The UMD-APC Database, a Model of Nation-Wide Knowledge Base: Update with Data from 3,581 Variations

International audienceFamilial adenomatous polyposis (FAP) is a rare autosomal-inherited disease that highly predisposes to colorectal cancer, characterized by a diffuse duodenal and colorectal polyposis associated with various extradigestive tumors and linked to germline mutations within the APC gene. A French consortium of laboratories involved in APC mutation screening has progressively improved the description of the variation spectrum, inferred functional significance of nontruncating variations, and delineated phenotypic characteristics of the disease. The current version of the UMD-APC database is described here. The total number of variations has risen to 5,453 representing 1,473 distinct variations. The published records initially registered into the database were extended with 3,581 germline variations found through genetic testing performed by the eight licensed laboratories belonging to the French APC network. Sixty six of 149 variations of previously unknown significance have now been classified as (likely) causal or neutral. The database is available on the Internet (http://www.umd.be/APC/) and updated twice per year according to the consensus rules of the network. The UMD-APC database is thus expected to facilitate functional classification of rare synonymous, nonsynonymous, and intronic mutations and consequently improve genetic counseling and medical care in FAP families

Insuffisance ovarienne prématurée chez deux patientes présentant une délétion Xq

National audienceObjet L’insuffisance ovarienne prématurée (IOP) est une pathologie caractérisée par une absence ou un arrêt de la fonction ovarienne normale avant l’âge de 40 ans. Elle peut se manifester par une aménorrhée ou par une ménopause précoce. Elle est caractérisée au niveau hormonal par un hypo-œstrogénisme avec augmentation de l’excrétion des hormones gonadotrophiques. Les étiologies sont très hétérogènes et les anomalies chromosomiques semblent représenter 15 à 20 % des causes rapportées. Neuf régions critiques (premature ovarian failure [POF] 1 à 9) ont été décrites dans la littérature dont les loci POF1 et POF2 localisées sur le bras long du chromosome X (Xq26-Xq28 et Xq13.3-Xq21.1, respectivement). Ces deux régions seraient porteuses de gènes impliqués dans le développement ovarien. Parmi les gènes candidats localisés au niveau de ces régions, outre FMR1 (Xq27.3), on peut retenir le gène DIAPH2 (Xq22), le gène XPNPEP2 (Xq25) et le gène ZFX (Xq22.2-Xp21.3). Méthode Des analyses cytogénétiques : caryotype en bandes RHG, analyse chromosomique par puce à ADN (ACPA) et FISH ont été réalisés chez 2 femmes présentant une IOP. Résultats La première patiente est porteuse d’une délétion terminale Xq27.2q28 d’environ 14,4 Mb, incluant POF1 dont le principal gène candidat est FMR1. La deuxième patiente est porteuse d’une duplication interstitielle Xq23.32q22.1 d’environ 8,4 Mb au niveau de POF2 avec le gène DIAPH2, et d’une délétion terminale Xq22.1q28 d’environ 53,5Mb incluant POF1. Ces deux remaniements sont localisés sur le même chromosome X et résultent d’un mécanisme d’inversion-délétion-duplication non médié par recombinaison homologue non allélique (NAHR). Discussion La présence d’une délétion Xq terminale impliquant POF1 chez ces deux patientes conforte le rôle de cette région dans la survenue d’une IOP. Par ailleurs, aucun cas d’inversion-délétion-duplication du bras long du chromosome X chez une femme présentant une IOP n’est rapporté dans la littérature. Une perte de fonction du gène DIAPH2 a quant à elle été décrite comme responsable d’IOP, cependant, le rôle d’une duplication impliquant POF2 et ce gène DIAPH2 reste à établi

Nonvisualization of fetal gallbladder increases the risk of cystic fibrosis.

