Mutation, exome sequencing and linkage analyses in Turkish CMT families

Charcot-Marie-Tooth disease (CMT) also known as hereditary motor and sensory neuropathy (HMSN) is the most frequent inherited neuropathy. The patients with CMT generally have distal muscle weakness and atrophy in the peroneal muscles. In the first part of this study, GJB1, PRPS1, GDAP1 and SH3TC2 were screened for mutations in a total of 34 Turkish CMT patients. Four variations have been identified for GJB1, including two mutations in its 5?UTR. Two other variations identified were in GDAP1 and SH3TC2. Exome sequencing was performed for two families for which mutation analysis in the known CMT genes did not give a positive result. A novel variation was observed in the 5?UTR of GJB1 in one of these families. For the second family, whole genome linkage analysis was conducted since exome sequencing was not informative by itself. Combination of these two analyses helped to identify three candidate genes in the family. In the third part of the study, X chromosome linkage analysis was performed for four families. For three them, the analysis did not give any conclusive results. For the forth family, the locus linked to the disease was about 102 Mb that harbor about 1100 genes. Additional analysis should be performed for those families to identify the causative gene. This study contributed to the genetics of CMT with two major findings. First, the variations that were identified in the 5?UTR of GJB1 have been shown to cause the disease with a higher incidence than expected. Besides, known CMT genes were excluded in one family and consequently three candidate genes have been identified. Determination of the causative gene among these candidates with future studies is crucial in understanding the genetic basis and will help molecular diagnosis of the disease.