Phenotypes linked to duplication upstream of SOX9: new insights into presentation and diagnosis

Unal E; Tekmenuray-Unal A; Cayir A; Papatya Cakir ED; Beyazit N; Kolbasi B; Gurpinar Tosun B; Yigit G; Zibat A; Wollnik B; Demirbilek H; Guran T

doi:10.1530/ey.22.6.7

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ESPE Yearbook of Paediatric Endocrinology (2025) 22 6.7 | DOI: 10.1530/ey.22.6.7

ESPEYB25 6. DSD and Gender Incongruence DSD Papers: Testicular-OvotesticularDSD (2 abstracts)

6.7. Phenotypes linked to duplication upstream of SOX9: new insights into presentation and diagnosis

Unal E , Tekmenuray-Unal A , Cayir A , Papatya Cakir ED , Beyazit N , Kolbasi B , Gurpinar Tosun B , Yigit G , Zibat A , Wollnik B , Demirbilek H & Guran T

J Clin Endocrinol Metab. 2025 Jan 15:dgaf020. doi: 10.1210/clinem/dgaf020

Brief summary: This study describes twelve 46,XX individuals carrying heterozygous duplications upstream of SOX9, ranging from 107–941kb, identified via karyotyping, targeted genetic panels, microarrays, multiplex ligation-dependent probe amplification (MLPA), or whole-genome sequencing. Among them, 7 (58%) exhibited testicular or ovotesticular DSD, while 5 (42%) were asymptomatic carriers, discovered during family screening. There was no clear correlation between duplication size and clinical phenotype. Familial inheritance was found, 3 from fathers and 2 from asymptomatic mothers, and in one case, the duplication had been missed by a 300K microarray but detected by MLPA and a 750K microarray.

The study highlights that the phenotype of 46,XX individuals with upstream SOX9 duplications can range from complete gonadal sex reversal to asymptomatic carrier. From a genetic counseling standpoint, identifying asymptomatic 46,XX and 46,XY individuals carrying duplications upstream of SOX9 is just as crucial as accurately diagnosing the index case. This recognition enables informed reproductive decisions and supports the use of preimplantation genetic diagnosis to promote healthy future generations. Additionally, high-resolution microarrays (>500K) are recommended as the diagnostic method of choice for 46,XX SRY-negative individuals suspected of DSD, as they can detect both large and small copy-number variants effectively.

The presence of asymptomatic carriers suggests variable penetrance, but the study did not explore molecular or environmental modifiers that might explain why some carriers are unaffected. Therefore, mechanisms underlying this phenotypic variability remain unclear. In conclusion, this study expands the clinical and diagnostic spectrum of SOX9 upstream duplications in 46,XX DSD but is limited by small sample size and lack of mechanistic insight.