{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T19:46:05Z","timestamp":1790711165888,"version":"4.1.0"},"reference-count":44,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2022,11,28]],"date-time":"2022-11-28T00:00:00Z","timestamp":1669593600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2023,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    46,XY gonadal dysgenesis (GD) is a Disorder\/Difference of Sex Development (DSD) that can present with phenotypes ranging from ambiguous genitalia to complete male\u2010to\u2010female sex reversal. Around 50% of 46,XY DSD cases receive a molecular diagnosis. In mice, Fibroblast growth factor 9 (FGF9) is an important component of the male sex\u2010determining pathway. Two\n                    <jats:italic>FGF9<\/jats:italic>\n                    variants reported to date disrupt testis development in mice, but not in humans. Here, we describe a female patient with 46,XY GD harbouring the rare\n                    <jats:italic>FGF9<\/jats:italic>\n                    variant (missense mutation), NM_002010.2:c.583G\u2009&gt;\u2009A;p.(Asp195Asn) (D195N). By biochemical and cell\u2010based approaches, the D195N variant disrupts FGF9 protein homodimerisation and FGF9\u2010heparin\u2010binding, and reduces both Sertoli cell proliferation and\n                    <jats:italic>Wnt4<\/jats:italic>\n                    repression. XY\n                    <jats:italic>Fgf9<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>D195N\/D195N<\/jats:italic>\n                    <\/jats:sup>\n                    foetal mice show a transient disruption of testicular cord development, while XY\n                    <jats:italic>Fgf9<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>D195N\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    foetal mice show partial male\u2010to\u2010female gonadal sex reversal. In the general population, the D195N variant occurs at an allele frequency of 2.4\u00a0\u00d7\u200910\n                    <jats:sup>\u22125<\/jats:sup>\n                    , suggesting an oligogenic basis for the patient's DSD. Exome analysis of the patient reveals several known and novel variants in genes expressed in human foetal Sertoli cells at the time of sex determination. Taken together, our results indicate that disruption of FGF9 homodimerization impairs testis determination in mice and, potentially, also in humans in combination with other variants.\n                  <\/jats:p>","DOI":"10.1111\/cge.14261","type":"journal-article","created":{"date-parts":[[2022,11,9]],"date-time":"2022-11-09T05:19:06Z","timestamp":1667971146000},"page":"277-287","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["<i>FGF9<\/i>\n                    variant in 46,\n                    <scp>XY DSD<\/scp>\n                    patient suggests a role for dimerization in sex determination"],"prefix":"10.1111","volume":"103","author":[{"given":"Brittany","family":"Croft","sequence":"first","affiliation":[{"name":"Hudson Institute of Medical Research Monash Medical Centre  Melbourne Australia"},{"name":"Department of Molecular &amp; Translational Science Monash University  Melbourne Australia"},{"name":"Murdoch Children's Research Institute  Melbourne Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony D.","family":"Bird","sequence":"additional","affiliation":[{"name":"Hudson Institute of Medical Research Monash Medical Centre  Melbourne Australia"},{"name":"Department of Molecular &amp; Translational Science Monash University  Melbourne Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0551-1665","authenticated-orcid":false,"given":"Makoto","family":"Ono","sequence":"additional","affiliation":[{"name":"Hudson Institute of Medical Research Monash Medical Centre  Melbourne Australia"},{"name":"Department of Paediatrics Chiba Kaihin Municipal Hospital  Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Eggers","sequence":"additional","affiliation":[{"name":"Murdoch Children's Research Institute  Melbourne 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