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We hypothesize that de novo mutations play an important role in severe male infertility and explain a portion of the genetic causes of this understudied disorder. To test this hypothesis, we utilize trio-based exome\u00a0sequencing in a cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare (MAF\u2009&lt;\u20090.1%) protein-altering de novo mutations are classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of loss-of-function de novo mutations in loss-of-function-intolerant genes (\n                    <jats:italic>p<\/jats:italic>\n                    -value = 1.00 \u00d7 10\n                    <jats:sup>\u22125<\/jats:sup>\n                    ) in infertile men compared to controls. Additionally, we detected a significant increase in predicted pathogenic de novo missense mutations affecting missense-intolerant genes (\n                    <jats:italic>p<\/jats:italic>\n                    -value = 5.01 \u00d7 10\n                    <jats:sup>\u22124<\/jats:sup>\n                    ) in contrast to predicted benign de novo mutations. One gene we identify,\n                    <jats:italic>RBM5<\/jats:italic>\n                    , is an essential regulator of male germ cell pre-mRNA splicing and has been previously implicated in male infertility in mice. In a follow-up study, 6 rare pathogenic missense mutations affecting this gene are observed in a cohort of 2,506 infertile patients, whilst we find no such mutations in a cohort of 5,784 fertile men (\n                    <jats:italic>p<\/jats:italic>\n                    -value\u2009=\u20090.03). Our results provide evidence for the role of de novo mutations in severe male infertility and point to new candidate genes affecting fertility.\n                  <\/jats:p>","DOI":"10.1038\/s41467-021-27132-8","type":"journal-article","created":{"date-parts":[[2022,1,10]],"date-time":"2022-01-10T06:02:59Z","timestamp":1641794579000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":75,"title":["A de novo paradigm for male infertility"],"prefix":"10.1038","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9513-3030","authenticated-orcid":false,"given":"M. S.","family":"Oud","sequence":"first","affiliation":[]},{"given":"R. M.","family":"Smits","sequence":"additional","affiliation":[]},{"given":"H. E.","family":"Smith","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0579-1895","authenticated-orcid":false,"given":"F. 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