A Family With X-Linked Charcot-Marie-Tooth Disease Type 1: A Case for Reclassifying a Variant of Uncertain Significance in GJB1and Review of the Literature.

Objectives: X-linked Charcot-Marie-Tooth disease Type 1 (CMTX1), caused by gap junction beta-1 (GJB1) mutations, is the second most common form of CMT. Patients present with length-dependent sensorimotor polyneuropathy and split hand syndrome. Males are more severely affected; females show variable symptoms because of skewed X-inactivation. This study reclassifies a GJB1 variant of uncertain significance as pathogenic using American College of Medical Genetics criteria.

Methods: A family with neurologic symptoms underwent clinical evaluation, electrodiagnostic studies, genetic testing, and imaging.

Results: Affected individuals exhibited a sensorimotor polyneuropathy in an X-linked inheritance pattern with males having earlier, more severe symptoms. Characteristic findings included split hand syndrome and the suggestion of stroke-like episodes. Genetic testing revealed a GJB1 c.841T>C p.(Ser281Pro) variant. Analysis met American College of Medical Genetics criteria (1 strong, 3 moderate, 1 supporting) for pathogenicity.

Conclusions: The Ser281Pro GJB1 variant meets pathogenic criteria for CMTX1, extending known pathogenic regions beyond the C-terminal Arg220 codon.