{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T10:05:26Z","timestamp":1788257126380,"version":"build-2803163510"},"reference-count":37,"publisher":"Wiley","issue":"15","license":[{"start":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T00:00:00Z","timestamp":1753833600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82171655"],"award-info":[{"award-number":["82171655"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2025,8,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    To systematically evaluate the contributions of parental and fetal genetic factors in recurrent spontaneous abortion (RSA) through trio\u2010based exome sequencing and transmission disequilibrium test (TDT). We conducted whole\u2010exome sequencing on 31 trios (mother, father, and miscarried fetus) affected by RSA, collected from Nanjing Drum Tower Hospital between March 2021 and December 2023. Using TDT, we analyzed common genetic variants to identify associations with RSA and performed parent\u2010of\u2010origin analysis to assess the independent contributions of paternal and maternal alleles. Rare variant TDT analysis was also conducted to identify associations at the gene level. Significant findings underwent computational validation (population genetics, functional prediction, gene constraint and mouse phenotypes). We identified one common variant (rs2034910825 in the DNA repair gene\n                    <jats:italic>LIG1<\/jats:italic>\n                    ) and 15 suggestive SNPs associated with RSA. Computational validation showed 14\/17 top SNPs enriched in East Asians. Functional predictions indicated potential deleterious effects or regulatory impacts for several variants, and mouse knockout models supported embryonic developmental roles for key genes (e.g.,\n                    <jats:italic>Lig1<\/jats:italic>\n                    ,\n                    <jats:italic>Lrp2<\/jats:italic>\n                    , and\n                    <jats:italic>Flywch1<\/jats:italic>\n                    ). Additionally, our analysis revealed a paternal transmission bias at two loci (\n                    <jats:italic>PRAMEF4<\/jats:italic>\n                    and\n                    <jats:italic>SLC24A4<\/jats:italic>\n                    ), where alleles from fathers were preferentially transmitted to affected pregnancies. Gene\u2010level rare variant analysis further implicated eight genes (\n                    <jats:italic>PSG1<\/jats:italic>\n                    ,\n                    <jats:italic>D2HGDH<\/jats:italic>\n                    ,\n                    <jats:italic>OAS2<\/jats:italic>\n                    , etc.) in placental development, angiogenesis, and DNA repair. This study reveals paternal genetic contributions and fetal\u2010placental dysfunction pathways in RSA. Trio exome sequencing coupled with TDT provides a robust framework for unmasking familial transmission patterns, offering actionable markers for early risk prediction and personalized counseling.\n                  <\/jats:p>","DOI":"10.1096\/fj.202501656r","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T11:29:39Z","timestamp":1753874979000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Trio Exome Sequencing Reveal Paternal Transmission Bias and Novel Gene Loci in Recurrent Spontaneous Abortion"],"prefix":"10.1096","volume":"39","author":[{"given":"Honglei","family":"Duan","sequence":"first","affiliation":[{"name":"Center for Obstetrics and Gynecology Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shanghai\u2010MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation Shanghai Institute for Biomedical and Pharmaceutical Technologies  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Center for Obstetrics and Gynecology Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Jia","sequence":"additional","affiliation":[{"name":"Shanghai Fujungenetics Biotechnology Co., Ltd.  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Obstetrics and Gynecology Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6767-2763","authenticated-orcid":false,"given":"Jing","family":"Du","sequence":"additional","affiliation":[{"name":"Shanghai\u2010MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation Shanghai Institute for Biomedical and Pharmaceutical Technologies  Shanghai China"},{"name":"Key Laboratory of Research on Clinical Molecular Diagnosis for High Incidence Diseases in Western Guangxi of Guangxi Higher Education Institutions, Reproductive Medicine of Guangxi Medical and Health Key Discipline Construction Project Affiliated Hospital of Youjiang Medical University for Nationalities  Baise China"},{"name":"Industrial College of Biomedicine and Health Industry Youjiang Medical University for Nationalities  Baise China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,7,30]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)00682-6"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-020-00228-z"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2019.04.001"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12920-024-01902-x"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/molehr\/gaw008"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0186149"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dead039"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2024.1462649"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-19742-5"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-49993-5"},{"issue":"2","key":"e_1_2_12_12_1","first-page":"455","article-title":"The Transmission Disequilibrium Test\u2014History, Subdivision and Admixture","volume":"57","author":"Ewens W. J.","year":"1995","journal-title":"American Journal of Human Genetics"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg1839"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2022.04.014"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2021.02.001"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-017-1809-4"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1159\/000102174"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2010.09.003"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nut.2021.111349"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clnu.2020.12.029"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1272\/jnms.JNMS.2024_91-313"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0215745"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2020.165948"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.matbio.2019.11.002"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-022-04285-3"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1387\/ijdb.140011da"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2024.1486608"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tjog.2020.07.024"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2023.06.014"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1530\/REP-20-0169"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12014-019-9256-y"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells8111369"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom14030293"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2012-2468"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-020-0619-7"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12903-022-02051-2"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1111\/pedi.12818"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41435-023-00214-x"}],"container-title":["The FASEB Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.202501656R","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T15:45:51Z","timestamp":1761666351000},"score":1,"resource":{"primary":{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/10.1096\/fj.202501656R"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,30]]},"references-count":37,"journal-issue":{"issue":"15","published-print":{"date-parts":[[2025,8,15]]}},"alternative-id":["10.1096\/fj.202501656R"],"URL":"https:\/\/doi.org\/10.1096\/fj.202501656r","archive":["Portico"],"relation":{},"ISSN":["0892-6638","1530-6860"],"issn-type":[{"value":"0892-6638","type":"print"},{"value":"1530-6860","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,30]]},"assertion":[{"value":"2025-05-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70888"}}