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Their distant relative, P3 (30\u00a0years; 46,XY), presented bilateral cryptorchidism and cryptozoospermia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design<\/jats:title><jats:p>Exome sequencing was targeted to P1\u2010P3 and five unaffected family members.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>P1\u2010P2 were identified as heterozygous carriers of <jats:italic>NR5A1<\/jats:italic> c.991\u20101G\u00a0&gt;\u00a0C. <jats:italic>NR5A1<\/jats:italic> encodes the steroidogenic factor\u20101 essential in gonadal development and specifically expressed in adrenal, spleen, pituitary and testes. Together with a previous PGD case from Belgium (Robevska et al 2018), c.991\u20101G\u00a0&gt;\u00a0C represents the first recurrent <jats:italic>NR5A1<\/jats:italic> splice\u2010site mutation identified in patients. The majority of previous reports on <jats:italic>NR5A1<\/jats:italic> mutation carriers have not included phenotype\u2010genotype data of the family members. Segregation analysis across three generations showed incomplete penetrance (&lt;50%) and phenotypic variability among the carriers of <jats:italic>NR5A1<\/jats:italic> c.991\u20101G\u00a0&gt;\u00a0C. The variant pathogenicity was possibly modulated by rare heterozygous variants inherited from the other parent, <jats:italic>OTX2<\/jats:italic> p.P134R (P1) or <jats:italic>PROP1<\/jats:italic> c.301_302delAG (P2). For P3, the pedigree structure supported a distinct genetic cause. He carries a previously undescribed likely pathogenic variant SOS1 p.Y136H. <jats:italic>SOS1<\/jats:italic>, critical in Ras\/MAPK signalling and foetal development, is a strong novel candidate gene for cryptorchidism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Detailed genetic profiling facilitates counselling and clinical management of the probands, and supports unaffected mutation carriers in the family for their reproductive decision making.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cen.14381","type":"journal-article","created":{"date-parts":[[2020,12,10]],"date-time":"2020-12-10T18:03:51Z","timestamp":1607623431000},"page":"656-666","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["<i>NR5A1<\/i> c.991\u20101G\u00a0&gt;\u00a0C splice\u2010site variant causes familial 46,XY partial gonadal dysgenesis with incomplete penetrance"],"prefix":"10.1111","volume":"94","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8519-243X","authenticated-orcid":false,"given":"Maris","family":"Laan","sequence":"first","affiliation":[{"name":"Institute of Biomedicine and Translational Medicine University of Tartu Tartu Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4182-2396","authenticated-orcid":false,"given":"Laura","family":"Kasak","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine and Translational Medicine University of Tartu Tartu Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K\u0119stutis","family":"Timinskas","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology Life Sciences Center Vilnius University Vilnius 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