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

J Med Genet

was previously implicated in periventricular nodular heterotopia (PVNH) in only five individuals and systematic clinical characterisation was not available. The aim of this study is to provide a comprehensive description of the phenotypic and genotypic spectrum of -related neurodevelopmental disorder. We collected detailed phenotypes of an international cohort of individuals (n=17) with variants assembled through the GeneMatcher platform. Missense variants were structurally modelled, and the impact of several were functionally validated. De novo variants (10 missense, 1 frameshift, 1 splice altering resulting in 9 residues insertion) in were identified among 17 unrelated individuals. Detailed phenotypes included intellectual disability (ID), microcephaly, seizures and PVNH. No specific facial characteristics were consistent across all cases, however microretrognathia was common. Various hearing and visual defects were recurrent, and interestingly, some inflammatory features were reported. MRI of the brain frequently showed abnormalities consistent with a neuronal migration disorder. We confirm the role of in an autosomal dominant syndrome with a phenotypic spectrum including severe ID, microcephaly, seizures and PVNH due to impaired neuronal migration

A targeted next-generation sequencing assay for the molecular diagnosis of genetic disorders with orodental involvement.

BACKGROUND: Orodental diseases include several clinically and genetically heterogeneous disorders that can present in isolation or as part of a genetic syndrome. Due to the vast number of genes implicated in these disorders, establishing a molecular diagnosis can be challenging. We aimed to develop a targeted next-generation sequencing (NGS) assay to diagnose mutations and potentially identify novel genes mutated in this group of disorders. METHODS: We designed an NGS gene panel that targets 585 known and candidate genes in orodental disease. We screened a cohort of 101 unrelated patients without a molecular diagnosis referred to the Reference Centre for Oro-Dental Manifestations of Rare Diseases, Strasbourg, France, for a variety of orodental disorders including isolated and syndromic amelogenesis imperfecta (AI), isolated and syndromic selective tooth agenesis (STHAG), isolated and syndromic dentinogenesis imperfecta, isolated dentin dysplasia, otodental dysplasia and primary failure of tooth eruption. RESULTS: We discovered 21 novel pathogenic variants and identified the causative mutation in 39 unrelated patients in known genes (overall diagnostic rate: 39%). Among the largest subcohorts of patients with isolated AI (50 unrelated patients) and isolated STHAG (21 unrelated patients), we had a definitive diagnosis in 14 (27%) and 15 cases (71%), respectively. Surprisingly, COL17A1 mutations accounted for the majority of autosomal-dominant AI cases. CONCLUSIONS: We have developed a novel targeted NGS assay for the efficient molecular diagnosis of a wide variety of orodental diseases. Furthermore, our panel will contribute to better understanding the contribution of these genes to orodental disease. TRIAL REGISTRATION NUMBERS: NCT01746121 and NCT02397824.journal articleresearch support, non-u.s. gov't2016 Feb2015 10 26importe

Nephrocalcinosis (enamel renal syndrome) caused by autosomal recessive FAM20A mutations

Calcium homeostasis requires regulated cellular and interstitial systems interacting to modulate the activity and movement of this ion. Disruption of these systems in the kidney results in nephrocalcinosis and nephrolithiasis, important medical problems whose pathogenesis is incompletely understood

ETUDE CYTOGENETIQUE ET MOLECULAIRE D'UNE DELETION FAMILIALE DE LA REGION 15Q11Q13 SOUMISE A EMPREINTE GENOMIQUE PARENTALE (DES GENETIQUE MEDICALE)

STRASBOURG-Medecine (674822101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Production durable d’extraits naturels biocides de deux Pipéracées à La Réunion

