Delineating the genetic landscape of Charcot–Marie–tooth disease in Türkiye: Distinct distribution, rare phenotypes, and novel variants

Abstract Background Charcot–Marie‐Tooth (CMT) disease is the most common inherited neuropathy. In this study, we aimed to analyze the genetic spectrum and describe phenotypic features in a large cohort from Türkiye. Methods Demographic and clinical findings were recorded. Patients were initially screened for PMP22 duplication. Targeted sequencing or whole‐exome sequencing was performed in duplication‐negative patients. Results Overall, 311 patients from 265 families were included. Demyelinating CMT (67.4%) was more common than axonal (20.5%) and intermediate subtypes (11.7%). PMP22 duplication was the most frequent mutation, followed by pathogenic variants in GJB1 , MFN2 , SH3TC2 , and GDAP1 genes. MPZ ‐neuropathy was rare in our cohort (3.0%). Interestingly, CMT4 is the second most common type after CMT1. Lower extremity weakness and foot deformities were the most frequent presenting complaints. Striking clinical features included a high frequency of scoliosis in SH3TC2 , peripheral hyperexcitability in HINT1 , and central nervous system findings in GJB1 . Autosomal recessive CMT subtypes had higher CMTESv2 scores when compared to autosomal dominant ones (12.39 ± 4.81 vs. 8.36 ± 4.15, p : 0.023). Twenty‐one patients used wheelchairs during their last examination. Among them, 16 had an autosomal recessive subtype. Causative variants were identified in 31 genes, including 28 novel pathogenic or likely pathogenic changes. Conclusions Our findings provided robust data regarding the genetic distribution of CMT in Türkiye, which may pave the path for building population‐specific diagnostic gene panels. Rare autosomal recessive subtypes were relatively frequent in our cohort. By analyzing genotype–phenotype correlations, our data may provide clinical clues for clinicians.