PT  - JOURNAL ARTICLE
AU  - Cortese, Andrea
AU  - Wilcox, Janel E.
AU  - Polke, James M.
AU  - Poh, Roy
AU  - Skorupinska, Mariola
AU  - Rossor, Alexander M.
AU  - Laura, Matilde
AU  - Tomaselli, Pedro J.
AU  - Houlden, Henry
AU  - Shy, Michael E.
AU  - Reilly, Mary M.
TI  - Targeted next-generation sequencing panels in the diagnosis of Charcot-Marie-Tooth disease
AID  - 10.1212/WNL.0000000000008672
DP  - 2020 Jan 07
TA  - Neurology
PG  - e51--e61
VI  - 94
IP  - 1
4099  - http://n.neurology.org/content/94/1/e51.short
4100  - http://n.neurology.org/content/94/1/e51.full
SO  - Neurology2020 Jan 07; 94
AB  - Objective To investigate the effectiveness of targeted next-generation sequencing (NGS) panels in achieving a molecular diagnosis in Charcot-Marie-Tooth disease (CMT) and related disorders in a clinical setting.Methods We prospectively enrolled 220 patients from 2 tertiary referral centers, one in London, United Kingdom (n = 120), and one in Iowa (n = 100), in whom a targeted CMT NGS panel had been requested as a diagnostic test. PMP22 duplication/deletion was previously excluded in demyelinating cases. We reviewed the genetic and clinical data upon completion of the diagnostic process.Results After targeted NGS sequencing, a definite molecular diagnosis, defined as a pathogenic or likely pathogenic variant, was reached in 30% of cases (n = 67). The diagnostic rate was similar in London (32%) and Iowa (29%). Variants of unknown significance were found in an additional 33% of cases. Mutations in GJB1, MFN2, and MPZ accounted for 39% of cases that received genetic confirmation, while the remainder of positive cases had mutations in diverse genes, including SH3TC2, GDAP1, IGHMBP2, LRSAM1, FDG4, and GARS, and another 12 less common genes. Copy number changes in PMP22, MPZ, MFN2, SH3TC2, and FDG4 were also accurately detected. A definite genetic diagnosis was more likely in cases with an early onset, a positive family history of neuropathy or consanguinity, and a demyelinating neuropathy.Conclusions NGS panels are effective tools in the diagnosis of CMT, leading to genetic confirmation in one-third of cases negative for PMP22 duplication/deletion, thus highlighting how rarer and previously undiagnosed subtypes represent a relevant part of the genetic landscape of CMT.CMT=Charcot-Marie-Tooth disease; CMTES=CMT examination score; CMTNS=Charcot-Marie-Tooth neuropathy score; dHMN=distal hereditary motor neuropathy; HSN=hereditary sensory neuropathy; MLPA=multiplex ligation-dependent probe amplification; NGS=next-generation sequencing; NHNN=National Hospital for Neurology and Neurosurgery; VUS=variants of unknown significance; WES=whole exome sequencing