist in the Chinese population at a relatively high mutation rate. We revealed a complex genotype–phenotype correlation with MORC2 mutations. This report adds a new piece to the puzzle of the genetics of CMT and contributes to a better understanding of the disease mechanisms.

【 授权许可】

CC BY