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Improved phenotypic classification of male infertility to promote discovery of genetic causes

Nature Reviews Urology volume 21, pages 91–101 (2024)Cite this article

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Abstract

An increasing number of genes are being described in the context of non-syndromic male infertility. Linking the underlying genetic causes of non-syndromic male infertility with clinical data from patients is important to establish new genotype–phenotype correlations. This process can be facilitated by using universal nomenclature, but no standardized vocabulary is available in the field of non-syndromic male infertility. The International Male Infertility Genomics Consortium aimed at filling this gap, providing a standardized vocabulary containing nomenclature based on the Human Phenotype Ontology (HPO). The “HPO tree” was substantially revised compared with the previous version and is based on the clinical work-up of infertile men, including physical examination and hormonal assessment. Some causes of male infertility can already be suspected based on the patient’s clinical history, whereas in other instances, a testicular biopsy is needed for diagnosis. We assembled 49 HPO terms that are linked in a logical hierarchy and showed examples of morphological features of spermatozoa and testicular histology of infertile men with identified genetic diagnoses to describe the phenotypes. This work will help to record patients’ phenotypes systematically and facilitate communication between geneticists and andrologists. Collaboration across institutions will improve the identification of patients with the same phenotypes, which will promote the discovery of novel genetic causes for non-syndromic male infertility.

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Fig. 1: The novel HPO tree.
Fig. 2: Selected HPO terms and associated semen and testicular phenotypes.
Fig. 3: Spermatogenic phenotypes of men with aberrant sperm morphology.
Fig. 4: Broad spectrum of testicular phenotypes observed in histology samples from infertile men with a genetic diagnosis.

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Acknowledgements

The authors thank C. Brenker for providing pictures of sperm phenotypes shown in Fig. 3 and C. Brennecka for language editing. This study was carried out within the framework of and supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) sponsored Clinical Research Unit ‘Male Germ Cells’ (CRU326, project number 329621271). C.K., F.T. and J.A.V. belong to Action CA20119 ‘ANDRONET’, which is supported by COST (European Cooperation in Science and Technology, https://www.cost.eu/).

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Author notes

  1. These authors contributed equally: Margot J. Wyrwoll, Godfried W. van der Heijden.

Authors and Affiliations

  1. Institute of Reproductive Genetics, University of Münster, Münster, Germany

    Margot J. Wyrwoll & Frank Tüttelmann

  2. Department of Obstetrics and Gynecology, Radboud University Medical Center, Nijmegen, Netherlands

    Godfried W. van der Heijden & Liliana Ramos

  3. Department of Biomedical, Experimental and Clinical Sciences “Mario Serio”, University of Florence, University Hospital of Careggi (AOUC), Florence, Italy

    Csilla Krausz

  4. Andrology and IVF Laboratory, Department of Surgery (Urology), University of Utah, Salt Lake City, UT, USA

    Kenneth I. Aston

  5. Centre of Reproductive Medicine and Andrology, Department of Clinical and Surgical Andrology, University of Münster, Münster, Germany

    Sabine Kliesch

  6. Department of Clinical Research, Hudson Institute of Medical Research, Melbourne, Victoria, Australia

    Robert McLachlan

  7. Department of Genetics, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, USA

    Donald F. Conrad

  8. School of BioSciences and Bio21 Institute, The University of Melbourne, Parkville, Victoria, Australia

    Moira K. O’Bryan

  9. Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK

    Joris A. Veltman

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Contributions

F.T., M.J.W. and G.W.v.d.H. researched data for the article. All authors contributed substantially to discussion of the content. F.T., M.J.W. and G.W.v.d.H. wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Frank Tüttelmann.

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Nature Reviews Urology thanks Francesco Lotti, Sandro Esteves and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Wyrwoll, M.J., van der Heijden, G.W., Krausz, C. et al. Improved phenotypic classification of male infertility to promote discovery of genetic causes. Nat Rev Urol 21, 91–101 (2024). https://doi.org/10.1038/s41585-023-00816-0

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