{"doi":"10.1101/2021.02.27.433155","title":"A <i>de novo</i> paradigm for male infertility","abstract":"Introduction De novo mutations (DNMs) are known to play a prominent role in sporadic disorders with reduced fitness 1 . We hypothesize that DNMs play an important role in male infertility and explain a significant fraction of the genetic causes of this understudied disorder. To test this hypothesis, we performed trio-based exome-sequencing in a unique cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare protein altering DNMs were classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of Loss-of-Function (LoF) DNMs in LoF-intolerant genes (p-value=1.00×10-5) as well as predicted pathogenic missense DNMs in missense-intolerant genes (p-value=5.01×10-4). One DNM gene identified, RBM5, is an essential regulator of male germ cell pre-mRNA splicing 2 . In a follow-up study, 5 rare pathogenic missense mutations affecting this gene were observed in a cohort of 2,279 infertile patients, with no such mutations found in a cohort of 5,784 fertile men (p-value=0.009). Our results provide the first evidence for the role of DNMs in severe male infertility and point to many new candidate genes affecting fertility.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":222048,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9627,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":823190,"name":"RM Smits","orcid":null,"position":1,"is_corresponding":false},{"id":823191,"name":"H E Smith","orcid":null,"position":2,"is_corresponding":false},{"id":823192,"name":"FK Mastrorosa","orcid":null,"position":3,"is_corresponding":false},{"id":823193,"name":"GS Holt","orcid":null,"position":4,"is_corresponding":false},{"id":823194,"name":"BJ Houston","orcid":null,"position":5,"is_corresponding":false},{"id":823195,"name":"PF de Vries","orcid":null,"position":6,"is_corresponding":false},{"id":823196,"name":"BKS Alobaidi","orcid":null,"position":7,"is_corresponding":false},{"id":823197,"name":"LE Batty","orcid":null,"position":8,"is_corresponding":false},{"id":822706,"name":"Hoda Ismail","orcid":"0000-0002-0016-6647","position":9,"is_corresponding":false},{"id":822707,"name":"Joel Greenwood","orcid":"0000-0003-2426-8004","position":10,"is_corresponding":false},{"id":822708,"name":"Harsh Sheth","orcid":"0000-0001-9626-0971","position":11,"is_corresponding":false},{"id":822709,"name":"Aneta Mikulášová","orcid":"0000-0003-3842-512X","position":12,"is_corresponding":false},{"id":823198,"name":"GDN Astuti","orcid":null,"position":13,"is_corresponding":false},{"id":56999,"name":"Christian Gilissen","orcid":"0000-0003-1693-9699","position":14,"is_corresponding":false},{"id":278854,"name":"Kevin McEleny","orcid":"0000-0001-9827-8139","position":15,"is_corresponding":false},{"id":822710,"name":"H Turner","orcid":"0009-0006-7198-714X","position":16,"is_corresponding":false},{"id":36265,"name":"Jonathan Coxhead","orcid":"0000-0002-6128-9560","position":17,"is_corresponding":false},{"id":822711,"name":"Simon Cockell","orcid":"0000-0002-6831-9806","position":18,"is_corresponding":false},{"id":823199,"name":"D.D.M. 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