Whole-genome sequencing in clinically diagnosed Charcot–Marie–Tooth disease undiagnosed by whole-exome sequencing

• Published in: Brain communications Vol. 5; no. 3; p. fcad139
• Main Authors: Kim, Young-gon, Kwon, Hyemi, Park, Jong-ho, Nam, Soo Hyun, Ha, Changhee, Shin, Sunghwan, Heo, Won Young, Kim, Hye Jin, Chung, Ki Wha, Jang, Ja-Hyun, Kim, Jong-Won, Choi, Byung-Ok
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 2023
• Subjects: Original; Charcot–Marie–Tooth disease; whole-exome sequencing; whole-genome sequencing; genotype-driven analysis
• ISSN: 2632-1297; 2632-1297
• DOI: 10.1093/braincomms/fcad139

Abstract Whole-genome sequencing is the most comprehensive form of next-generation sequencing method. We aimed to assess the additional diagnostic yield of whole-genome sequencing in patients with clinically diagnosed Charcot–Marie–Tooth disease when compared with whole-exome sequencing, which has not been reported in the literature. Whole-genome sequencing was performed on 72 families whose genetic cause of clinically diagnosed Charcot–Marie–Tooth disease was not revealed after the whole-exome sequencing and 17p12 duplication screening. Among the included families, 14 (19.4%) acquired genetic diagnoses that were compatible with their phenotypes. The most common factor that led to the additional diagnosis in the whole-genome sequencing was genotype-driven analysis (four families, 4/14), in which a wider range of genes, not limited to peripheral neuropathy-related genes, were analysed. Another four families acquired diagnosis due to the inherent advantage of whole-genome sequencing such as better coverage than the whole-exome sequencing (two families, 2/14), structural variants (one family, 1/14) and non-coding variants (one family, 1/14). In conclusion, an evident gain in diagnostic yield was obtained from whole-genome sequencing of the whole-exome sequencing-negative cases. A wide range of genes, not limited to inherited peripheral neuropathy-related genes, should be targeted during whole-genome sequencing. Kim et al. report the diagnostic yield of whole-genome sequencing from whole-exome sequencing-negative Charcot–Marie–Tooth disease patients. Among 72 families, 14 (19.4%) acquired genetic diagnosis by whole-genome sequencing. Whole-genome sequencing could be more widely used in the genetic diagnosis of Charcot–Marie–Tooth disease. Graphical Abstract Graphical abstract