Clinical and molecular spectrum of an Iranian Charcot-Marie-Tooth 2T cohort, and the diagnostic importance of whole exome sequencing in identifying co-occurrence inherited disorders.

The late-onset axonal Charcot-Marie-Tooth type 2T (CMT2T) is a form of sensorimotor peripheral polyneuropathy caused by mutations in the membrane metalloendopeptidase (MME) gene and inherited either as an autosomal recessive (AR) or as an autosomal dominant (AD) manner with incomplete penetrance. Here, we describe the clinical presentations and genetic profiles of 11 unrelated Iranian families (15 cases) diagnosed with CMT2T. Whole exome sequencing (WES) was utilized to detect genetic variants, and Sanger sequencing was subsequently performed to validate the identified variants. Among our patients, 13 exhibited AR-CMT2T, whereas two presented AD-CMT2T. Altogether, six variants in MME were detected, four of which were novel. The known c.499T>A, the most prevalent, and c.1861T>C variants in total occurred in 7/11 families. Interestingly, in one patient, an additional likely-pathogenic variant was identified alongside the MME variant within the DNA2 gene. His muscle biopsy revealed mixed neurogenic and rimmed vacuole myopathic changes. Our findings highlight the clinical and genetic heterogeneity among CMT2T patients. The presence of both c.499T>A and c.1861T>C variants in multiple Iranian families suggests potential founder mutations. Furthermore, the evidence presented in our study underscores the importance of WES as a crucial diagnostic tool for detecting concomitant genetic disorders.