Large-scale analyses of the X chromosome in 2,354 infertile men discover recurrently affected genes associated with spermatogenic failure

Antoni Riera-Escamilla; Matthias Vockel; Liina Nagirnaja; Miguel J Xavier; Albert Carbonell; Daniel Moreno-Mendoza; Marc Pybus; Ginevra Farnetani; Viktoria Rosta; Francesca Cioppi; Corinna Friedrich; Manon S Oud; Godfried W van der Heijden; Armin Soave; Thorsten Diemer; Elisabet Ars; Josvany Sánchez-Curbelo; Sabine Kliesch; Moira K O'Bryan; Eduard Ruiz-Castañe; GEMINI Consortium; Fernando Azorín; Joris A Veltman; Kenneth I Aston; Donald F Conrad; Frank Tüttelmann; Csilla Krausz

doi:10.1016/j.ajhg.2022.06.007

Large-scale analyses of the X chromosome in 2,354 infertile men discover recurrently affected genes associated with spermatogenic failure

Am J Hum Genet. 2022 Aug 4;109(8):1458-1471. doi: 10.1016/j.ajhg.2022.06.007. Epub 2022 Jul 8.

Authors

Antoni Riera-Escamilla¹, Matthias Vockel², Liina Nagirnaja³, Miguel J Xavier⁴, Albert Carbonell⁵, Daniel Moreno-Mendoza⁶, Marc Pybus⁷, Ginevra Farnetani⁸, Viktoria Rosta⁸, Francesca Cioppi⁸, Corinna Friedrich⁹, Manon S Oud¹⁰, Godfried W van der Heijden¹¹, Armin Soave¹², Thorsten Diemer¹³, Elisabet Ars⁷, Josvany Sánchez-Curbelo¹, Sabine Kliesch¹⁴, Moira K O'Bryan¹⁵, Eduard Ruiz-Castañe¹; GEMINI Consortium; Fernando Azorín⁵, Joris A Veltman⁴, Kenneth I Aston¹⁶, Donald F Conrad¹⁷, Frank Tüttelmann⁹, Csilla Krausz¹⁸

Affiliations

¹ Andrology Department, Fundació Puigvert, Universitat Autònoma de Barcelona, Instituto de Investigaciones Biomédicas Sant Pau, Barcelona, 08025 Catalonia, Spain.
² Institute of Human Genetics, University of Münster, Vesaliusweg 12-14, 48149 Münster, Germany.
³ Division of Genetics, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006, USA.
⁴ Faculty of Medical Sciences, Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
⁵ Institute of Molecular Biology of Barcelona, CSIC, Baldiri Reixac, 4, Barcelona, 08028 Catalonia, Spain; Institute for Research in Biomedicine, IRB Barcelona, The Barcelona Institute for Science and Technology, Baldiri Reixac, 10, Barcelona, 08028 Catalonia, Spain.
⁶ Andrology Department, Fundació Puigvert, Universitat Autònoma de Barcelona, Instituto de Investigaciones Biomédicas Sant Pau, Barcelona, 08025 Catalonia, Spain; Department of Urology, Hospital del Oriente de Asturias, Arriondas, 33540 Asturias, Spain.
⁷ Molecular Biology Laboratory, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau, Universitat Autònoma de Barcelona, Barcelona, 08025 Catalonia, Spain.
⁸ Department of Biomedical, Experimental and Clinical Sciences Mario Serio, University of Florence, Florence 50139, Italy.
⁹ Institute of Reproductive Genetics, University of Münster, Vesaliusweg 12-14, 48149 Münster, Germany.
¹⁰ Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboudumc, Nijmegen 6525, the Netherlands.
¹¹ Department of Obstetrics and Gynaecology, Radboudumc, Nijmegen 6525, the Netherlands.
¹² Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany.
¹³ Clinic for Urology, Paediatric Urology and Andrology, Justus Liebig University, Gießen 35392, Germany.
¹⁴ Centre of Reproductive Medicine and Andrology, Department of Clinical and Surgical Andrology, University Hospital Münster, Münster 48149, Germany.
¹⁵ The School of BioScience that the Bio21 Institute, The Faculty of Science, The University of Melbourne, Melbourne, VIC 3010, Australia.
¹⁶ Andrology and IVF Laboratories, Division of Urology, Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
¹⁷ Division of Genetics, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006, USA; Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
¹⁸ Department of Biomedical, Experimental and Clinical Sciences Mario Serio, University of Florence, Florence 50139, Italy. Electronic address: [email protected].

Abstract

Although the evolutionary history of the X chromosome indicates its specialization in male fitness, its role in spermatogenesis has largely been unexplored. Currently only three X chromosome genes are considered of moderate-definitive diagnostic value. We aimed to provide a comprehensive analysis of all X chromosome-linked protein-coding genes in 2,354 azoospermic/cryptozoospermic men from four independent cohorts. Genomic data were analyzed and compared with data in normozoospermic control individuals and gnomAD. While updating the clinical significance of known genes, we propose 21 recurrently mutated genes strongly associated with and 34 moderately associated with azoospermia/cryptozoospermia not previously linked to male infertility (novel). The most frequently affected prioritized gene, RBBP7, was found mutated in ten men across all cohorts, and our functional studies in Drosophila support its role in germ stem cell maintenance. Collectively, our study represents a significant step towards the definition of the missing genetic etiology in idiopathic severe spermatogenic failure and significantly reduces the knowledge gap of X-linked genetic causes of azoospermia/cryptozoospermia contributing to the development of future diagnostic gene panels.

Keywords: RBBP7; X chromosome; azoospermia; cryptozoospermia; genes; genetics; genomics; male infertility; next-generation sequencing; spermatogenesis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Azoospermia* / genetics
Humans
Infertility, Male* / genetics
Male
Oligospermia*
Spermatogenesis / genetics
X Chromosome

Abstract

Publication types

MeSH terms

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