Genetic landscape of Charcot-Marie-Tooth disease in Vietnam: A prospective multicenter study.

Background: In many developing regions, genetic data on Charcot-Marie-Tooth disease (CMT) remains scarce.

Objective: This study aimed to investigate the genetic landscape of CMT in Vietnam to guide the development of cost-effective diagnostic algorithms for patients with suspected genetic neuropathies.

Methods: We recruited 44 patients with a diagnosis of CMT from three tertiary centers between March 2021 and December 2023 and recorded their clinical and electrophysiological characteristics. All patients were analyzed for duplications or deletions of , , , and via multiplex ligation-dependent probe amplification (MLPA) and for 94 genes via targeted next-generation sequencing (NGS). The identified variants were classified per the American College of Medical Genetics and Genomics 2015 guidelines using VarSome, a bioinformatics engine.

Results: Among 44 patients, 24 carried a total of 26 variants. Of these 26 variants, 15 were (57.7%) pathogenic, 6 (23.1%) were likely pathogenic, and 5 (19.2%) were variants of uncertain significance (VUS). Excluding the VUS, the diagnostic yield of the targeted sequencing was 43.2% (19/44). Through MLPA, duplications were identified in 10 patients with the demyelinating type of CMT and 1 patient with the unclassified CMT type. The combined yield of MLPA and gene panels was 68.2% (30/44). We detected three novel pathogenic/likely pathogenic variants in , , and , as well as three novel VUS in , , and . may represent the most prevalent autosomal recessive gene associated with CMT in Vietnam.

Conclusions: We propose a sequential genetic testing approach for CMT in resource-limited settings, with the initial testing via MLPA for demyelinating CMT, followed by NGS for those who test negative. Our findings broaden the CMT genotype-phenotype profile of the Vietnamese population by identifying six novel candidate variants.