Exome sequencing is an efficient tool for genetic screening of Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth disease (CMT) is one of the most common inherited neuropathies and is a genetically and clinically heterogeneous disorder with variable inheritance modes. As several molecules have been reported to have therapeutic effects on CMT, depending on the underlying genetic causes, exact genetic diagnostics have become very important for executing personalized therapy. Whole-exome sequencing has recently been introduced as an available method to identify rare or novel genetic defects from genetic disorders. Particularly, CMT is a model disease to apply exome sequencing because more than 50 genes (loci) are involved in its development with weak genotype-phenotype correlation. This study performed the exome sequencing in 25 unrelated CMT patients who revealed neither 17p12 duplication/deletion nor several major CMT genes. This study identified eight causative heterozygous mutations (32%). This detection rate seems rather high because each sample was tested before the study for major genetic causes. Therefore, this study suggests that the exome sequencing can be a highly exact, rapid, and economical molecular diagnostic tool for CMT patients who are tested for major genetic causes.

A novel Lys141Thr mutation in small heat shock protein 22 (HSPB8) gene in Charcot-Marie-Tooth disease type 2L.

Charcot-Marie-Tooth disease (CMT) is a group of clinically and genetically heterogeneous peripheral neuropathies. HSPB8 gene encodes heat shock protein 22 (HSP22) which belongs to the superfamily of small stress induced proteins. Mutations in HSPB8 are implicated to CMT2L and distal hereditary motor neuropathy 2A (dHMN2A). All three reported HSPB8 mutations are interestingly located in the Lys141 residue. In the present study, we examined a Korean axonal CMT patient who presented distal limb atrophy, sensory loss, areflexia, and axonal loss of large myelinated fibers. Whole exome sequencing identified a novel missense mutation c.422A>C (p.Lys141Thr) in HSPB8 as the underlying cause of the CMT2 patient. The mutation was regarded as a de novo case because both unaffected parents have no such mutation. The patient with HSPB8 mutation is the first case in Koreans. Clinical heterogeneities have been revealed in patients with Lys141 mutation; the present patient revealed similar phenotype of CMT2L. In addition, the lower limb MRI revealed a similarity between our HSPB8 and HSPB1 patients. It seems that the Lys141 site in the alpha-crystallin domain of HSPB8 is regarded as a mutational hot spot for peripheral neuropathy development, and mutations even in the same codon can exhibit different CMT phenotypes.

SET binding factor 1 (SBF1) mutation causes Charcot-Marie-Tooth disease type 4B3.

OBJECTIVE: To identify the genetic cause of an autosomal recessive demyelinating Charcot-Marie-Tooth disease type 4B (CMT4B) family. METHODS: We enrolled 14 members of a Korean family in which 3 individuals had demyelinating CMT4B phenotype and obtained distal sural nerve biopsies from all affected participants. We conducted exome sequencing on 6 samples (3 affected and 3 unaffected individuals). RESULTS: One pair of heterozygous missense mutations in the SET binding factor 1 (SBF1) gene (22q13.33), also called MTMR5, was identified as the underlying cause of the CMT4B family illness. Clinical phenotypes of affected study participants with CMT4B were similar, to some extent, to patients with CMT4B1 and CMT4B2. We found a similar loss of large myelinated fibers and focally folded myelin sheaths in our patients, but the actual number of myelinated fibers was different from CMT4B1 and CMT4B2. CONCLUSIONS: We suggest that the compound heterozygous mutations in SBF1 are the underlying causes of a novel CMT4B subtype, designated as CMT4B3. We believe that this study will lead to mechanistic studies to discover the function of SBF1 and to the development of molecular diagnostics for CMT disease.