International audienceThe BIOPIPER project is a French Innovation and Partnership project that took place in Reunion Islandfrom 2015 to 2018 with different partners of Research & Development. Its purpose was to producenatural extracts of two Piperaceae (Peperomia borbonensis and Piper borbonense) in a sustainableapproach, for a use in the context of agroecological crop protection. There were 3 general objectives:(1) Synergize the skills of partners with complementary mandates on the use of endemic plants; (2)Design and implement sustainable production of both plant extracts and evaluate their efficacy asbioprotection agents; (3) Disseminate and enhance the obtained results and products. The project wasstructured around four actions. Action 1 made it possible to design, develop and optimize the productionof the two Piperaceae to ensure optimal production of foliar biomass. Action 2 made it possible toproduce and characterize phytochemical extracts of different ecotypes of wild and cultivated plants.Action 3 measured the biocidal efficacy of extracts on various crop pests (bacteria, arthropods) of ageneric nature and of economic importance in Reunion Island and at the French national level. On fruitflies, which are fearsome pests worldwide, LD 50 and LD 95 (lethal doses of 50% and 95% of thepopulation) were measured on five species (Zeugodacus cucurbitae, Bactrocera zonata, Bactroceradorsalis, Ceratitis quilicii and Neoceratitis cyanescens), with essential oil-based extracts. Analysis of theLD 50 results showed differences between plants, ecotypes and types of extracts. LD 50 tests withessential oils were carried out on other economically important pests (Bemisia tabaci, Frankliniellaoccidentalis), a non-pest fly (Drosophila melanogaster). The essential oil of P. borbonensis has alsobeen tested on various temperate pests (Delia radicum, Meligethes aeneus, Psylliodes chrysocephala).A biocidal effect was found on all insects tested with significant variations in sensitivity. Olfactometrictests were also carried out and revealed that the essential oil of P. borbonensis is not repellent. Thisresult is encouraging and makes it possible to consider a targeted application of essential oil via bait inan "attract & kill" approach. Action 4 initiated the process of developing a regulatory folder for thecommercial use of plant or extract production. Finally, the BIOPIPER project has made it possible tocreate an operational and original consortium in partnership in order to screen, for research or servicepurposes, the biocidal activity of extracts from different plants.Le projet BIOPIPER est un projet Casdar (Innovation et partenariat) qui s’est déroulé à La Réunion de2015 à 2018 avec différents partenaires de la Recherche et du Développement. Sa finalité est deproduire durablement des extraits naturels de deux Pipéracées (Peperomia borbonensis et Piperborbonense), en vue de leur utilisation dans le cadre de la Protection agroécologique des cultures. Ondistingue 3 objectifs généraux : (1) Mettre en synergie les compétences de partenaires aux mandatscomplémentaires sur l'utilisation de plantes endémiques comme outils de biocontrôle ; (2) Concevoir etmettre au point la production durable des deux plantes en vue de leur utilisation comme outils debiocontrôle ; (3) Diffuser et valoriser les résultats et produits obtenus. Le projet s’est articulé autour de 4actions. L’action 1 a permis de concevoir, de mettre au point et d’optimiser la production des deuxPipéracées permettant d’assurer une production optimale de biomasse foliaire. L’action 2 a permis deproduire et de caractériser sur le plan phytochimique les extraits de différents écotypes des plantessauvages et cultivées. L’action 3 a mesuré l’efficacité biocide des extraits sur divers bioagresseurs(bactéries, arthropodes) de caractère générique et d’importance économique à La Réunion et àl’échelle nationale. Sur les Mouches des fruits, ravageurs redoutables à l’échelle mondiale, les DL 50 etDL 95 (doses létales de 50 % et 95 % de la population) ont été mesurées sur 5 espèces (Zeugodacuscucurbitae, Bactrocera zonata, Bactrocera dorsalis, Ceratitis quilicii et Neoceratitis cyanescens), avecdes extraits à base d’huile essentielle. L’analyse des résultats des DL 50 montre des différences entreles plantes, les écotypes et les types d’extraits. Les tests de DL 50 avec les huiles essentielles ont étéconduits sur d’autres ravageurs d’importance économique (Bemisia tabaci, individus issus d’élevage ;Frankliniella occidentalis, individus prélevés en culture de poivron sous serre), une drosophile(Drosophila melanogaster, individus issus d’élevage). L’huile essentielle de P. borbonense a égalementété testée sur différents ravageurs des légumes métropolitains (la Mouche du chou, Delia radicum, leméligèthe Meligethes aeneus et l’altise d’hiver, Psylliodes chrysocephala). Un effet biocide a été trouvésur tous les insectes testés avec des variations importantes de sensibilité. Des tests olfactométriquesont également été réalisés et ont révélé que l’huile essentielle de P. borbonense n’est pas répulsive. Cerésultat est encourageant et permet d’envisager une application ciblée du produit toxique via lanourriture ou les sites de nutrition du ravageur (approche « attract & kill »). L’action 4 a initié leprocessus visant à constituer un dossier réglementaire en vue de l’utilisation commerciale de laproduction des plantes ou des extraits. Le projet BIOPIPER a permis la création d’un dispositif enpartenariat opérationnel et original, permettant de screener, à des fins de recherches ou de prestationsde service, l’activité biocide d’extraits de différentes plantes

