Angad Jolly1, Yavuz Bayram1, Serap Turan2, Zehra Aycan3, Tulay Tos4, Zehra Yavas Abali5, Bulent Hacihamdioglu6, Zeynep Hande Coban Akdemir1, Hadia Hijazi1, Serpil Bas2, Zeynep Atay2, Tulay Guran2, Saygin Abali2, Firdevs Bas5, Feyza Darendeliler5, Roberto Colombo7,8, Tahsin Stefan Barakat9, Tuula Rinne10, Janson J White1, Gozde Yesil11, Alper Gezdirici12, Elif Yilmaz Gulec12, Ender Karaca13, Davut Pehlivan1,14, Shalini N Jhangiani15, Donna M Muzny15, Sukran Poyrazoglu5, Abdullah Bereket2, Richard A Gibbs1,15, Jennifer E Posey1, James R Lupski1,15,16,17. 1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas. 2. Department of Pediatric Endocrinology and Diabetes, Marmara University School of Medicine, Istanbul, Turkey. 3. Department of Pediatric Endocrinology, Sami Ulus Children's Hospital, Ankara, Turkey. 4. Department of Medical Genetics, Sami Ulus Children's Hospital, Ankara, Turkey. 5. Department of Pediatric Endocrinology, İstanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey. 6. Department of Pediatric Endocrinology, Istinye University, Istanbul, Turkey. 7. Center for the Study of Rare Inherited Diseases (CeSMER), Niguarda Ca' Granda Metropolitan Hospital, Milan, Italy. 8. Faculty of Medicine, Catholic University, IRCCS Policlinico Gemelli University Hospital, Rome, Italy. 9. Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. 10. Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands. 11. Department of Medical Genetics, Bezmialem University, Istanbul, Turkey. 12. Department of Medical Genetics, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey. 13. Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama. 14. Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, Texas. 15. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas. 16. Department of Pediatrics, Baylor College of Medicine, Houston, Texas. 17. Texas Children's Hospital, Houston, Texas.
Abstract
CONTEXT: Primary ovarian insufficiency (POI) encompasses a spectrum of premature menopause, including both primary and secondary amenorrhea. For 75% to 90% of individuals with hypergonadotropic hypogonadism presenting as POI, the molecular etiology is unknown. Common etiologies include chromosomal abnormalities, environmental factors, and congenital disorders affecting ovarian development and function, as well as syndromic and nonsyndromic single gene disorders suggesting POI represents a complex trait. OBJECTIVE: To characterize the contribution of known disease genes to POI and identify molecular etiologies and biological underpinnings of POI. DESIGN, SETTING, AND PARTICIPANTS: We applied exome sequencing (ES) and family-based genomics to 42 affected female individuals from 36 unrelated Turkish families, including 31 with reported parental consanguinity. RESULTS: This analysis identified likely damaging, potentially contributing variants and molecular diagnoses in 16 families (44%), including 11 families with likely damaging variants in known genes and five families with predicted deleterious variants in disease genes (IGSF10, MND1, MRPS22, and SOHLH1) not previously associated with POI. Of the 16 families, 2 (13%) had evidence for potentially pathogenic variants at more than one locus. Absence of heterozygosity consistent with identity-by-descent mediated recessive disease burden contributes to molecular diagnosis in 15 of 16 (94%) families. GeneMatcher allowed identification of additional families from diverse genetic backgrounds. CONCLUSIONS: ES analysis of a POI cohort further characterized locus heterogeneity, reaffirmed the association of genes integral to meiotic recombination, demonstrated the likely contribution of genes involved in hypothalamic development, and documented multilocus pathogenic variation suggesting the potential for oligogenic inheritance contributing to the development of POI.
CONTEXT: Primary ovarian insufficiency (POI) encompasses a spectrum of premature menopause, including both primary and secondary amenorrhea. For 75% to 90% of individuals with hypergonadotropic hypogonadism presenting as POI, the molecular etiology is unknown. Common etiologies include chromosomal abnormalities, environmental factors, and congenital disorders affecting ovarian development and function, as well as syndromic and nonsyndromic single gene disorders suggesting POI represents a complex trait. OBJECTIVE: To characterize the contribution of known disease genes to POI and identify molecular etiologies and biological underpinnings of POI. DESIGN, SETTING, AND PARTICIPANTS: We applied exome sequencing (ES) and family-based genomics to 42 affected female individuals from 36 unrelated Turkish families, including 31 with reported parental consanguinity. RESULTS: This analysis identified likely damaging, potentially contributing variants and molecular diagnoses in 16 families (44%), including 11 families with likely damaging variants in known genes and five families with predicted deleterious variants in disease genes (IGSF10, MND1, MRPS22, and SOHLH1) not previously associated with POI. Of the 16 families, 2 (13%) had evidence for potentially pathogenic variants at more than one locus. Absence of heterozygosity consistent with identity-by-descent mediated recessive disease burden contributes to molecular diagnosis in 15 of 16 (94%) families. GeneMatcher allowed identification of additional families from diverse genetic backgrounds. CONCLUSIONS: ES analysis of a POI cohort further characterized locus heterogeneity, reaffirmed the association of genes integral to meiotic recombination, demonstrated the likely contribution of genes involved in hypothalamic development, and documented multilocus pathogenic variation suggesting the potential for oligogenic inheritance contributing to the development of POI.
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