title: Rapid Identification of Pathogenic Variants in Two Cases of Charcot-Marie-Tooth Disease by Gene-Panel Sequencing.
abstract: Charcot-Marie-Tooth disease (CMT) is a common inherited peripheral neuropathy affecting up to 1 in 1214 of the general population with more than 60 nuclear genes implicated in its pathogenesis. Traditional molecular diagnostic pathways based on relative prevalence and clinical phenotyping are limited by long turnaround time, population-specific prevalence of causative variants and inability to assess multiple co-existing variants. In this study, a CMT gene panel comprising 27 genes was used to uncover the pathogenic mutations in two index patients. The first patient is a 15-year-old boy, born of consanguineous parents, who has had frequent trips and falls since infancy, and was later found to have inverted champagne bottle appearance of bilateral legs and foot drop. His elder sister is similarly affected. The second patient is a 37-year-old woman referred for pre-pregnancy genetic diagnosis. During early adulthood, she developed progressive lower limb weakness, difficulties in tip-toe walking and thinning of calf muscles. Both patients are clinically compatible with CMT, have undergone multiple genetic testings and have not previously received a definitive genetic diagnosis. Patients 1 and 2 were found to have pathogenic homozygousHSPB1:NM_001540:c.250G>A (p.G84R) variant and heterozygousGDAP1:NM_018972:c.358C>T (p.R120W) variant, respectively. Advantages and limitations of the current approach are discussed.
authors.affiliation: Department of Clinical Pathology, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong, China. hcc604@ha.org.hk.
authors.forename: Chi-Chun
authors.initials: CC
authors.lastname: Ho
authors.affiliation: Department of Paediatrics & Adolescent Medicine, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong, China. taism1@ha.org.hk.
authors.forename: Shuk-Mui
authors.initials: SM
authors.lastname: Tai
authors.affiliation: Department of Medicine, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong, China. leecn2@ha.org.hk.
authors.forename: Edmond Chi-Nam
authors.initials: EC
authors.lastname: Lee
authors.affiliation: Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China. timothy.mak@hku.hk.
authors.forename: Timothy Shin-Heng
authors.initials: TS
authors.lastname: Mak
authors.affiliation: Department of Paediatrics & Adolescent Medicine, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong, China. liukt1@ha.org.hk.
authors.forename: Timothy Kam-Tim
authors.initials: TK
authors.lastname: Liu
authors.affiliation: Department of Clinical Pathology, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong, China. tangwlv@ha.org.hk.
authors.forename: Victor Wai-Lun
authors.initials: VW
authors.lastname: Tang
authors.affiliation: Department of Clinical Pathology, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong, China. poonwt@ha.org.hk.
authors.forename: Wing-Tat
authors.initials: WT
authors.lastname: Poon
mesh_terms: D000293:Adolescent; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D008297:Male; D009154:Mutation; D055815:Young Adult
keywords: Charcot-Marie-Tooth disease (CMT); gene panel; hereditary motor and sensory neuropathy (HMSN); next-generation sequencing (NGS); pathogenic variants