Sustainable production of natural biocidal extracts from two Piperaceae in Reunion Island

The Biopiper project is a French Innovation and Partnership project that took place in Reunion Island from 2015 to 2018. Its purpose was to produce natural extracts of two Piperaceae (Peperomia borbonensisand Piper borbonense) in a sustainable approach, for a use in the context of agroecological crop protection. There were 3 general objectives: (1) Synergize the skills of partners withcomplementary mandates on the use of endemic plants; (2) Design and implement sustainable production of both plant extracts and evaluate their efficacy as biocontrol agents; (3) Disseminate and enhance theobtained results and products. The project partners were: Association Réunionnaise pour la Modernisation de l'Economie Fruitière, Légumière et Horticole (ARMEFLHOR); Centre de Coopération Internationale en Recherche Agronomique pour le Développement (CIRAD); Institut Technique de l'Agriculture Biologique(ITAB); Plant Advanced Technologies (PAT); Société Horticole de Bassin Plat (SHBP); Université de Rennes 1; Université de La Réunion. The project was structured around fouractions. Action 1 made it possible to design, develop and optimise the productionof the two Piperaceae to ensure optimal production of foliar biomass. Action 2 made it possible to produce and characterize phytochemical extracts of different ecotypes of wild and cultivated plants. Action 3 measured the biocidal efficacy of extracts on various crop pests (bacteria, arthropods) of a generic nature and of economic importance in Reunion Island and at the French national level. On fruit flies, which are formidable pests worldwide, LD 50 and LD 95 (lethal doses of 50% and 95% of the population) were measured on fivespecies (Zeugodacus cucurbitae, Bactrocera zonata, Bactrocera dorsalis, Ceratitis quiliciiand Neoceratitis cyanescens), with essential oil-based extracts. Analysis of the LD 50 results showed differences between plants, ecotypes and types of extracts. LD 50 tests with essential oils were carried out on other economically important pests (Bemisia tabaci, Frankliniella occidentalis), a non-pest fly (Drosophila melanogaster). The essential oil of P. borbonensishas also been tested onvarious Brassicaceae pests (Delia radicum, Meligethes aeneus, Psylliodes chrysocephala). A biocidal effect was found on all insects tested with significant variations in sensitivity. Olfactometric tests were also carried out and revealed that the essential oil of P. borbonensisis not repellent. This result is encouraging and makes it possible to consider a targeted application of essential oil via bait in an "attract & kill" approach.Action 4 initiated the process of developing a regulatory folder for the commercial use of plant or extract production. Finally, the Biopiper project has made it possible to create an operational and original consortium in partnership in order to screen, for research or service purposes, the biocidal activity of extracts fromdifferent plant

Mutational Spectrum in Holoprosencephaly Shows That FGF is a New Major Signaling Pathway

International audienceHoloprosencephaly (HPE) is the most common congenital cerebral malformation in humans, characterized by impaired forebrain cleavage and midline facial anomalies. It presents a high heterogeneity, both in clinics and genetics. We have developed a novel targeted next-generation sequencing (NGS) assay and screened a cohort of 257 HPE patients. Mutations with high confidence in their deleterious effect were identified in approximately 24% of the cases and were held for diagnosis, whereas variants of uncertain significance were identified in 10% of cases. This study provides a new classification of genes that are involved in HPE. SHH, ZIC2, and SIX3 remain the top genes in term of frequency with GLI2, and are followed by FGF8 and FGFR1. The three minor HPE genes identified by our study are DLL1, DISP1, and SUFU. Here, we demonstrate that fibroblast growth factor signaling must now be considered a major pathway involved in HPE. Interestingly, several cases of double mutations were found and argue for a polygenic inheritance of HPE. Altogether, it supports that the implementation of NGS in HPE diagnosis is required to improve genetic counseling