Dataset Information

Hearing loss in inherited peripheral neuropathies: Molecular diagnosis by NGS in a French series.

ABSTRACT:

Background

The most common inherited peripheral neuropathy is Charcot-Marie-Tooth disease (CMT), with a prevalence of 1/2500. Other symptoms can be associated to the condition, such as hearing loss. Currently, no global hearing impairment assessment has been determined, and the physiopathology is not well known.

Methods

The aim of the study was to analyze among a French series of 3,412 patients with inherited peripheral neuropathy (IPN), the ones who also suffer from hearing loss, to establish phenotype-genotype correlations. An NGS strategy for IPN one side and nonsyndromic hearing loss (NSHL) on the other side, were performed.

Results

Hearing loss (HL) was present in only 44 patients (1.30%). The clinical data of 27 patients were usable. Demyelinating neuropathy was diagnosed in 15 cases and axonal neuropathy in 12 cases. HL varied from mild to profound. Five cases of auditory neuropathy were noticed. Diagnosis was made for 60% of these patients. Seven novel pathogenic variants were discovered in five different genes: PRPS1; MPZ; SH3TC2; NEFL; and ABHD12. Two patients with PMP22 variant, had also an additional variant in COCH and MYH14 respectively. No pathogenic variant was found at the DFNB1 locus. Genotype-phenotype correlations do exist, especially with SH3TC2, PRPS1, ABHD12, NEFL, and TRPV4.

Conclusion

Involvement of PMP22 is not enough to explain hearing loss in patients suffering from IPN. HL can be due to cochlear impairment and/or auditory nerve dysfunction. HL is certainly underdiagnosed, and should be evaluated in every patient suffering from IPN.

SUBMITTER: Lerat J

PROVIDER: S-EPMC6732311 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Publications

Hearing loss in inherited peripheral neuropathies: Molecular diagnosis by NGS in a French series.

Lerat Justine J Magdelaine Corinne C Roux Anne-Françoise AF Darnaud Léa L Beauvais-Dzugan Hélène H Naud Steven S Richard Laurence L Derouault Paco P Ghorab Karima K Magy Laurent L Vallat Jean-Michel JM Cintas Pascal P Bieth Eric E Arne-Bes Marie-Christine MC Goizet Cyril C Espil-Taris Caroline C Journel Hubert H Toutain Annick A Urtizberea Jon Andoni JA Boespflug-Tanguy Odile O Laffargue Fanny F Corcia Philippe P Pasquier Laurent L Fradin Mélanie M Napuri Sylva S Ciron Jonathan J Boulesteix Jean-Marc JM Sturtz Franck F Lia Anne-Sophie AS

Molecular genetics & genomic medicine 20190808 9

<h4>Background</h4>The most common inherited peripheral neuropathy is Charcot-Marie-Tooth disease (CMT), with a prevalence of 1/2500. Other symptoms can be associated to the condition, such as hearing loss. Currently, no global hearing impairment assessment has been determined, and the physiopathology is not well known.<h4>Methods</h4>The aim of the study was to analyze among a French series of 3,412 patients with inherited peripheral neuropathy (IPN), the ones who also suffer from hearing loss, ...[more]

PMID: 31393079

Similar Datasets

Project description:PurposeInherited peripheral neuropathies (IPN) represent a large heterogenous group of hereditary diseases with more than 100 causative genes reported to date. In this context, targeted next-generation sequencing (NGS) offers the opportunity to screen all these genes with high efficiency in order to unravel the genetic basis of the disease. Here, we compare the diagnostic yield of targeted NGS with our previous gene by gene Sanger sequencing strategy. We also describe several novel likely pathogenic variants.Design and participantsWe have completed the targeted NGS of 81 IPN genes in a cohort of 123 unrelated patients affected with diverse forms of IPNs, mostly Charcot-Marie-Tooth disease (CMT): 23% CMT1, 52% CMT2, 9% distal hereditary motor neuropathy, 7% hereditary sensory and autonomic neuropathy and 6.5% intermediate CMT.ResultsWe have solved the molecular diagnosis in 49 of 123 patients (~40%). Among the identified variants, 26 variants were already reported in the literature. In our cohort, the most frequently mutated genes are respectively: MFN2, SH3TC2, GDAP1, NEFL, GAN, KIF5A and AARS. Panel-based NGS was more efficient in familial cases than in sporadic cases (diagnostic yield 49%vs19%, respectively). NGS-based search for copy number variations, allowed the identification of three duplications in three patients and raised the diagnostic yield to 41%. This yield is two times higher than the one obtained previously by gene Sanger sequencing screening. The impact of panel-based NGS screening is particularly important for demyelinating CMT (CMT1) subtypes, for which the success rate reached 87% (36% only for axonal CMT2).ConclusionNGS allowed to identify causal mutations in a shorter and cost-effective time. Actually, targeted NGS is a well-suited strategy for efficient molecular diagnosis of IPNs. However, NGS leads to the identification of numerous variants of unknown significance, which interpretation requires interdisciplinary collaborations between molecular geneticists, clinicians and (neuro)pathologists.

Dataset Information

Hearing loss in inherited peripheral neuropathies: Molecular diagnosis by NGS in a French series.

Background

Methods

Results

Conclusion

Publications

Hearing loss in inherited peripheral neuropathies: Molecular diagnosis by NGS in a French series.

Similar Datasets

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