Cohort Analysis of 67 Charcot-Marie-Tooth Italian Patients: Identification of New Mutations and Broadening of Phenotype Expression Produced by Rare Variants

Abstract

Charcot-Marie-Tooth (CMT) disease is the most prevalent inherited motor sensory neuropathy, which clusters a clinically and genetically heterogeneous group of disorders with more than 90 genes associated with different phenotypes. The goal of this study is to identify the genetic features in the recruited cohort of patients, highlighting the role of rare variants in the genotype-phenotype correlation. We enrolled 67 patients and applied a diagnostic protocol including multiple ligation-dependent probe amplification for copy number variation (CNV) detection of PMP22 locus, and next-generation sequencing (NGS) for sequencing of 47 genes known to be associated with CMT and routinely screened in medical genetics. This approach allowed the identification of 26 patients carrying a whole gene CNV of PMP22. In the remaining 41 patients, NGS identified the causative variants in eight patients in the genes HSPB1, MFN2, KIF1A, GDAP1, MTMR2, SH3TC2, KIF5A, and MPZ (five new vs. three previously reported variants; three sporadic vs. five familial variants). Familial segregation analysis allowed to correctly interpret two variants, initially reported as “variants of uncertain significance” but re-classified as pathological. In this cohort is reported a patient carrying a novel familial mutation in the tail domain of KIF5A [a protein domain previously associated with familial amyotrophic lateral sclerosis (ALS)], and a CMT patient carrying a HSPB1 mutation, previously reported in ALS. These data indicate that combined tools for gene association in medical genetics allow dissecting unexpected phenotypes associated with previously known or unknown genotypes, thus broadening the phenotype expression produced by either pathogenic or undefined variants.Clinical trial registration: ClinicalTrials.gov (NCT03084224).

Mutational screening of Greek patients with axonal Charcot‐Marie‐Tooth disease using targeted next‐generation sequencing: Clinical and molecular spectrum delineation

“…The mutation hit‐rate of 33.3% compares favourably with other studies that have screened similar axonal CMT cohorts with larger NGS gene panels, which included the genes presently screened for. These studies have reported diagnostic yields of 20.7%–44.5% 17–23 . This confirms that a substantial proportion of CMT2 cases are caused by a relatively small number of genes 4 …”

“…These studies have reported diagnostic yields of 20.7%-44.5%. [17][18][19][20][21][22][23] This confirms that a substantial proportion of CMT2 cases are caused by a relatively small number of genes. 4 The most frequently involved genes were GJB1 (11.7%), MPZ (5%) MFN2 (5%), DNM2 (3.3%) and LRSAM1 (3.3%).…”

Phosphatidylinositol 3,5-bisphosphate facilitates axonal vesicle transport and presynapse assembly

“…Mutations in KIF1A are linked to epilepsy, hereditary spastic paraplegia [a rare gait disorder caused by axonal defects or axonal degeneration in the spinal cord ( 53 – 55 )], and the peripheral neuropathy Charcot-Marie-Tooth disease ( 56 ). We thus speculate that defects in PI(3,5)P 2 -regulated axonal PV transport may be linked to some of these rare inherited neurological disorders and peripheral neuropathies.…”

Genetic Workup for Charcot–Marie–Tooth Neuropathy: A Retrospective Single-Site Experience Covering 15 Years

“…This approach has been transformed by the advent of NGS, where several disease-associated genes are tested in parallel. Nevertheless, the diagnostic rate of massive parallel sequencing tests described in the literature ranges from 4.6% to 93%, according to the analyzed cohort [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. In routine clinical practice, the NGS approach more realistically allows us to reach a genetic diagnosis in 30% of genetically undetermined patients when PMP22 duplication has been previously ruled out [ 32 ].…”