Abstract
We report the frequency, positive rate, and type of mutations in 14 genes (PMP22, GJB1, MPZ, MFN2, SH3TC2, GDAP1, NEFL, LITAF, GARS, HSPB1, FIG4, EGR2, PRX, and RAB7A) associated with Charcot–Marie–Tooth disease (CMT) in a cohort of 17,880 individuals referred to a commercial genetic testing laboratory. Deidentified results from sequencing assays and multiplex ligation-dependent probe amplification (MLPA) were analyzed including 100,102 Sanger sequencing, 2338 next-generation sequencing (NGS), and 21,990 MLPA assays. Genetic abnormalities were identified in 18.5% (n = 3312) of all individuals. Testing by Sanger and MLPA (n = 3216) showed that duplications (dup) (56.7%) or deletions (del) (21.9%) in the PMP22 gene accounted for the majority of positive findings followed by mutations in the GJB1 (6.7%), MPZ (5.3%), and MFN2 (4.3%) genes. GJB1 del and mutations in the remaining genes explained 5.3% of the abnormalities. Pathogenic mutations were distributed as follows: missense (70.6%), nonsense (14.3%), frameshift (8.7%), splicing (3.3%), in-frame deletions/insertions (1.8%), initiator methionine mutations (0.8%), and nonstop changes (0.5%). Mutation frequencies, positive rates, and the types of mutations were similar between tests performed by either Sanger (n = 17,377) or NGS (n = 503). Among patients with a positive genetic finding in a CMT-related gene, 94.9% were positive in one of four genes (PMP22, GJB1, MPZ, or MFN2).
Highlights
Charcot–Marie–Tooth disease (CMT) is a common, clinically heterogeneous group of inherited peripheral neuropathies with an estimated prevalence of 1 in 2500 individuals (Wiszniewski et al 2013)
Positive rate, and type of mutations in 14 genes (PMP22, GJB1, MPZ, MFN2, SH3TC2, GDAP1, NEFL, LITAF, GARS, HSPB1, FIG4, EGR2, PRX, and RAB7A) associated with Charcot–Marie–Tooth disease (CMT) in a cohort of 17,880 individuals referred to a commercial genetic testing laboratory
Mutation frequencies were similar for MPZ, differences were found between PMP22 copy number variations (CNVs) (78.6% vs. 70%) and GJB1 (6.7% vs. 12.0%), and MFN2 (4.3% of CMT vs. 33.0% CMT2;9.3% CMT)
Summary
Charcot–Marie–Tooth disease (CMT) is a common, clinically heterogeneous group of inherited peripheral neuropathies with an estimated prevalence of 1 in 2500 individuals (Wiszniewski et al 2013). The salient clinical features include an average onset at age 12, impaired tendon reflexes, a progressive weakness of distal musculature, and abnormalities of the peripheral nerve axon or its adjacent myelin sheath (De Jonghe et al 1997; Keller and Chance 1999; Nelis et al 1999). Research studies have shown that CMT is a complex molecular disorder with over a 1000 different putative mutations in 80 diseaseassociated genes (Timmerman et al 2014). 30 genes involved in axonal transport, myelin structure, and membrane metabolism have been found in multiple unrelated families or confirmed by functional studies (Saifi et al 2003; Saporta et al 2011). The large spectrum of genetically identifiable disease alleles complicates the molecular diagnosis, but a few genes account for over 90% of known genetic causes (Siskind et al 2013).
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
