Dataset Information

Modifier Gene Candidates in Charcot-Marie-Tooth Disease Type 1A: A Case-Only Genome-Wide Association Study.

ABSTRACT: BACKGROUND:Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by a uniform 1.5-Mb duplication on chromosome 17p, which includes the PMP22 gene. Patients often present the classic neuropathy phenotype, but also with high clinical variability. OBJECTIVE:We aimed to identify genetic variants that are potentially associated with specific clinical outcomes in CMT1A. METHODS:We genotyped over 600,000 genomic markers using DNA samples from 971 CMT1A patients and performed a case-only genome-wide association study (GWAS) to identify potential genetic association in a subset of 644 individuals of European ancestry. A total of 14 clinical outcomes were analyzed in this study. RESULTS:The analyses yielded suggestive association signals in four clinical outcomes: difficulty with eating utensils (lead SNP rs4713376, chr6?:?30773314, P?=?9.91×10-7, odds ratio?=?3.288), hearing loss (lead SNP rs7720606, chr5?:?126551732, P?=?2.08×10-7, odds ratio?=?3.439), decreased ability to feel (lead SNP rs17629990, chr4?:?171224046, P?=?1.63×10-7, odds ratio?=?0.336), and CMT neuropathy score (lead SNP rs12137595, chr1?:?4094068, P?=?1.14×10-7, beta?=?3.014). CONCLUSIONS:While the results require validation in future genetic and functional studies, the detected association signals may point to novel genetic modifiers in CMT1A.

SUBMITTER: Tao F

PROVIDER: S-EPMC6597974 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Modifier Gene Candidates in Charcot-Marie-Tooth Disease Type 1A: A Case-Only Genome-Wide Association Study.

Tao Feifei F Beecham Gary W GW Rebelo Adriana P AP Blanton Susan H SH Moran John J JJ Lopez-Anido Camila C Svaren John J Abreu Lisa L Rizzo Devon D Kirk Callyn A CA Wu Xingyao X Feely Shawna S Verhamme Camiel C Saporta Mario A MA Herrmann David N DN Day John W JW Sumner Charlotte J CJ Lloyd Thomas E TE Li Jun J Yum Sabrina W SW Taroni Franco F Baas Frank F Choi Byung-Ok BO Pareyson Davide D Scherer Steven S SS Reilly Mary M MM Shy Michael E ME Züchner Stephan S

Journal of neuromuscular diseases 20190101 2

<h4>Background</h4>Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by a uniform 1.5-Mb duplication on chromosome 17p, which includes the PMP22 gene. Patients often present the classic neuropathy phenotype, but also with high clinical variability.<h4>Objective</h4>We aimed to identify genetic variants that are potentially associated with specific clinical outcomes in CMT1A.<h4>Methods</h4>We genotyped over 600,000 genomic markers using DNA samples from 971 CMT1A patients and performed a cas ...[more]

PMID: 30958311

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Project description:Charcot-Marie-Tooth disease type 1A, caused by a duplication of the gene peripheral myelin protein 22 kDa, is the most frequent subtype of hereditary peripheral neuropathy with an estimated prevalence of 1:5000. Patients suffer from sensory deficits, muscle weakness and foot deformities. There is no treatment approved for this disease. Outcome measures in clinical trials were based mainly on clinical features but did not evaluate the actual nerve damage. In our case-control study, we aimed to provide objective and reproducible outcome measures for future clinical trials. We collected skin samples from 48 patients with Charcot-Marie-Tooth type 1A, 7 patients with chronic inflammatory demyelinating polyneuropathy, 16 patients with small fibre neuropathy and 45 healthy controls. To analyse skin innervation, 40-µm cryosections of glabrous skin taken from the lateral index finger were double-labelled by immunofluorescence. The disease severity of patients with Charcot-Marie-Tooth type 1A was assessed by the Charcot-Marie-Tooth neuropathy version 2 score, which ranged from 3 (mild) to 27 (severe) and correlated with age (P < 0.01, R = 0.4). Intraepidermal nerve fibre density was reduced in patients with Charcot-Marie-Tooth type 1A compared with the healthy control group (P < 0.01) and negatively correlated with disease severity (P < 0.05, R = -0.293). Meissner corpuscle (MC) density correlated negatively with age in patients with Charcot-Marie-Tooth type 1A (P < 0.01, R = -0.45) but not in healthy controls (P = 0.07, R = 0.28). The density of Merkel cells was reduced in patients with Charcot-Marie-Tooth type 1A compared with healthy controls (P < 0.05). Furthermore, in patients with Charcot-Marie-Tooth type 1A, the fraction of denervated Merkel cells was highly increased and correlated with age (P < 0.05, R = 0.37). Analysis of nodes of Ranvier revealed shortened paranodes and a reduced fraction of long nodes in patients compared with healthy controls (both P < 0.001). Langerhans cell density was increased in chronic inflammatory demyelinating polyneuropathy, but not different in Charcot-Marie-Tooth type 1A compared with healthy controls. Our data suggest that intraepidermal nerve fibre density might be used as an outcome measure in Charcot-Marie-Tooth type 1A disease, as it correlates with disease severity. The densities of Meissner corpuscles and Merkel cells might be an additional tool for the evaluation of the disease progression. Analysis of follow-up biopsies will clarify the effects of Charcot-Marie-Tooth type 1A disease progression on cutaneous innervation.

Dataset Information

Modifier Gene Candidates in Charcot-Marie-Tooth Disease Type 1A: A Case-Only Genome-Wide Association Study.

Publications

Modifier Gene Candidates in Charcot-Marie-Tooth Disease Type 1A: A Case-Only Genome-Wide Association Study.

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