Wide phenotypic variations in Charcot-Marie-Tooth 1A neuropathy with rare copy number variations on 17p12

Abstract

Charcot-Marie-Tooth disease (CMT) is clinically heterogeneous hereditary motor and sensory neuropathies with genetic heterogeneity, age-dependent penetrance, and variable expressivity. Rare copy number variations by nonrecurrent rearrangements have recently been suggested to be associated with Charcot-Marie-Tooth 1A (CMT1A) neuropathy. In our previous study, we found three Korean CMT1A families with rare copy number variations (CNVs) on 17p12 by nonrecurrent rearrangement. Careful clinical examinations were performed in all the affected individuals with rare CNVs (n 019), which may be the first full study of a subject from a large CMT1A family with nonrecurrent rearrangement. The clinical phenotype showed no significant difference compared with common CMT1A patients, but with variable phenotypes. In particular, a broad intrafamilial phenotypic spectrum was observed within the same family, which may suggest the existence of a genetic modifier. This study may broaden the understanding of the role of CNVs in the pathogenesis of CMT.

Investigating Mutations of 288 Genes in a Family with Charcot-Marie-Tooth Disease by the Whole-Exome Sequencing Method in Khuzestan Province

“…Additionally, CMT is often categorized into 2 main types: CMT1 (demyelinating) and CMT2 (axonal), distinguished based on upper limb motor conduction velocities (MCV) (4). The molecular diagnosis of CMT poses significant challenges due to several key factors: (1) the diverse manifestations resulting from a single mutation, (2) the complex genetic spectrum of etiology, and (3) the considerable overlap in symptoms with amyotrophic diseases (5,6). These complexities highlight the intricate nature of CMT and emphasize the need for sophisticated diagnostic approaches to address its multifaceted genetic and clinical presentation.…”

A study concept of expeditious clinical enrollment for genetic modifier studies in Charcot–Marie–Tooth neuropathy 1A

“…[11][12][13][14] CMT1A is usually dominantly inherited, but 10%-20% of CMT1A patients seen in clinic have de novo duplications. [15][16][17] PMP22 is an integral membrane protein highly expressed by myelinating Schwann cells and is localized to compact myelin. [18][19][20] Three copies of PMP22 lead to an overexpression of the PMP22 protein, causing destabilization of the myelin sheath and leading to demyelination and secondary axonal loss.…”

“…In nearly all patients, CMT1A is caused by a recurrent 1.5 Mb duplication caused by nonallelic homologous recombination which contains the gene encoding peripheral myelin protein 22 (PMP22) on chromosome 17p11.2 11–14 . CMT1A is usually dominantly inherited, but 10%–20% of CMT1A patients seen in clinic have de novo duplications 15–17 …”

Genotype–phenotype characteristics of Vietnamese patients diagnosed with Charcot–Marie–Tooth disease

“…CMT is traditionally classified into two types, CMT1 (demyelinating) and CMT2 (axonal), based on upper limb motor conduction velocities (MCV) (Pareyson & Marchesi, 2009 ). The molecular diagnosis of CMT remains challenging because of (i) the diverse phenotypes of a single mutation, (ii) the complex causal genetic spectrum, and (iii) the highly overlapping phenotypes between amyotrophic diseases (Kanwal et al., 2011 ; Mersiyanova et al., 2000 ; Pipis et al., 2019 ; Szigeti & Lupski, 2009 ). These factors reflect the clinically and genetically heterogeneous nature of CMT.…”