Genotype and phenotype distribution of 435 patients with Charcot-Marie-Tooth disease from Central South China.

OBJECTIVE: To provide an overview of genotype and phenotype distribution in a cohort of patients with Charcot-Marie-Tooth disease (CMT) and related disorders from Central South China.

METHODS: We enrolled 435 patients and collected detailed clinical data. Multiplex ligation-dependent probe amplification for PMP22 duplication/deletion and CMT multi-gene panels sequencing were performed. Whole-exome sequencing was further applied in the remaining patients who failed to achieve molecular diagnosis.

RESULTS: Among the 435 patients, 216 had CMT1, 14 had HNPP, 178 had CMT2, 24 had dHMN and 3 had HSAN. The overall molecular diagnosis rate was 70%: 75.7% in CMT1, 100% in HNPP, 64.6% in CMT2, 41.7% in dHMN, and 33.3% in HSAN. The most common four genotypes accounted for 68.9% of molecular diagnosed patients. Relatively frequent causes were missense changes in PMP22 (4.6%) and SH3TC2 (2.3%) in CMT1; and GDAP1 (5.1%), IGHMBP2 (4.5%) and MORC2 (3.9%) in CMT2. Twenty out of 160 detected pathogenic variants and the associated phenotypes were not previously reported. Broad phenotype spectra were observed in six genes, among which the pathogenic variants in BAG3 and SPTLC1 were detected in two sporadic patients presenting with CMT2 phenotype.

CONCLUSIONS: Our results provided a unique genotypic and phenotypic landscape of patients with CMT and related disorders from Central South China, including relatively high proportion of CMT2 and lower occurrence of PMP22 duplication. The broad phenotype spectra in certain genes advanced our understanding of CMT.