A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function

Genetic landscape of a large cohort of Primary Ovarian Insufficiency : New genes and pathways and implications for personalized medicine

Background Primary Ovarian Insufficiency (POI), a public health problem, affects 1-3.7% of women under 40 yield-ing infertility and a shorter lifespan. Most causes are unknown. Recently, genetic causes were identified, mostly in single families. We studied an unprecedented large cohort of POI to unravel its molecular pathophysiology.Methods 375 patients with 70 families were studied using targeted (88 genes) or whole exome sequencing with pathogenic/likely-pathogenic variant selection. Mitomycin-induced chromosome breakages were studied in patients' lymphocytes if necessary. Findings A high-yield of 29.3% supports a clinical genetic diagnosis of POI. In addition, we found strong evidence of pathogenicity for nine genes not previously related to a Mendelian phenotype or POI: ELAVL2, NLRP11, CENPE, SPATA33, CCDC150, CCDC185, including DNA repair genes: C17orf53(HROB), HELQ, SWI5 yielding high chromo-somal fragility. We confirmed the causal role of BRCA2, FANCM, BNC1, ERCC6, MSH4, BMPR1A, BMPR1B, BMPR2, ESR2, CAV1, SPIDR, RCBTB1 and ATG7 previously reported in isolated patients/families. In 8.5% of cases, POI is the only symptom of a multi-organ genetic disease. New pathways were identified: NF-kB, post-translational regulation, and mitophagy (mitochondrial autophagy), providing future therapeutic targets. Three new genes have been shown to affect the age of natural menopause supporting a genetic link.Interpretation We have developed high-performance genetic diagnostic of POI, dissecting the molecular pathogene-sis of POI and enabling personalized medicine to i) prevent/cure comorbidities for tumour/cancer susceptibility genes that could affect life-expectancy (37.4% of cases), or for genetically-revealed syndromic POI (8.5% of cases), ii) predict residual ovarian reserve (60.5% of cases). Genetic diagnosis could help to identify patients who may benefit from the promising in vitro activation-IVA technique in the near future, greatly improving its success in treating infertility.Funding Universite? Paris Saclay, Agence Nationale de Biome?decine.Copyright (c) 2022 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)Peer reviewe

Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5(p)15.33 TERT-CLPTM1Ll Region

Introduction: Inherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer. Methods: We conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer. Results: We detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722-0.820; p value 5.31 x 10(-16)), rs380286 (OR: 0.770, 95% CI: 0.723-0.820; p value 4.32 x 10(-16)), and rs4975616 OR: 0.778, 95% CI: 0.730-0.829; p value 1.04 x 10(-14)). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate. Conclusions: We found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits

Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.Peer reviewe

Nat Genet

The function of the majority of genes in the mouse and human genomes remains unknown. The mouse embryonic stem cell knockout resource provides a basis for the characterization of relationships between genes and phenotypes. The EUMODIC consortium developed and validated robust methodologies for the broad-based phenotyping of knockouts through a pipeline comprising 20 disease-oriented platforms. We developed new statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes with high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no previous functional annotation. We captured data from over 27,000 mice, finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. New phenotypes were uncovered for many genes with previously unknown function, providing a powerful basis for hypothesis generation and further investigation in diverse systems.Comment in : Genetic differential calculus. [Nat Genet. 2015] Comment in : Scaling up phenotyping studies. [Nat Biotechnol. 2015

Lynch syndrome-associated breast cancers: Clinicopathologic characteristics of a case series from the colon cancer family registry

