title: The allelic spectrum of Charcot-Marie-Tooth disease in over 17,000 individuals with neuropathy.
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).
authors.affiliation: Quest Diagnostics, Athena Diagnostics Marlborough, Massachusetts.
authors.forename: Christina
authors.initials: C
authors.lastname: DiVincenzo
authors.affiliation: Quest Diagnostics, Athena Diagnostics Marlborough, Massachusetts.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Elzinga
authors.affiliation: Quest Diagnostics, Athena Diagnostics Marlborough, Massachusetts.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Medeiros
authors.affiliation: Quest Diagnostics, Athena Diagnostics Marlborough, Massachusetts.
authors.forename: Izabela
authors.initials: I
authors.lastname: Karbassi
authors.affiliation: Quest Diagnostics, Athena Diagnostics Marlborough, Massachusetts.
authors.forename: Jeremiah R
authors.initials: JR
authors.lastname: Jones
authors.affiliation: Quest Diagnostics, Athena Diagnostics Marlborough, Massachusetts.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Evans
authors.affiliation: Quest Diagnostics, Athena Diagnostics Marlborough, Massachusetts.
authors.forename: Corey D
authors.initials: CD
authors.lastname: Braastad
authors.affiliation: Quest Diagnostics, Athena Diagnostics Marlborough, Massachusetts.
authors.forename: Crystal M
authors.initials: CM
authors.lastname: Bishop
authors.affiliation: Quest Diagnostics, Athena Diagnostics Marlborough, Massachusetts.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Jaremko
authors.affiliation: Quest Diagnostics, Athena Diagnostics Marlborough, Massachusetts.
authors.forename: Zhenyuan
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Quest Diagnostics, Athena Diagnostics Marlborough, Massachusetts.
authors.forename: Khalida
authors.initials: K
authors.lastname: Liaquat
authors.affiliation: Quest Diagnostics, Athena Diagnostics Marlborough, Massachusetts.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Hoffman
authors.affiliation: Quest Diagnostics, Athena Diagnostics Marlborough, Massachusetts.
authors.forename: Michelle D
authors.initials: MD
authors.lastname: York
authors.affiliation: Quest Diagnostics, Athena Diagnostics Marlborough, Massachusetts.
authors.forename: Sat D
authors.initials: SD
authors.lastname: Batish
authors.affiliation: Departments of Molecular and Human Genetics and Pediatrics, Baylor College of Medicine Houston, Texas.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: Quest Diagnostics, Athena Diagnostics Marlborough, Massachusetts.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Higgins
keywords: Charcot–Marie–Tooth disease; genetic testing; high-throughput nucleotide sequencing; molecular epidemiology; peripheral neuropathy