The infertility of many couples seems to rest on an enigmatic dysfunction of the men's sperm, rendering early diagnosis and evidence-based treatment by medically assisted reproduction impossible. Using a novel laboratory test, we assessed the function of the flagellar calcium channel CatSper in sperm of almost 2,300 men undergoing a fertility workup. Thereby, we identified a group of men with mutations in CATSPER genes affecting the function of the channel. Although standard semen and computer-assisted sperm analysis were unremarkable, the couples required intracytoplasmic sperm injection (ICSI) to conceive a child. We show that their seemingly unexplained infertility and need for ICSI is, in fact, due to the failure of CatSper-deficient human sperm to hyperactivate and penetrate the egg coat. In summary, our study reveals that defective CatSper function represents the most common cause of unexplained male-factor infertility known thus far and that CatSper-related infertility can readily be diagnosed, enabling evidence-based treatment.

S.Y., C.S., C.Br., and T.S. are inventors on a patent application filed by the University of Münster, Germany, related to CatSper-Activity-Test presented in this paper and co-founders of a company that further develops the test.

B.R., D.W., S.K., S.S., F.T., C.B. and T.S. are supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - project numbers 329621271 (CRU326; B.R., S.K., S.S., F.T., C.B., T.S,), 420653497 (CRC1450; B.R.), 432325352 (SFB1454; D.W.), 450149205 (TRR333/1; D.W.), and 390873048 (EXC2151; D.W.). D.W. is also supported by the Else-Kröner-Fresenius Foundation (2021.EKFSE.53) and intramural funding from the University of Bonn, T.S. by the Interdisciplinary Center for Clinical Research Münster (IZKF; Str/014/21) and the Europäischer Fonds fuer regionale Entwicklung (EFRE; 0400305), C.B. by the 'Innovative Medical Research' of the University of Muenster Medical School (IMF; BR 121507), and S.Y/C.S by the EXIST program of the Federal Ministry of Economic Affairs and Climate Action and European (Europäischer Sozialfonds; 03EFQNW261).

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All participants gave written informed consent according to the protocols approved by the Ethics Committee of the Ärztekammer Westfalen-Lippe and the Medical Faculty Münster (4INie, 2021-402-f-S, and 2010-578-f-S) and according to the Declaration of Helsinki.

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