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

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

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.

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 PMP22, GJB1, MPZ, and MFN2 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.

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, PMP22 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 GJB1, INF2, and IGHMBP2, as well as three novel VUS in MPZ, PMP22, and INF2. IGHMBP2 may represent the most prevalent autosomal recessive gene associated with CMT in Vietnam.

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.