biostudies-literatureMaric TScientific Center of Excellence for Reproductive and Regenerative Medicine, Republic of CroatiaUS National Institutes of HealthNICHD NIH HHSEstonian Research CouncilNIGMS NIH HHS481-491https://www.ebi.ac.uk/biostudies/studies/S-EPMC11891871biostudies-literatureUnknown34(6)The most severe form of male infertility is idiopathic non-obstructive azoospermia (NOA), a complete sperm absence in the ejaculate. We performed exome sequencing in the Croatian infertile brothers with NOA and found a variant in DMRT1 (Doublesex and mab-3 related transcription factor 1) gene that was further assessed by the EMSA assay and molecular dynamic simulations. We additionally screened for DMRT1 mutations in 1940 infertile men diagnosed with spermatogenic failure, 644 normozoospermic controls, and 105 females with primary ovarian insufficiency (POI) recruited to the GEnetics of Male INfertility Initiative (GEMINI) or Estonian Andrology (ESTAND) cohorts. DMRT1 p.Pro74Leu (chr9:g.842059C > T) variant was detected in infertile brothers in the highly conserved position within the DNA Human molecular geneticsDiminished DNA binding affinity of DMRT1 caused by heterozygous DM domain mutations is a cause of male infertility.PMC11891871R01 HD078641R01 GM127379PRG1021P50 HD096723GM127379Aston KIJezek DMurphy MWVugrek OConrad DFStendahl AMTrgovec-Greif LGoncalves JBojanac AKJuchnewitsch AGMendoza DMDutta ALaan MLopes AMBertosa BCastillo-Madeen HPunab MZunic LBarbalic MSorgic AMMaric TBeluzic RAlmstrup KKlaric MLBarisic APomm KLillepea KfalseDiminished DNA binding affinity of DMRT1 caused by heterozygous DM domain mutations is a cause of male infertility.The most severe form of male infertility is idiopathic non-obstructive azoospermia (NOA), a complete sperm absence in the ejaculate. We performed exome sequencing in the Croatian infertile brothers with NOA and found a variant in DMRT1 (Doublesex and mab-3 related transcription factor 1) gene that was further assessed by the EMSA assay and molecular dynamic simulations. We additionally screened for DMRT1 mutations in 1940 infertile men diagnosed with spermatogenic failure, 644 normozoospermic controls, and 105 females with primary ovarian insufficiency (POI) recruited to the GEnetics of Male INfertility Initiative (GEMINI) or Estonian Andrology (ESTAND) cohorts. DMRT1 p.Pro74Leu (chr9:g.842059C > T) variant was detected in infertile brothers in the highly conserved position within the DNA 2025-01-01T00:00:00Z2025 Mar2026-06-06T19:34:18.41Z2026-06-04T03:10:51.539ZS-EPMC118918713977745810.1093/hmg/ddae197