Purpose: The recognition of breast cancer as a spectrum tumor in Lynch syndrome remains controversial. The aim of this study was to explore features of breast cancers arising in Lynch syndrome families. Experimental Design: This observational study involved 107 cases of breast cancer identified from the Colorectal Cancer Family Registry (Colon CFR) from 90 families in which (a) both breast and colon cancer co-occurred, (b) families met either modified Amsterdam criteria, or had at least one early-onset (<50 years) colorectal cancer, and (c) breast tissue was available within the biospecimen repository for mismatch repair (MMR) testing. Eligibility criteria for enrollment in the Colon CFR are available online. Breast cancers were reviewed by one pathologist. Tumor sections were stained for MLH1, PMS2, MSH2, and MSH6, and underwent microsatellite instability testing. Results: Breast cancer arose in 35 mutation carriers, and of these, 18 (51%) showed immunohistochemical absence of MMR protein corresponding to the MMR gene mutation segregating the family. MMR-deficient breast cancers were more likely to be poorly differentiated (P = 0.005) with a high mitotic index (P = 0.002), steroid hormone receptor–negative (estrogen receptor, P = 0.031; progesterone receptor, P = 0.022), and to have peritumoral lymphocytes (P = 0.015), confluent necrosis (P = 0.002), and growth in solid sheets (P < 0.001) similar to their colorectal counterparts. No difference in age of onset was noted between the MMR-deficient and MMR-intact groups. Conclusions: MMR deficiency was identified in 51% of breast cancers arising in known mutation carriers. Breast cancer therefore may represent a valid tissue option for the detection of MMR deficiency in which spectrum tumors are lackin

SPLF/SMFU/SRLF/SFAR/SFCTCV Guidelines for the management of patients with primary spontaneous pneumothorax

Abstract Introduction Primary spontaneous pneumothorax (PSP) is the presence of air in the pleural space, occurring in the absence of trauma and known lung disease. Standardized expert guidelines on PSP are needed due to the variety of diagnostic methods, therapeutic strategies and medical and surgical disciplines involved in its management. Methods Literature review, analysis of the literature according to the GRADE (Grading of Recommendation, Assessment, Development and Evaluation) methodology; proposals for guidelines rated by experts, patients and organizers to reach a consensus. Only expert opinions with strong agreement were selected. Results A large PSP is defined as presence of a visible rim along the entire axillary line between the lung margin and the chest wall and ≥ 2 cm at the hilum level on frontal chest X-ray. The therapeutic strategy depends on the clinical presentation: emergency needle aspiration for tension PSP; in the absence of signs of severity: conservative management (small PSP), needle aspiration or chest tube drainage (large PSP). Outpatient treatment is possible if a dedicated outpatient care system is previously organized. Indications, surgical procedures and perioperative analgesia are detailed. Associated measures, including smoking cessation, are described. Conclusion These guidelines are a step towards PSP treatment and follow-up strategy optimization in France

SPLF/SMFU/SRLF/SFAR/SFCTCV Guidelines for the management of patients with primary spontaneous pneumothorax

Introduction: Primary spontaneous pneumothorax (PSP) is the presence of air in the pleural space, occurring in the absence of trauma and known lung disease. Standardized expert guidelines on PSP are needed due to the variety of diagnostic methods, therapeutic strategies and medical and surgical disciplines involved in its management.Methods: Literature review, analysis of literature according to the GRADE (Grading of Recommendation Assessment, Development and Evaluation) methodology; proposals for guidelines rated by experts, patients, and organizers to reach a consensus. Only expert opinions with strong agreement were selected.Results: A large PSP is defined as presence of a visible rim along the entire axillary line between the lung margin and the chest wall and ≥2 cm at the hilum level on frontal chest x-ray. The therapeutic strategy depends on the clinical presentation: emergency needle aspiration for tension PSP; in the absence of signs of severity: conservative management (small PSP), needle aspiration or chest tube drainage (large PSP). Outpatient treatment is possible if a dedicated outpatient care system is previously organized. Indications, surgical procedures and perioperative analgesia are detailed. Associated measures, including smoking cessation, are described.Conclusion: These guidelines are a step towards PSP treatment and follow-up strategy optimization in France

Genome-wide association study confirms lung cancer susceptibility loci on chromosomes 5p15 and 15q25 in an African-American population.

