Hamed Alali1,2, Mirna Assoum3, Naif Alhathal1, Sateesh Maddirevula3, Serdar Coskun4, Thomas Morris4, Hesham A Deek4, Soha A Hamed4, Shaheed Alsuhaibani5, Abdulmalik Mirdawi1, Nour Ewida3, Mashael Al-Qahtani3, Niema Ibrahim3, Firdous Abdulwahab3, Waleed Altaweel1, Majed J Dasouki3,4, Abdullah Assiri6, Wafa Qabbaj7, Fowzan S Alkuraya8,9. 1. Department of Urology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. 2. Department of Urology, King Fahad Specialist Hospital, Dammam, Saudi Arabia. 3. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. 4. Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center and College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. 5. Department of Urology, King Fahad University Hospital, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia. 6. Comparative Medicine Department, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. 7. Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center and College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. wqubbaj@kfshrc.edu.sa. 8. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa. 9. Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.
Abstract
PURPOSE: Male infertility remains poorly understood at the molecular level. We aimed in this study to investigate the yield of a "genomics first" approach to male infertility. METHODS: Patients with severe oligospermia and nonobstructive azoospermia were investigated using exome sequencing (ES) in parallel with the standard practice of chromosomal analysis. RESULTS: In 285 patients, 10.5% (n = 30) had evidence of chromosomal aberrations while nearly a quarter (n = 69; 24.2%) had a potential monogenic form of male infertility. The latter ranged from variants in genes previously reported to cause male infertility with or without other phenotypes in humans (24 patients; 8.4%) to those in novel candidate genes reported in this study (37 patients; 12.9%). The 33 candidate genes have biological links to male germ cell development including compatible mouse knockouts, and a few (TERB1 [CCDC79], PIWIL2, MAGEE2, and ZSWIM7) were found to be independently mutated in unrelated patients in our cohort. We also found that male infertility can be the sole or major phenotypic expression of a number of genes that are known to cause multisystemic manifestations in humans (n = 9 patients; 3.1%). CONCLUSION: The standard approach to male infertility overlooks the significant contribution of monogenic causes to this important clinical entity.
PURPOSE: Male infertility remains poorly understood at the molecular level. We aimed in this study to investigate the yield of a "genomics first" approach to male infertility. METHODS: Patients with severe oligospermia and nonobstructive azoospermia were investigated using exome sequencing (ES) in parallel with the standard practice of chromosomal analysis. RESULTS: In 285 patients, 10.5% (n = 30) had evidence of chromosomal aberrations while nearly a quarter (n = 69; 24.2%) had a potential monogenic form of male infertility. The latter ranged from variants in genes previously reported to cause male infertility with or without other phenotypes in humans (24 patients; 8.4%) to those in novel candidate genes reported in this study (37 patients; 12.9%). The 33 candidate genes have biological links to male germ cell development including compatible mouse knockouts, and a few (TERB1 [CCDC79], PIWIL2, MAGEE2, and ZSWIM7) were found to be independently mutated in unrelated patients in our cohort. We also found that male infertility can be the sole or major phenotypic expression of a number of genes that are known to cause multisystemic manifestations in humans (n = 9 patients; 3.1%). CONCLUSION: The standard approach to male infertility overlooks the significant contribution of monogenic causes to this important clinical entity.
Authors: J Hardy; N Pollock; T Gingrich; P Sweet; A Ramesh; J Kuong; A Basar; H Jiang; K Hwang; J Vukina; T Jaffe; M Olszewska; M Kurpisz; A N Yatsenko Journal: J Assist Reprod Genet Date: 2022-07-18 Impact factor: 3.357
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Authors: Jimmaline J Hardy; Margot J Wyrwoll; William Mcfadden; Agnieszka Malcher; Nadja Rotte; Nijole C Pollock; Sarah Munyoki; Maria V Veroli; Brendan J Houston; Miguel J Xavier; Laura Kasak; Margus Punab; Maris Laan; Sabine Kliesch; Peter Schlegel; Thomas Jaffe; Kathleen Hwang; Josip Vukina; Miguel A Brieño-Enríquez; Kyle Orwig; Judith Yanowitz; Michael Buszczak; Joris A Veltman; Manon Oud; Liina Nagirnaja; Marta Olszewska; Moira K O'Bryan; Donald F Conrad; Maciej Kurpisz; Frank Tüttelmann; Alexander N Yatsenko Journal: Hum Genet Date: 2021-05-07 Impact factor: 5.881
Authors: Albert Salas-Huetos; Frank Tüttelmann; Margot J Wyrwoll; Sabine Kliesch; Alexandra M Lopes; João Goncalves; Steven E Boyden; Marius Wöste; James M Hotaling; Liina Nagirnaja; Donald F Conrad; Douglas T Carrell; Kenneth I Aston Journal: Hum Genet Date: 2020-11-19 Impact factor: 4.132