International audienceOBJECTIVE: The aim of our study is to evaluate the prevalence of cystic fibrosis (CF) in fetuses referred for genetic testing because of ultrasonographic sign (nonvisualized fetal gallbladder--NVFGB). METHOD: We reviewed the results of CFTR gene analysis over the period 2002 to 2009 in all consecutive cases referred because of NVFGB in Western France. We correlated these data with the presence of a more classical ultrasonographic finding (fetal echogenic bowel - FEB). RESULTS: Cystic fibrosis was diagnosed in 5 of the 37 fetuses with NVFGB (13.5%, 95% confidence interval (CI): [2.5%; 24.5%]) and in only 9 of the 229 other cases referred because of FEB (3.9%, 95% CI: [3.2%; 14.7%]). In our series, all CF-affected fetuses with NVFGB also had FEB. The risk of CF was 11.6-fold higher in fetuses with both indications (NVFGB + FEB) than in fetuses with isolated FEB (45.5% vs 3.9%, RR = 11.6, 95% CI: [4.7%; 28.8%], p = 0.0001). We also estimated that the residual risk of CF was less than 1 in 68 (1.5%) when a single mutation was identified in the fetus by our molecular protocol. CONCLUSION: Ultrasonographic evidence of NVFGB is an additional risk factor for CF in cases with FEB

Highlighting the impact of cascade carrier testing in cystic fibrosis families

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Genomic variations integrated database for MUTYH -associated adenomatous polyposis

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CFTR mutation combinations producing frequent complex alleles with different clinical and functional outcomes

International audienceGenotype-phenotype correlations in cystic fibrosis (CF) may be difficult to establish because of phenotype variability, which is associated with certain CF transmembrane conductance regulator (CFTR) gene mutations and the existence of complex alleles. To elucidate the clinical significance of complex alleles involving p.Gly149Arg, p.Asp443Tyr, p.Gly576Ala, and p.Arg668Cys, we performed a collaborative genotype-phenotype correlation study, collected epidemiological data, and investigated structure-function relationships for single and natural complex mutants, p.[Gly576Ala;Arg668Cys], p.[Gly149Arg;Gly576Ala;Arg668Cys], and p.[Asp443Tyr;Gly576Ala;Arg668Cys]. Among 153 patients carrying at least one of these mutations, only three had classical CF and all carried p.Gly149Arg in the triple mutant. Sixty-four had isolated infertility and seven were healthy individuals with a severe mutation in trans, but none had p.Gly149Arg. Functional studies performed on all single and natural complex mutants showed that (1) p.Gly149Arg results in a severe misprocessing defect; (2) p.Asp443Tyr moderately alters CFTR maturation; and (3) p.Gly576Ala, a known splicing mutant, and p.Arg668Cys mildly alter CFTR chloride conductance. Overall, the results consistently show the contribution of p.Gly149Arg to the CF phenotype, and suggest that p.[Arg668Cys], p.[Gly576Ala;Arg668Cys], and p.[Asp443Tyr;Gly576Ala;Arg668Cys] are associated with CFTR-related disorders. The present study emphasizes the importance of comprehensive genotype-phenotype and functional studies in elucidating the impact of mutations on clinical phenotype

Multiexon skipping leading to an artificial DMD protein lacking amino acids from exons 45 through 55 could rescue up to 63% of patients with Duchenne muscular dystrophy.

International audienceApproximately two-thirds of Duchenne muscular dystrophy (DMD) patients show intragenic deletions ranging from one to several exons of the DMD gene and leading to a premature stop codon. Other deletions that maintain the translational reading frame of the gene result in the milder Becker muscular dystrophy (BMD) form of the disease. Thus the opportunity to transform a DMD phenotype into a BMD phenotype appeared as a new treatment strategy with the development of antisense oligonucleotides technology, which is able to induce an exon skipping at the pre-mRNA level in order to restore an open reading frame. Because the DMD gene contains 79 exons, thousands of potential transcripts could be produced by exon skipping and should be investigated. The conventional approach considers skipping of a single exon. Here we report the comparison of single- and multiple-exon skipping strategies based on bioinformatic analysis. By using the Universal Mutation Database (UMD)-DMD, we predict that an optimal multiexon skipping leading to the del45-55 artificial dystrophin (c.6439_8217del) could transform the DMD phenotype into the asymptomatic or mild BMD phenotype. This multiple-exon skipping could theoretically rescue up to 63% of DMD patients with a deletion, while the optimal monoskipping of exon 51 would rescue only 16% of patients