D.P.5 Whole exome sequencing applied to Charcot–Marie–Tooth (CMT) disease

Charcot–Marie–Tooth disease (CMT) is a common inherited peripheral neuropathy associated with mutations in 54 known genes. CMT is characterized by distal wasting of the legs and later hands. Skeletal deformations are frequent including pes cavus and hammer toes. CMT is subdivided into three subtypes: CMT1 is demyelinating, CMT2 axonal, and intermediate CMT mixed. The clinical and molecular heterogeneity of this disease means many families remain without a molecular diagnosis. This proof of principal study aimed to investigate the use of whole exome sequencing (WES), allied with linkage analysis, to detect known or novel mutations in CMT families in which CMT1A had been excluded. We looked at three families, two dominant and one consanguineous. All other known CMT regions were excluded by linkage analysis in one dominant family; all CMT regions except MPZ, by homozygosity mapping in the consanguineous family. In both these families, WES excluded all known CMT genes including MPZ in the consanguineous family. This suggests the CMT genes in these two families are novel. The second dominant family presented with pes cavus and hammer toes in the first decade followed by difficulty in participation in sports in the second decade. Nerve conduction studies showed a severe sensorimotor axonal peripheral neuropathy. Linkage analysis excluded all known CMT genes except a 65 Mbp region on chromosome 16 including three known CMT genes. One of these, AARS (encoding alanyl-tRNA synthetase), fitted with the autosomal dominant inheritance in the family. WES of the proband identified a heterozygous variant, c.G986A (p.R329H) in AARS, which is a known pathogenic mutation. The variant was confirmed by Sanger sequencing in the proband and all other affected family members available, indicating the mutation is the cause of the disease in the family. Our study highlights the potential of WES in diagnostics and that more CMT genes remain to be found.