Hypospadias: genes and variants

Genes linked to Hypospadias

• PIK3CA: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform

  Its p110-alpha catalytic activity generates PIP3 and activates AKT-dependent growth, survival, and metabolic signaling downstream of many receptors. Activating variants are frequent cancer drivers and, when present mosaically during development, can cause PIK3CA-related overgrowth spectrum.

  1 disease-causing and 0 uncertain variants in PIK3CA are linked to Hypospadias.

• 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.

  1 disease-causing and 3 uncertain variants in AR are linked to Hypospadias.

• HSD3B2: 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2

  It catalyzes an early essential step in adrenal and gonadal steroid synthesis, converting pregnenolone and related 3-beta-hydroxysteroids into progesterone-class intermediates. Biallelic deficiency causes congenital adrenal hyperplasia with impaired cortisol and aldosterone synthesis and variable disordered sex development.

  1 disease-causing and 0 uncertain variants in HSD3B2 are linked to Hypospadias.

Known disease-causing variants in Hypospadias

Same protein, different disease

• Androgen resistance syndrome is also caused by AR variants; they fall mostly in different places as the Hypospadias variants (85 disease-causing).
• Kennedy disease is also caused by AR variants; they fall mostly in different places as the Hypospadias variants (46 disease-causing).
• Differences in sex development is also caused by AR variants; they fall mostly in different places as the Hypospadias variants (9 disease-causing).
• Male infertility is also caused by AR variants; they fall mostly in different places as the Hypospadias variants (7 disease-causing).
• Partial androgen insensitivity syndrome is also caused by AR variants; they fall mostly in different places as the Hypospadias variants (7 disease-causing).
• 3 beta-Hydroxysteroid dehydrogenase deficiency is also caused by HSD3B2 variants; they fall mostly in different places as the Hypospadias variants (17 disease-causing).
• Congenital adrenal hyperplasia is also caused by HSD3B2 variants; they fall mostly in different places as the Hypospadias variants (8 disease-causing).
• PIK3CA related overgrowth syndrome is also caused by PIK3CA variants; they fall mostly in different places as the Hypospadias variants (30 disease-causing).
• Cowden syndrome is also caused by PIK3CA variants; they fall mostly in different places as the Hypospadias variants (23 disease-causing).
• Megalencephaly-capillary malformation-polymicrogyria syndrome is also caused by PIK3CA variants; they fall mostly in different places as the Hypospadias variants (22 disease-causing).
• Ovarian neoplasm is also caused by PIK3CA variants; they fall mostly in different places as the Hypospadias variants (5 disease-causing).
• PIK3CA constitutional syndrome is also caused by PIK3CA variants; they fall mostly in different places as the Hypospadias variants (4 disease-causing).

Diseases related to Hypospadias

• Ovarian cancer, also linked to AR and PIK3CA
• Noonan syndrome, also linked to PIK3CA
• Androgen resistance syndrome, also linked to AR
• Cowden syndrome, also linked to PIK3CA
• Congenital adrenal hyperplasia, also linked to HSD3B2
• Kennedy disease, also linked to AR
• PIK3CA related overgrowth syndrome, also linked to PIK3CA
• Familial cancer of breast, also linked to PIK3CA
• Megalencephaly-capillary malformation-polymicrogyria syndrome, also linked to PIK3CA
• Differences in sex development, also linked to AR
• Colorectal cancer, also linked to PIK3CA
• Gastric cancer, also linked to PIK3CA

Frequently asked questions

Which genes are linked to Hypospadias?

In CATVariant, Hypospadias is linked to 3 analyzed proteins: PIK3CA (Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform), AR (Androgen receptor) and HSD3B2 (3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2).

How many genetic variants are linked to Hypospadias?

6 variants: 3 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 3 are of uncertain significance or have conflicting reports.

Which uncertain variants in Hypospadias 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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