Targeted next-generation sequencing panels in the diagnosis of Charcot-Marie-Tooth disease.

Abstract

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. 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. <i>PMP22</i> duplication/deletion was previously excluded in demyelinating cases. We reviewed the genetic and clinical data upon completion of the diagnostic process. 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 <i>GJB1</i>, <i>MFN2</i>, and <i>MPZ</i> accounted for 39% of cases that received genetic confirmation, while the remainder of positive cases had mutations in diverse genes, including <i>SH3TC2</i>, <i>GDAP1</i>, <i>IGHMBP2</i>, <i>LRSAM1</i>, <i>FDG4</i>, and <i>GARS</i>, and another 12 less common genes. Copy number changes in <i>PMP22</i>, <i>MPZ</i>, <i>MFN2</i>, <i>SH3TC2</i>, and <i>FDG4</i> 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. NGS panels are effective tools in the diagnosis of CMT, leading to genetic confirmation in one-third of cases negative for <i>PMP22</i> duplication/deletion, thus highlighting how rarer and previously undiagnosed subtypes represent a relevant part of the genetic landscape of CMT.