Heterozygous loss-of-function variants in LHX8 cause female infertility characterized by oocyte maturation arrest |
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| Institution: | 1. Institute of Pediatrics, Children''s Hospital of Fudan University, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China;2. NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai, China;3. Human Phenome Institute, Fudan University, Shanghai, China;4. Reproductive Medicine Center, Shanghai Ninth Hospital, Shanghai Jiao Tong University, Shanghai, China;5. Hainan Jinghua Hejing Hospital for Reproductive Medicine, Haikou, China;6. Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China;7. Center for Reproduction and Genetics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China;8. Shenyang Jinghua Hospital, Liaoning, China;9. Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China;10. State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China;1. Hunan Normal University School of Medicine, Changsha, Hunan, China;2. National Engineering and Research Center of Human Stem Cells, Changsha, China;3. Hunan International Scientific and Technological Cooperation Base of Development and Carcinogenesis, Changsha, Hunan, China;4. BGI-Shenzhen, Shenzhen, China;5. Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Science, Central South University, Changsha, Hunan, China;6. Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, Hunan, China;7. BGI Education Center, University of Chinese Academy of Sciences, Shenzhen, China;1. Paris Brain Institute (Institut du Cerveau, ICM), INSERM, CNRS, Assistance Publique-Hôpitaux de Paris (AP-HP), Sorbonne Université, Paris, France;2. Pasteur Institute, Centre National de la Recherche Scientifique UMR 3691, Paris, France;3. Université de Bordeaux, CNRS, EPHE, INCIA, UMR 5287, Bordeaux, France;4. Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands;5. Département de Génétique, AP-HP, GH Pitié-Salpêtrière, Sorbonne Université, Paris, France;6. Sorbonne Université, Inserm, UMS Production et Analyse des données en Sciences de la vie et en Santé, PASS, Plateforme Post-génomique de la Pitié-Salpêtrière, P3S, Paris, France;7. Rare Neurological Diseases Unit, Department of Neurology, Attikon University Hospital, Medical School of the University of Athens, Athens, Greece;8. Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany;9. Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands;1. Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN;2. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN;3. Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY;4. Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL;5. Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children’s Hospital Medical Center, Cincinnati, OH;6. Department of Medicine, Brigham and Women’s Hospital, Boston MA;7. Genomic Medicine Institute, Geisinger, Danville, PA;8. The Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA;9. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;10. Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA;11. Division of Pulmonary Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA;12. Division of Medical Genetics, Department of Medicine, University of Washington Medical Center, Seattle, WA;13. Department of Genome Sciences, University of Washington Medical Center, Seattle, WA;14. Department of Pediatrics, Columbia University Irving Medical Center, New York, NY;15. Department of Medicine, Columbia University Irving Medical Center, New York, NY;16. Division of Genomic Medicine, National Human Genome Research Institute, Bethesda, MD;17. Gonda Vascular Center, Mayo Clinic, Rochester, MN;1. Department of Bioethics, Clinical Center, National Institutes of Health, Bethesda, MD;2. Department of Medical Humanities and Bioethics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR;3. Centralized Sequencing Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;4. NHGRI/NCI/JHU Genetic Counseling Training Program, National Human Genome Research Insitute, Bethesda, MD;5. Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD;6. Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD;1. Social and Behavioral Research Branch, National Human Genome Research Institute, Bethesda, MD;1. Department of Pediatrics, Stanford University School of Medicine, Stanford, CA;2. Division of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA;3. Division of Developmental and Behavioral Pediatrics, Department of Pediatrics, Stanford Medicine, Stanford, CA |
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| Abstract: | PurposeThe genetic causes of oocyte maturation arrest leading to female infertility are largely unknown, and no population-based genetic analysis has been applied in cohorts of patients with infertility. We aimed to identify novel pathogenic genes causing oocyte maturation arrest by using a gene-based burden test.MethodsThrough comparison of exome sequencing data from 716 females with infertility characterized by oocyte maturation arrest and 3539 controls, we performed a gene-based burden test and identified a novel pathogenic gene LHX8. Splicing event was evaluated using a minigene assay, expression of LHX8 protein was assessed in HeLa cells, and nuclear subcellular localization was determined in both HeLa cells and mouse oocytes.ResultsA total of 5 heterozygous loss-of-function LHX8 variants were identified from 6 independent families (c.389+1G>T, c.412C>T p.Arg1381], c.282C>A p.Cys941]; c.257dup p.Tyr861]; and c.180del, p.Ser61Profs130]). All the identified variants in LHX8 produced truncated LHX8 protein and resulted in loss of LHX8 nuclear localization in both HeLa cells and mouse oocytes.ConclusionBy combining genetic evidence and functional evaluations, we identified a novel pathogenic gene LHX8 and established the causative relationship between LHX8 haploinsufficiency and female infertility characterized by oocyte maturation arrest. |
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| Keywords: | Female infertility Gene-based burden test Loss-of-function variants Oocyte maturation arrest |
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