Clinical and histopathological study of Charcot-Marie-Tooth neuropathy with a novel S90W mutation in BSCL2

Abstract

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.

Comprehensive Analysis to Improve the Validation Rate for Single Nucleotide Variants Detected by Next-Generation Sequencing

“…To avoid sample-specific bias, we previously examined differences in the number or SNPQ value patterns of non-synonymous SNVs among 30 exome-seq data sets [14], [15], and observed no significant differences in distribution patterns of SNPQ value (Figure S1). …”

“…The study included 30 Korean Charcot-Marie-Tooth disease patients with whole exome data available from previous studies [14], [15]. Written informed consent was obtained from all Korean participants according to the protocol approved by the Institutional Review Board of Ewha Woman’s University (Mokdong Hospital) and Korea National Institute of Health (KNIH).…”

Missense mutations ofmitofusin 2in axonal Charcot–Marie–Tooth neuropathy: polymorphic or incomplete penetration?

“…In view of our new findings of normal MFN2 mutant carriers, the phenomenon of ''incomplete penetrance'' in the expression of this gene is now in question. Thus far, incomplete penetrance in CMT has been reported only for the BSCL2 gene where more than 20% of mutation carriers are asymptomatic or sub-clinically affected (Auer-Grumbach et al 2005;Cafforio et al 2008;Choi et al 2013).…”

BSCL2 S90L mutation in a Chinese family with Silver syndrome with a review of the literature

“…Interestingly, Silver syndrome is not the only phenotype of these mutations. Distal hereditary motor neuropathy V (dHMN V) and CharcotMarie-Tooth disease type 2 (CMT2) have also been reported [3][4][5][6]. We report, to our knowledge, the first Chinese family with Silver syndrome associated with the BSCL2 S90L mutation and review the clinical phenotypes of S90L.…”