Data from: Targeted next-generation sequencing panels in the diagnosis of Charcot Marie Tooth disease

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.