Extreme multifunctional proteins identified from a human protein interaction network.

International audienceMoonlighting proteins are a subclass of multifunctional proteins whose functions are unrelated. Although they may play important roles in cells, there has been no large-scale method to identify them, nor any effort to characterize them as a group. Here, we propose the first method for the identification of 'extreme multifunctional' proteins from an interactome as a first step to characterize moonlighting proteins. By combining network topological information with protein annotations, we identify 430 extreme multifunctional proteins (3% of the human interactome). We show that the candidates form a distinct subgroup of proteins, characterized by specific features, which form a signature of extreme multi-functionality. Overall, extreme multifunctional proteins are enriched in linear motifs and less intrinsically disordered than network hubs. We also provide MoonDB, a database containing information on all the candidates identified in the analysis and a set of manually curated human moonlighting proteins

OISO, traitement informatisé de la prise en charge en oncogénétique clinique

International audienceOncogenetics is a long-term process, which requires a close relation between patients and medical teams, good familial links allowing lifetime follow-up. Numerous documents are exchanged in between the medical team, which has to frequently interact. We present here a new tool that has been conceived specifically for this management

Clinical Significance of Aortic Root Modification Associated With Bicuspid Aortic Valve in Marfan Syndrome.

International audienceBACKGROUND:Both bicuspid aortic valve (BAV) and Marfan syndrome have been associated with aortic dissection risk, but it is unknown whether the presence of BAV is associated with an increased aortic risk in patients with an FBN1 gene mutation. We evaluated aortic diameters, aortic valve function, and aortic shape in Marfan syndrome patients with and without BAV and reported aortic events during follow-up.METHODS:All patients with an FBN1 gene mutation evaluated in our clinic were included. Aortic root diameters were measured, and the aortic valve was studied using echocardiography at each visit.RESULTS:Of the 1437 patients with an FBN1 gene mutation, 26 patients (1.8%) had a BAV. Both aortic root maximal diameter and normalized Z score were larger at all ages, in patients with BAV when compared with patients with tricuspid aortic valve. Prophylactic aortic root surgery tended to be performed in younger patients when BAV was present, although aortic diameter threshold was similar in the 2 populations. No aortic dissection was observed in Marfan syndrome patients with BAV.CONCLUSIONS:In patients with a FBN1 mutation, BAV is associated with larger aortic root diameter, with no difference in evolution of Z score with age. We found a trend towards prophylactic aortic root surgery at younger ages but similar aortic diameter thresholds without occurrence of aortic dissection. We did not find any evidence for lowering aortic diameter thresholds used to propose preventive aortic root surgery in the presence of BAV in patients with FBN1 mutations

WES/WGS Reporting of Mutations from Cardiovascular "Actionable" Genes in Clinical Practice: A Key Role for UMD Knowledgebases in the Era of Big Databases

International audienceHigh-throughput next-generation sequencing such as whole-exome and whole-genome sequencing are being rapidly integrated into clinical practice. The use of these techniques leads to the identification of secondary variants for which decisions about the reporting or not to the patient need to be made. The American College of Medical Genetics and Genomics recently published recommendations for the reporting of these variants in clinical practice for 56 "actionable" genes. Among these, seven are involved in Marfan Syndrome And Related Disorders (MSARD) resulting from mutations of the FBN1, TGFBR1 and 2, ACTA2, SMAD3, MYH11 and MYLK genes. Here, we show that mutations collected in UMD databases for MSARD genes (UMD-MSARD) are rarely reported, including the most frequent ones, in global scale initiatives for variant annotation such as the NHLBI GO Exome Sequencing Project (ESP), the Exome Aggregation Consortium (ExAC), and ClinVar. The predicted pathogenic mutations reported in global scale initiatives but absent in locus-specific databases (LSDBs) mainly correspond to rare events. UMD-MSARD databases are therefore the only resources providing access to the full spectrum of known pathogenic mutations. They are the most comprehensive resources for clinicians and geneticists to interpret MSARD-related variations not only primary variants but also secondary variants

UMD-MEN1 database: an overview of the 370 MEN1 variants present in 1,676 patients from the French population

