Characterization of genotype\u2013phenotype correlation with MORC2 mutated Axonal Charcot\u2013Marie\u2013Tooth disease in a cohort of Chinese patients

Xiaohui Duan,Dongsheng Fan,Qing Sun,Zhenhua Cao,Xiaoxuan Liu,Min Xu,Yuwei Da,Weihong Gu,Yuting Zhang,Guochun Wang,Yuanyuan Chen,Shaojie Sun,Mingrui Dong,Jing Li,Wei Wang,Ying Hao,Renbin Wang

doi:10.1186/s13023-021-01881-7

Abstract

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.

Highlights

Charcot–Marie–Tooth (CMT) disease is an exciting field of study, with a growing number of causal genes and an expanding phenotypic spectrum
microrchidia family CW-type zinc finger 2 gene (MORC2) is a member of the MORC protein family (MORC1 to MORC4) in human, which shares four conserved domains, an N-terminal catalytically active ATPase module, a central CW-type zinc finger (CW-ZF) domain, a C-terminal chromo-like domain, and distinct coiled-coil (CC) domains [3, 4]
We reviewed the literature to further refine the clinical spectrum of MORC2-related neuropathies, to investigate the relationship between the genotype and the phenotype

Summary

Introduction

Charcot–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. In 2016, the microrchidia family CW-type zinc finger 2 gene (MORC2) was identified as a causative gene of autosomal dominant axonal Charcot–Marie–Tooth disease type 2Z (CMT2Z, MIM# 616688) in Spanish families [2]. MORC2 encodes a DNAdependent ATPase, which appears to be involved in many biological functions, such as DNA repair, transcriptional regulation, chromatin remodeling, and lipid homeostasis [5, 6]. These functions suggest several putative roles contributing to the development of axonal CMT

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