Whole exome sequencing combined with linkage analysis identifies N88S and novel
S90W BSCL2 mutations in Charcot-Marie-Tooth families
Mi-Hyun Park1, Hae-Mi Woo1, Byung-Ok Choi2, Ki Wha Chung3, Soo Kyung Koo1
1
Division of Intractable Diseases, Center for Biomedical Sciences, National Institute of
Health, Cheongwon-Gun 363-951, Korea;
2
Department of Neurology, Ewha Womans
University School of Medicine, Seoul 158-710, Korea; 3Department of Biological Science and
Research Center for Biotechnology, Kongju National University, Gongju 314-701,
Chungnam, Korea
Charcot-Marie-Tooth disease (CMT) is a genetically and clinically heterogeneous hereditary
disorder involving motor and sensory peripheral neuropathies. We investigated the diseasecausing mutation in two unrelated families with autosomal dominant axonal CMT neuropathy
(FC51 and FC305) using exome sequencing in combination with linkage analysis, and we
examined the genotype-phenotype associations. Through whole exome sequencing, we
identified the average 20,152 coding variants from two individuals within each family. And
we also identified the evidences of linkage mapped to chromosome 11p11-11q13.3 with LOD
scores of 3.0 (FC51) and 3.6 (FC305), respectively. Among these variants in linkage region,
we detected two causative heterozygous mutations (N88S and S90W) of BSCL2 gene, after
filtering 31 Korean control exomes and integrating the results from the two individuals. The
clinical features of families were confirmed by electrophysiologic and pathologic findings.
Interestingly, patients of FC305 family with novel mutation (S90W) had similar sural nerve
histopathologic features, showing a distinct difference from previous reported mutations. We
demonstrate that exome sequencing is crucial for drawing more accurate genotype-phenotype
evaluating, and it could be efficiently applied to the genetic diagnostic testing and counseling
in a heterogeneous disorder. We also suggest that the identified mutation in BSCL2 expands
the phenotypic spectrum of this gene.