Novel Heterozygous Variant in a Child with Axonal Charcot-Marie-Tooth disease

Charcot-Marie-Tooth (CMT) disease comprises a genetically diverse range of disorders affecting the peripheral nervous system. We report an axonal CMT (CMT 2) case from India with a novel heterozygous variant of uncertain significance detected in the ganglioside-induced differentiation-associated protein 1 (GDAP1) gene. A 12-year-old male patient presented with severe distal lower limb weakness (bilateral foot drop) progressing proximally. Bilateral pes-cavus, high-steppage gait, reduced power in bilateral lower limbs, bilaterally absent ankle jerks, and no cerebellar or pyramidal signs/vocal cord paresis were salient clinical findings that suggested the clinical diagnosis of Hereditary motor and sensory neuropathy (HMSN)/CMT disease. Neurophysiological tests revealed axonal CMT. Genetic studies showed a novel heterozygous missense variant classified as a variant of uncertain significance in the GDAP1 gene. Although the causative role of the variant remained unclear, mutation in the GDAP1 gene, clinical features, and characteristic electrophysiological findings exhibiting axonal CMT supported the subtype diagnosis as probable CMT type 2K in the patient. The present report emphasizes the significance of clinical and neurophysiological findings in CMT when analyzing sequencing data in the era of next-generation sequencing, particularly when variant of uncertain significance are found.