Objective: To investigate the effectiveness of targeted NGS panels in achieving a molecular diagnosis in CMT and related disorders in a clinical setting Methods: We prospectively enrolled 220 patients from two tertiary referral centres, one in London, UK (n=120) and one in Iowa, US (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, MPZ accounted for 39% of cases who received genetic confirmation, while the remainder of positive cases had mutations in diverse genes, including SH3TC2, GDAP1, IGHMBP2, LRSAM1, FDG4, 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 the genetic confirmation in one third cases negative for PMP22 duplication/deletion, thus highlighting how rarer and previously undiagnosed subtypes represent today a relevant part of the genetic landscape of CMT.