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

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. 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 , , and accounted for 39% of cases that received genetic confirmation, while the remainder of positive cases had mutations in diverse genes, including , , , , , and , and another 12 less common genes. Copy number changes in , , , , and 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 duplication/deletion, thus highlighting how rarer and previously undiagnosed subtypes represent a relevant part of the genetic landscape of CMT.