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Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

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Table 2.

Allelic Nonsyndromic Disorders/Differences of Sex Development Conditions

Gene 1ConditionMolecular PathogenesisClinical Characteristics / Comment
NR5A1 246,XY gonadal dysgenesis (OMIM 612965)Heterozygous loss-of-function variantsBroad spectrum: isolated male infertility, ambiguous genitalia, anorchia, female w/primary amenorrhea
46,XX premature ovarian insufficiency (OMIM 612964)Heterozygous loss-of-function variantsPrimary or secondary amenorrhea; irregular menstruation
46,XX ovotesticular DSD p.Arg92Trp variant See Differences between 46,XX ovotesticular DSD and 46,XX testicular DSD.
SOX3 46,XX ovotesticular DSD774-kb insertion translocated from chr 1 to a region 82 kb distal to SOX3, → upregulation of SOX3 expression 3
SOX9 46,XX ovotesticular DSDSee footnote 4.
SRY 46,XY complete gonadal dysgenesis (OMIM 400044)Hemizygous loss-of-function variantFemale external genitalia w/internal müllerian structures (uterus & fallopian tubes) but streak gonads w/o germ cells; affected persons most commonly come to medical attn at adolescence due to delayed puberty & amenorrhea.
46,XX ovotesticular DSDSee footnote 5.See Differences between 46,XX ovotesticular DSD and 46,XX testicular DSD.
WT1 46,XX ovotesticular DSDHeterozygous loss-of-function variants affecting the ZF4 domain

chr = chromosome; DSD = disorders/differences of sex development

1.

Genes are listed in alphabetic order.

2.

Heterozygous pathogenic variants in NR5A1 are associated with a wide range of DSD phenotypes in XY individuals, including dysgenic testes with female phenotype and fertile XY fathers (reviewed in Suntharalingham et al [2015]). Heterozygous pathogenic variants in NR5A1 are often inherited from XX mothers. Affected XX individuals can have a male phenotype due to testicular or ovotesticular DSD [Bashamboo et al 2016, Baetens et al 2017, Igarashi et al 2017, Knarston et al 2019].

3.
4.

46,XX ovotesticular DSD can also be caused by small duplications of regions upstream of SOX9 similar to those associated with the forms that present in adulthood with infertility (reviewed in Croft et al [2018b]). The duplicated regions overlap with but may be on average slightly larger than the regions duplicated in individuals presenting in adulthood with infertility.

5.

Most commonly as the result of abnormal interchange between an X and Y chromosome resulting in translocation of SRY onto the X chromosome. Phenotypic variability may result from differential X inactivation of the chromosome carrying Y material in different tissues.

6.

From: Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development

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