IF 5.789International audienceContext: Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant disease caused by mutations in the MEN1 gene characterized by a broad spectrum of clinical manifestations, of which the most frequent are primary hyperparathyroidism, pituitary adenomas, and neuroendocrine tumors. Objective: The aim of this work is to facilitate interpretation of variants and improve the genetic counseling and medical care of MEN1-patients’ families. Design, Setting, and Patients: The TENGEN network (French oncogenetics network of neuroendocrine tumors) has interpreted and collected all allelic variants and clinical characteristics of the MEN1-positive patients identified through genetic testing performed in the French population from 1997 to 2015. They were registered in a locus-specific database called the UMD-MEN1 database (www.umd.be/MEN1/). Main Outcomes: variant classification, age-related penetrance, odds ratio. Results: Three hundred seventy distinct variants reported in 1,676 patients, including 181 unpublished variants, have currently been registered. This database analysis pointed out the low frequency of benign or likely benign missense variants in MEN1 (only 6.6%). Eight families (1.9%) presented a familial isolated hyperparathyroidism and harbored the same mutation found in authentic MEN1-families. An association exists between large rearrangements and an earlier onset of the disease, whereas no difference was observed between truncating and non-truncating variants. Conclusion: UMD-MEN1 database provides an exhaustive overview of the MEN1 variants present in the French population. For each variant, a classification is publicly available. Clinical data collections allow the determination of genotype-phenotype correlation and age-related penetrance of lesions in the cohort

Pathogenic FBN1 Genetic Variation and Aortic Dissection in Patients With Marfan Syndrome

International audienceBackgroundAortic risk has not been evaluated in patients with Marfan syndrome and documented pathogenic variants in the FBN1 gene.ObjectivesThis study sought to describe aortic risk in a population with Marfan syndrome with pathogenic variants in the FBN1 gene as a function of aortic root diameter.MethodsPatients carrying an FBN1 pathogenic variant who visited our reference center at least twice were included, provided they had not undergone aortic surgery or had an aortic dissection before their first visit. Aortic events (aortic surgery or aortic dissection) and deaths were evaluated during the 2 years following each patient visit. The risk was calculated as the number of events divided by the number of years of follow-up.ResultsA total of 954 patients were included (54% women; mean age 23 years). During follow-up (9.1 years), 142 patients underwent prophylactic aortic root surgery, 5 experienced type A aortic dissection, and 12 died (noncardiovascular causes in 3, unknown etiology in 3, post-operative in 6). When aortic root diameter was <50 mm, risk for proven type A dissection (0.4 events/1,000 patient-years) and risk for possible aortic dissection (proven aortic dissection plus death of unknown cause, 0.7 events/1,000 patients-years) remained low in this population that was treated according to guidelines. Three type A aortic dissections occurred in this population during the 8,594 years of follow-up, including 1 in a patient with a tubular aortic diameter of 50 mm, but none in patients with a family history of aortic dissection. The risk for type B aortic dissection in the same population was 0.5 events/1,000 patient-years.ConclusionsIn patients with FBN1 pathogenic variants who receive beta-blocker therapy and who limit strenuous exercise, aortic risk remains low when maximal aortic diameter is <50 mm. The risk of type B aortic dissection is close to the remaining risk of type A aortic dissection in this population, which underlines the global aortic risk

Standardisation of pathogenicity classification for somatic alterations in solid tumours and haematologic malignancies

International audienceBackground: The difficulty in interpreting somatic alterations is correlated with the increase in sequencing panel size. To correctly guide the clinical management of patients with cancer, there needs to be accurate classification of pathogenicity followed by actionability assessment. Here, we describe a specific detailed workflow for the classification of the pathogenicity of somatic variants in cancer into five categories: benign, likely benign, unknown significance, likely pathogenic and pathogenic.Methods: Classification is obtained by combining a set of eight relevant criteria in favour of either a pathogenic or a benign effect (pathogenic stand-alone, pathogenic very strong, pathogenic strong, pathogenic moderate, pathogenic supporting, benign supporting, benign strong and benign stand-alone).Results: Our guide is concordant with the ACMG/AMP 2015 guidelines for germline variants. Interpretation of somatic variants requires considering specific criteria, such as the disease and therapeutic context, co-occurring genomic events in the tumour when available and the use of cancer-specific variant databases. In addition, the gene role in tumorigenesis (oncogene or tumour suppressor gene) also needs to be taken into consideration.Conclusion: Our classification could contribute to homogenize best practices on somatic variant pathogenicity interpretation and improve interpretation consistency both within and between laboratories

Self-report questionnaire vs. clinical evaluation form in the French National Registry on facioscapulohumeral dystrophy: a statistical comparison

5th Congress of the European-Academy-of-Neurology (EAN), Oslo, NORWAY, JUN 29-JUL 02, 2019International audienc