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

Abstract

Background 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. We aimed to describe the phenotypic-genetic spectrum of MORC2-related diseases in the Chinese population. Methods With 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. Results We 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. Conclusions Our 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.

Microrchidia CW-Type Zinc Finger 2, a Chromatin Modifier in a Spectrum of Peripheral Neuropathies

“…On the other side, the early onset SMA-like/DIGFAN syndrome characterized by central and peripheral nervous systems damage, and developmental anomalies. (Semplicini et al, 2017), p.Q400R (Ando et al, 2017), p.D466G (Duan et al, 2021;Sivera et al, 2021) were associated with a CMT2 scapuloperoneal phenotype, whereas p.R319C (Sivera et al, 2021), p.C407Y (Ando et al, 2017) were associated with a pure sensory-motor polyneuropathy without proximal involvement. This discrepancy in phenotype could be explained by a differential effect of the various mutations on MORC2 activity and/or by differences in the age of the patient at the time of examination.…”

“…direct sequencing in 52 unrelated probands, a de novo heterozygous missense mutation p.S87L was identified in a patient with infantile-onset SMA-like presentation associated with microcephaly, general weakness and areflexia (Sevilla et al, 2016). After this first report, clinicians re-examined sequencing data from patients with genetically unsolved neuropathies for mutations in MORC2 and identified a similar p.S87L mutation in two unrelated patients with infantile-onset SMA-like picture associated with generalized hypotonia, sensory loss, developmental delay, cataract, scoliosis, dysmorphic face (Hyun et al, 2016) or in one patient with scoliosis, cerebellar hypoplasia, and intellectual disability (Duan et al, 2021; Table 1). Besides the p.S87L mutation, patients with similar SMA-like picture were rapidly identified in two unrelated families with a de novo p.T424R (c.1271C > G) MORC2 mutation associated with cerebellar atrophy, diaphragmatic paralysis, developmental delay (Schottmann et al, 2016;Zanni et al, 2017).…”

Oncogenic MORC2 in cancer development and beyond

“…In the past decade, progress in genome-wide association studies has identified several independent genetic loci of MORC2 for diseases. For instance, MORC2 mutations are associated with some disorders, 34 , 35 , 36 including Charcot-Marie-Tooth (CMT) disease, 37 , 38 , 39 , 40 , 41 spinal muscular atrophy, 24 , 42 , 43 and neurological disorders, 44 especially Charcot-Marie-Tooth disease type 2Z (CMT2Z), 38 , 45 thus allowing a better understanding of the genetic architecture of MORC2. Mounting evidence has shown that mutations in MORC2 may be strongly associated with the development of multiple cancers.…”