Mutations in ganglioside-induced differentiation-associated-protein 1 (GDAP1) have been associated with both subtypes of Charcot-Marie-Tooth (CMT) disease, autosomal recessive (CMT4A and AR-CMT2K) and autosomal dominant (AD-CMT2K). Over 80 different mutations have been identified so far. With the use of Sanger sequencing and Next Generation Sequencing (NGS) technologies, we screened a cohort of 306 unrelated Chinese CMT patients and identified 8 variants in the GDAP1 gene in 4 families, 5 of which were novel (R41H, N201Kfs*5, Q38X, V215I and Q38R). Application of Bioinformatics tool and classification according to the American College of Medical Genetics (ACMG) predicted them of being likely pathogenic with the exception of one variant of uncertain significance (VUS). In addition, we detected the presence of a single heterozygous variant of uncertain significance H256R in one additional family from the CMT cohorts. We found a GDAP1 prevalence rate of 1.63% (5/306). Three families (families 1, 2 and 3) were found to have an autosomal recessive (AR) pattern of inheritance while family 4 displayed an autosomal dominant (AD) mode of inheritance. Electro-physiologic studies revealed an axonal type of neuropathy (AR-CMT2K and AD-CMT2K) in all affected individuals. Clinical characteristics and findings in our study demonstrated that the recessive form presented earlier in life and exhibited severe symptoms and rapid evolution compared to the dominant form. We observed a marked intra-familial variability within the AD family in terms of age at disease onset, symptom severity and clinical progression. Our study expands the mutational spectrum of GDAP1-related CMT disease with the identification of new and unreported GDAP1 variants and demonstrates the predominance of the axonal form of neuropathy in CMT disease associated with GDAP1. We highlight the clinical characteristics associated with these genotypes and describe the relative frequency of GDAP1 variants amongst the Chinese population.
Keywords: AD-CMT2K; AR-CMT2K; CMT; GDAP1; Genotype; Phenotype.