{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T17:17:46Z","timestamp":1783012666016,"version":"3.54.6"},"reference-count":21,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T00:00:00Z","timestamp":1774396800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T00:00:00Z","timestamp":1774396800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100011033","name":"Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The Homologous Recombination Factor With OB\u2010Fold (HROB) plays a role in homologous recombination and DNA replication, where it enhances the MCM8\u2010MCM9 helicase complex activity. Recent findings link biallelic germline\n                    <jats:italic>HROB<\/jats:italic>\n                    variants to primary gonadal insufficiency (hypergonadotropic hypogonadism), a phenotype also associated with MCM8\/MCM9 deficiency. Here, we describe a family where two individuals with biallelic\n                    <jats:italic>HROB<\/jats:italic>\n                    variants presented with hypergonadotropic hypogonadism and colonic polyposis. Exome sequencing identified three unique\n                    <jats:italic>HROB<\/jats:italic>\n                    variants: a likely pathogenic nonsense variant (c.1267C&gt;T [p.(Gln423*)]) in exon four, and two missense variants (c.1363C&gt;G [p.(Leu455Val)] and c.1318A&gt;G [p.(Ser440Gly)]) in exon five. RNA analysis and protein mapping indicate that the nonsense variant is likely pathogenic, whereas the missense variants remain of uncertain significance. Mutational signature analysis of polyposis tissue did not reveal signatures directly linked to HROB deficiency, yet a review of published cases and analyses of cohorts with unexplained polyposis\/cancer identified additional individuals with\n                    <jats:italic>HROB<\/jats:italic>\n                    variants exhibiting hypergonadotropic hypogonadism or colonic polyposis. These findings reinforce the association between biallelic germline\n                    <jats:italic>HROB<\/jats:italic>\n                    variants and hypergonadotropic hypogonadism and suggest a potential role in colonic polyposis predisposition. We recommend incorporating\n                    <jats:italic>HROB<\/jats:italic>\n                    into diagnostic gene panels for hypergonadotropic hypogonadism, especially in cases where colonic polyposis is also present. Furthermore, we emphasize the importance of additional studies to comprehensively characterize\n                    <jats:italic>HROB<\/jats:italic>\n                    's phenotypic impact and assess its contribution to disease risk.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.70128","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T08:46:26Z","timestamp":1774428386000},"page":"1773-1782","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Biallelic Germline Inactivation of\n                    <scp>\n                      <i>HROB<\/i>\n                    <\/scp>\n                    Causes Primary Gonadal Insufficiency and is Potentially Associated with Colonic Polyposis Predisposition"],"prefix":"10.1002","volume":"200","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9089-8907","authenticated-orcid":false,"given":"Noah C.","family":"Helderman","sequence":"first","affiliation":[{"name":"Department of Clinical Genetics Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carli M.","family":"Tops","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jelmer","family":"Legebeke","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine UC San Diego  La Jolla California USA"},{"name":"Department of Bioengineering UC San Diego  La Jolla California USA"},{"name":"Moores Cancer Center UC San Diego  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0658-0467","authenticated-orcid":false,"given":"Marcos D\u00edaz","family":"Gay","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine UC San Diego  La Jolla California USA"},{"name":"Department of Bioengineering UC San Diego  La Jolla California USA"},{"name":"Moores Cancer Center UC San Diego  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8090-8806","authenticated-orcid":false,"given":"Diantha","family":"Terlouw","sequence":"additional","affiliation":[{"name":"Department of Pathology Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa E. E. L. O.","family":"Lashley","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5228-1890","authenticated-orcid":false,"given":"Stefan","family":"Aretz","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Medical Faculty University of Bonn  Bonn Germany"},{"name":"National Center for Hereditary Tumor Syndromes University Hospital Bonn  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna K.","family":"Sommer","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Medical Faculty University of Bonn  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7813-1172","authenticated-orcid":false,"given":"Mariona","family":"Terradas","sequence":"additional","affiliation":[{"name":"Hereditary Cancer Program, Catalan Institute of Oncology; Oncobell Program, IDIBELL; CIBERONC Hospitalet de Llobregat  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Valle","sequence":"additional","affiliation":[{"name":"Hereditary Cancer Program, Catalan Institute of Oncology; Oncobell Program, IDIBELL; CIBERONC Hospitalet de Llobregat  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8222-0343","authenticated-orcid":false,"given":"Richarda M.","family":"de Voer","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Radboud University Medical Center, Radboud Institute for Molecular Life Sciences  Nijmegen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludmil B.","family":"Alexandrov","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine UC San Diego  La Jolla California USA"},{"name":"Department of Bioengineering UC San Diego  La Jolla California USA"},{"name":"Moores Cancer Center UC San Diego  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"Morreau","sequence":"additional","affiliation":[{"name":"Department of Pathology Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5773-7730","authenticated-orcid":false,"given":"Tom","family":"van Wezel","sequence":"additional","affiliation":[{"name":"Department of Pathology Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5351-1870","authenticated-orcid":false,"given":"Maartje","family":"Nielsen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,25]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-47936-8"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-1943-3"},{"key":"e_1_2_14_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12477"},{"key":"e_1_2_14_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2022.104246"},{"key":"e_1_2_14_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2023.106737"},{"issue":"4","key":"e_1_2_14_7_1","article-title":"Clinical syndromes linked to biallelic germline variants in MCM8 and MCM9","volume":"6","author":"Helderman N. 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D.","year":"2022","journal-title":"HGG Advances"},{"issue":"6","key":"e_1_2_14_20_1","first-page":"727","article-title":"Genetic analysis of novel pathogenic gene HROB in a family with primary ovarian insufficiency","volume":"52","author":"Wu X.","year":"2023","journal-title":"Zhejiang Da Xue Xue Bao. Yi Xue Ban"},{"key":"e_1_2_14_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-023-02550-4"},{"key":"e_1_2_14_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.13991"}],"container-title":["American Journal of Medical Genetics Part A"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.70128","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ajmg.a.70128","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.70128","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T16:29:16Z","timestamp":1783009756000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmg.a.70128"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,25]]},"references-count":21,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1002\/ajmg.a.70128"],"URL":"https:\/\/doi.org\/10.1002\/ajmg.a.70128","archive":["Portico"],"relation":{},"ISSN":["1552-4825","1552-4833"],"issn-type":[{"value":"1552-4825","type":"print"},{"value":"1552-4833","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,25]]},"assertion":[{"value":"2025-11-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-10","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-25","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}