ObjectivesGenome-wide association studies (GWAS) of lung cancer have identified regions of common genetic variation with lung cancer risk in Europeans who smoke and never-smoking Asian women. This study aimed to conduct a GWAS in African Americans, who have higher rates of lung cancer despite smoking fewer cigarettes per day when compared with Caucasians. This population provides a different genetic architecture based on underlying African ancestry allowing the identification of new regions and exploration of known regions for finer mapping.Materials and methodsWe genotyped 1,024,001 SNPs in 1737 cases and 3602 controls in stage 1, followed by a replication phase of 20 SNPs (p&lt;1.51×10(-5)) in an independent set of 866 cases and 796 controls in stage 2.Results and conclusionIn the combined analysis, we confirmed two loci to be associated with lung cancer that achieved the threshold of genome-wide significance: 15q25.1 marked by rs2036527 (p=1.3×10(-9); OR=1.32; 95% CI=1.20-1.44) near CHRNA5, and 5p15.33 marked by rs2853677 (p=2.8×10(-9); OR=1.28; 95% CI=1.18-1.39) near TERT. The association with rs2853677 is driven by the adenocarcinoma subtype of lung cancer (p=1.3×10(-8); OR=1.37; 95% CI=1.23-1.54). No SNPs reached genome-wide significance for either of the main effect models examining smoking - cigarettes per day and current or former smoker. Our study was powered to identify strong risk loci for lung cancer in African Americans; we confirmed results previously reported in African Americans and other populations for two loci near plausible candidate genes, CHRNA5 and TERT, on 15q25.1 and 5p15.33 respectively, are associated with lung cancer. Additional work is required to map and understand the biological underpinnings of the strong association of these loci with lung cancer risk in African Americans

Place de l’analyse des gènes du surfactant dans la démarche diagnostique des pneumopathies interstitiellesdiffuses de l’enfant et l’adulte

National audienceIntroductionLes pneumopathies interstitielles diffuses (PID) de l’enfant et l’adulte regroupent des pathologies hétérogènes et sévères. Une cause génétique est identifiée pour 2 à 20% des patients. Les gènes le plus souvent en cause sont ceux du complexe des télomérases, suivis des gènes du système du surfactant alvéolaire, qui sont communément associées à des formes pédiatriques de PID. Cette étude a pour but de rechercher des mutations des gènes du surfactant, sans a priori d’âge, dans une large cohorte prospective de PID.Matériel et méthodesLes patients ont été recrutés et inclus de façon prospective au sein de la filière de soins pour les maladies respiratoires rares RespiFIL. Les patients présentant des mutations des gènes du complexe des télomérases ont été exclus. Les exons et lesrégions introniques flanquantes des gènes SFTPA1, SFTPA2, SFTPB, SFTPC, ABCA3, NKX2-1 ont été séquencés. Les mutations retrouvées dans ces gènes ont été étudiées in silico et des tests fonctionnels sont en cours. Parallèlement, les données cliniques des patients ont été recueillies à l’aide d’une fiche standardisée.RésultatsEn 4 ans, 477 patients indépendants ont été inclus (190 enfants et 287 adultes). L’âge moyen au diagnostic de PID était de 33 ans (0-100), et le sexe ratio (hommes/femmes) de 1,47. La PID était familiale pour 22% des patients, et un antécédent personnel ou familial de cancer pulmonaire était retrouvé chez 44 patients. Une mutation dans l’un des gènes du système du surfactant a été identifiée chez 63 (13%) patients, dont 31 (16%) enfants et 32 (11%) adultes. Excepté les 2 mutations qui ont été identifiées dans SFTPB et retrouvées seulement chez l’adulte, tous les gènes étudiés ont été impliqués chez des adultes et des enfants.Discussion et conclusionContrairement aux idées reçues, les gènes du surfactant pulmonaire sont impliqués dans les PID à tout âge. Leur analyse semble donc indispensable à la démarche étiologique des PID, et ce sans a priori d’âge. La recherche systématique de mutations dans ces gènes, associée à une description précise du phénotype, permettra de progresser dans la description de ces maladies rares