{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T08:59:58Z","timestamp":1790845198240,"version":"4.1.0"},"reference-count":71,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2017,1,27]],"date-time":"2017-01-27T00:00:00Z","timestamp":1485475200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Actions Concertees InterPasteuriennes"},{"name":"EU","award":["FP7-INCO-2011-6"],"award-info":[{"award-number":["FP7-INCO-2011-6"]}]},{"name":"ESPE Collaborative Project","award":["40000767"],"award-info":[{"award-number":["40000767"]}]},{"name":"LABEX REVIVE"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2017,2]]},"abstract":"<jats:p>Human sex determination (<jats:styled-content style=\"fixed-case\">SD<\/jats:styled-content>) involves complex mutually antagonistic genetic interactions of testis\u2010 and ovary\u2010determining pathways. For many years, both male and female SD were considered to be regulated by a linear cascade of pro\u2010male and pro\u2010female genes, respectively; however, it has become clear that male and female development is achieved through the repression of the alternative state. A gene determining the formation of a testis may function by repressing the female state and vice versa. Uniquely in development, <jats:styled-content style=\"fixed-case\">SD<\/jats:styled-content> is achieved by suppression of the alternate fate and maintained in adulthood by a mutually antagonistic double\u2010repressive pathway. Here, we review genetic data generated through large\u2010scale sequencing approaches that are changing our view of how this system works, including the recently described recurrent <jats:styled-content style=\"fixed-case\">NR5A1<\/jats:styled-content> p.<jats:styled-content style=\"fixed-case\">R92W<\/jats:styled-content> mutation associated with testis development in 46,<jats:styled-content style=\"fixed-case\">XX<\/jats:styled-content> children. We also review some of the unique challenges in the field to establish that mutations, such as this are pathogenic. The impending surge of new genetic data on human SD from sequencing projects will create opportunities for the development of mechanistic models that will clarify how the system operates and importantly provide data to understand how selection and developmental processes interact to direct the evolution of <jats:styled-content style=\"fixed-case\">SD<\/jats:styled-content> across species.<\/jats:p>","DOI":"10.1111\/cge.12932","type":"journal-article","created":{"date-parts":[[2016,11,28]],"date-time":"2016-11-28T16:10:45Z","timestamp":1480349445000},"page":"143-156","source":"Crossref","is-referenced-by-count":74,"title":["Anomalies in human sex determination provide unique insights into the complex genetic interactions of early gonad development"],"prefix":"10.1111","volume":"91","author":[{"given":"A.","family":"Bashamboo","sequence":"first","affiliation":[{"name":"Human Developmental Genetics Unit Institut Pasteur  Paris 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