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Novel Pathogenic Variants in a French Cohort Widen the Mutational Spectrum of GNE Myopathy.

ABSTRACT: GNE myopathy is a rare autosomal recessively inherited muscle disease resulting from mutations in the gene encoding GNE (UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase), a key enzyme in sialic acid biosynthesis. 154 different pathogenic variants have been previously associated with GNE myopathy.Describe novel pathogenic variants associated with GNE myopathy in a large French cohort.We analyzed mutational data from 32 GNE myopathy index patients. Novel, as well as previously published pathogenic variants, were examined for possible deleterious effects on splicing.We describe 13 novel pathogenic variants in GNE, identified in the first large French cohort reported to date. We also find that 6 published pathogenic variants might have a previously unrecognized deleterious effect on splicing.Novel pathogenic GNE variants described here raise the total number of different pathogenic variants reported to 167, complementing the recently published GNE mutation update. Our novel findings on possible splice-disrupting effects by several variants suggest that the pathogenicity mechanism of these variants could be reinterpreted, expanding our knowledge about the GNE mutational spectrum.

SUBMITTER: Cerino M

PROVIDER: S-EPMC5278624 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Novel Pathogenic Variants in a French Cohort Widen the Mutational Spectrum of GNE Myopathy.

Cerino Mathieu M Gorokhova Svetlana S Béhin Anthony A Urtizberea Jon Andoni JA Kergourlay Virginie V Salvo Eric E Bernard Rafaëlle R Lévy Nicolas N Bartoli Marc M Krahn Martin M

Journal of neuromuscular diseases 20150601 2

<h4>Background</h4>GNE myopathy is a rare autosomal recessively inherited muscle disease resulting from mutations in the gene encoding GNE (UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase), a key enzyme in sialic acid biosynthesis. 154 different pathogenic variants have been previously associated with GNE myopathy.<h4>Objective</h4>Describe novel pathogenic variants associated with GNE myopathy in a large French cohort.<h4>Methods</h4>We analyzed mutational data from 32 GNE myopat ...[more]

PMID: 27858732

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Project description:BackgroundSpecific germline mutations in the hereditary breast-ovarian cancer susceptibility (HBC/HBOC) genes, BRCA1, BRCA2 and PALB2, have been shown to recur in French Canadians of Quebec, Canada, and this has been attributed to common ancestors. Germline TP53 mutation carriers are known to segregate in Li-Fraumeni syndrome families, which feature young age of onset breast cancer. We have reported rare TP53 mutation carriers in French Canadian HBC families, though none recurred possibly due to the limited number of cancer families investigated. Here we describe TP53 germline mutations found in French Canadian cancer families provided from hereditary cancer clinics; investigate 37 new BRCA1 and BRCA2 mutation-negative HBC/HBOC families for the TP53 mutations; and assess the frequency of TP53 mutations in a 1235 French Canadian breast cancer cases not selected for family history of cancer.MethodsTP53 mutation-positive pedigrees from French Canadian cancer families were provided from local hereditary cancer clinics. Bidirectional Sanger sequencing of all protein encoding exons of TP53 was performed using peripheral blood lymphocyte DNA from breast/ovarian cancer probands from 37 HBC/HBOC families of French Canadian descent. Targeted bidirectional Sanger sequencing assay of regions containing the identified TP53 mutations was performed on 1235 French Canadian breast cancer cases not selected for family history cancer.ResultsFive new TP53 mutations were identified in six pedigrees from hereditary cancer clinics. No deleterious mutations were identified in cancer probands from 37 HBC/HBOC families. A targeted mutation screen of the 1235 breast cancer cases identified a c.844C>T [p.Arg282Trp] mutation carrier. This mutation was also found among the six mutation-positive cancer families provided by the local hereditary cancer clinics. The targeted screen also uncovered a new TP53 mutation, c.685T>C [p.Cys229Arg] that was found in two breast cancer cases. All TP53 mutation carriers were among the 656 women with breast cancer diagnosed less than 50 years of age.ConclusionsIn all six new TP53 mutations were identified in French Canadians, where two each occurred in independently ascertained cases/families. Although all newly identified breast cancer mutation carriers reported a family history of cancer, none were consistent with features of Li-Fraumeni syndrome families.

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Novel Pathogenic Variants in a French Cohort Widen the Mutational Spectrum of GNE Myopathy.

Publications

Novel Pathogenic Variants in a French Cohort Widen the Mutational Spectrum of GNE Myopathy.

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