Charcot-Marie-Tooth disease (CMT) is one of the most common Mendelian disorders characterised by genetic heterogeneity, progressive distal muscle weakness and atrophy, foot deformities and distal sensory loss. In this report, we describe genetic testing data including comprehensive sequencing and copy number analysis of 34 CMT-related genes in a Canadian cohort of patients with suspected CMT. We have demonstrated a notable gender testing bias, with an overall diagnostic yield of 15% in males and 21% in females. We have identified a large number of novel pathogenic variants as well as variants of unknown clinical significance in CMT-related genes. In this largest to date analysis of gene CNVs in CMT, in addition to the common PMP22 deletion/duplication, we have described a significant contribution of pathogenic CNVs in several CMT-related genes. This study significantly expand the mutational spectrum of CMT genes, while demonstrating the clinical utility of a comprehensive sequence and copy number next-generation sequencing-based clinical genetic testing in patients with suspected diagnosis of CMT.
- clinical genetics
- genetic screening/counselling
- neuromuscular disease
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Contributors MV analysed data and drafted the manuscript. JK analysed data and contributed to drafting of manuscript, AS analysed data and contributed to drafting of manuscript. ML analysed data and contributed to drafting of manuscript. LIB contributed to drafting of manuscript. MAT contributed to drafting of manuscript. HL contributed to drafting of manuscript. PA contributed to drafting of manuscript. BS planned and oversaw the study and drafted the manuscript. All authors contributed to study conception and design and approved the final manuscript.
Funding This study was provided by the London Health Sciences Centre Pathology and Laboratory Medicine Research and Innovation Fund.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
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