Disorder of sexual differentiation: genes and variants

Genes linked to Disorder of sexual differentiation

• AR: Androgen receptor

  Androgen binding redirects its transcriptional program to control male sexual differentiation, reproductive physiology, muscle and bone biology, and other androgen-responsive processes. Loss-of-function variants cause androgen insensitivity, CAG expansion causes spinal and bulbar muscular atrophy, and persistent signaling drives prostate cancer.

  3 disease-causing and 0 uncertain variants in AR are linked to Disorder of sexual differentiation.

• HSD17B3: 17-beta-hydroxysteroid dehydrogenase type 3

  It converts androstenedione to testosterone in the testes, providing a key step in androgen synthesis during male sexual development. Biallelic loss-of-function variants cause 17-beta-hydroxysteroid dehydrogenase 3 deficiency, a 46,XY disorder of sex development.

  2 disease-causing and 0 uncertain variants in HSD17B3 are linked to Disorder of sexual differentiation.

• CACNA1A: Voltage-dependent P/Q-type calcium channel subunit alpha-1A

  Its P/Q-type calcium current is a major trigger for neurotransmitter release at central synapses and is especially important in cerebellar circuits. Pathogenic variants cause a spectrum including familial hemiplegic migraine, episodic ataxia, spinocerebellar ataxia type 6, epilepsy, and developmental disorders.

  1 disease-causing and 0 uncertain variants in CACNA1A are linked to Disorder of sexual differentiation.

Weakly linked (only a few uncertain records): FGFR2, LHCGR and WWOX.

Known disease-causing variants in Disorder of sexual differentiation

Same protein, different disease

• Androgen resistance syndrome is also caused by AR variants; they fall mostly in different places as the Disorder of sexual differentiation variants (85 disease-causing).
• Kennedy disease is also caused by AR variants; they fall mostly in different places as the Disorder of sexual differentiation variants (46 disease-causing).
• Differences in sex development is also caused by AR variants; they fall mostly in different places as the Disorder of sexual differentiation variants (9 disease-causing).
• Male infertility is also caused by AR variants; they fall mostly in different places as the Disorder of sexual differentiation variants (7 disease-causing).
• Partial androgen insensitivity syndrome is also caused by AR variants; they fall mostly in different places as the Disorder of sexual differentiation variants (7 disease-causing).
• Testosterone 17-beta-dehydrogenase deficiency is also caused by HSD17B3 variants; they fall mostly in different places as the Disorder of sexual differentiation variants (20 disease-causing).
• Episodic ataxia type 2 is also caused by CACNA1A variants; they fall mostly in different places as the Disorder of sexual differentiation variants (93 disease-causing).
• Spinocerebellar ataxia type 6 is also caused by CACNA1A variants; they fall mostly in different places as the Disorder of sexual differentiation variants (28 disease-causing).
• Migraine, familial hemiplegic, 1 is also caused by CACNA1A variants; they fall mostly in different places as the Disorder of sexual differentiation variants (26 disease-causing).
• CACNA1A-related complex neurodevelopmental disorder is also caused by CACNA1A variants; they fall mostly in different places as the Disorder of sexual differentiation variants (3 disease-causing).

Diseases related to Disorder of sexual differentiation

• Differences in sex development, also linked to AR and HSD17B3
• Episodic ataxia type 2, also linked to CACNA1A
• Androgen resistance syndrome, also linked to AR
• Migraine, familial hemiplegic, 1, also linked to CACNA1A
• Kennedy disease, also linked to AR
• Ovarian cancer, also linked to AR
• Spinocerebellar ataxia type 6, also linked to CACNA1A
• Testosterone 17-beta-dehydrogenase deficiency, also linked to HSD17B3
• Epilepsy, also linked to CACNA1A
• Male infertility with azoospermia or oligozoospermia due to single gene mutation, also linked to AR
• Male infertility, also linked to AR
• Partial androgen insensitivity syndrome, also linked to AR

Frequently asked questions

Which genes are linked to Disorder of sexual differentiation?

In CATVariant, Disorder of sexual differentiation is linked to 3 analyzed proteins: AR (Androgen receptor), HSD17B3 (17-beta-hydroxysteroid dehydrogenase type 3) and CACNA1A (Voltage-dependent P/Q-type calcium channel subunit alpha-1A).

How many genetic variants are linked to Disorder of sexual differentiation?

9 variants: 6 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 2 are of uncertain significance or have conflicting reports.

Which uncertain variants in Disorder of sexual differentiation look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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