The objective of the study was to investigate the disease-causing mutation in an autosomal dominant Charcot-Marie-Tooth disease type 2 family and examine the clinical and histopathological evaluation. We enrolled a family of Korean origin with axonal Charcot-Marie-Tooth disease neuropathy (FC305; 13 males, six females) and applied genome-wide linkage analysis. Whole exome sequencing was performed for two patients. In addition, sural nerve biopsies were obtained from two patients. Through whole exome sequencing, we identified an average of 20,336 coding variants from two patients. We also found evidence of linkage mapped to chromosome 11p11-11q13.3 (LOD score of 3.6). Among these variants in the linkage region, we detected a novel p.S90W mutation in the Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) gene, after filtering 31 Korean control exomes. Our p.S90W patients had frequent sensory disturbances, pyramidal tract signs, and predominant right thenar muscle atrophy in comparison with reported p.S90L patients. The phenotypic spectra were wide and demonstrated intrafamilial variability. Two patients with different clinical features underwent sural nerve biopsies; the myelinated fiber densities were increased slightly in both patients, which differed from two previous case reports of BSCL2 mutations (p.S90L and p.N88S). This report expands the variability of the clinical spectrum associated with the BSCL2 gene and describes the first family with the p.S90W mutation.

Microsatellite markers are an essential tool for genetic linkage analysis because of their high polymorphism content. Four hundred commercially available markers covering the entire genome were genotyped from 578 sib individuals from 249 Korean families. Allelic frequencies and heterozygosities were determined for each marker loci and compared between Korean, Taiwanese, Japanese and Caucasian populations. In the three Asian populations, 10-13% of the markers had less than 0.6 heterozygosity, whereas in the Caucasian population, only 0.5% of the markers had less than 0.6 heterozygosity. Mean identical by descent (IBD) values were calculated for 578 sib individuals.Analysis of IBD values greater than 0.5 suggested that markers with low heterozygosity can also provide positive linkages, at least for the IBD sharing method of model-free linkage analysis. The data presented in this study will be a useful reference for genome-wide screens of Koreans and comparative studies with other ethnic populations.