Congenital adrenal hyperplasia: genes and variants

Genes linked to Congenital adrenal hyperplasia

• CYP21A2: Steroid 21-hydroxylase

  It enables cortisol and aldosterone synthesis by 21-hydroxylating adrenal steroid precursors. Biallelic loss-of-function variants cause congenital adrenal hyperplasia, with cortisol deficiency, androgen excess, and in severe forms life-threatening salt wasting.

  16 disease-causing and 3 uncertain variants in CYP21A2 are linked to Congenital adrenal hyperplasia.

• CYP17A1: Steroid 17-alpha-hydroxylase/17,20 lyase

  Its 17-alpha-hydroxylase and 17,20-lyase activities direct adrenal and gonadal steroid synthesis toward glucocorticoids and sex steroids. Biallelic deficiency causes 17-alpha-hydroxylase/17,20-lyase deficiency with hypertension, hypokalemia, and impaired sexual development.

  13 disease-causing and 1 uncertain variants in CYP17A1 are linked to Congenital adrenal hyperplasia.

• CYP11B1: Cytochrome P450 11B1, mitochondrial

  It catalyzes the final step of cortisol synthesis and also contributes to adrenal steroid metabolism. Biallelic loss-of-function variants cause 11-beta-hydroxylase-deficient congenital adrenal hyperplasia, characterized by cortisol deficiency, androgen excess, and frequently hypertension.

  10 disease-causing and 4 uncertain variants in CYP11B1 are linked to Congenital adrenal hyperplasia.

• 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.

  8 disease-causing and 1 uncertain variants in HSD3B2 are linked to Congenital adrenal hyperplasia.

• POR: NADPH--cytochrome P450 reductase

  It transfers electrons from NADPH to microsomal cytochrome P450 enzymes, making it essential for steroid synthesis and metabolism of many drugs and xenobiotics. Biallelic pathogenic variants cause P450 oxidoreductase deficiency, with disordered steroidogenesis and skeletal abnormalities.

  2 disease-causing and 0 uncertain variants in POR are linked to Congenital adrenal hyperplasia.

Known disease-causing variants in Congenital adrenal hyperplasia

Which prediction tools work for Congenital adrenal hyperplasia

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• REVEL: 99 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 98 out of 100
• PolyPhen-2: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 92 out of 100
• SIFT: 92 out of 100

Same protein, different disease

• 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia is also caused by CYP21A2 variants; they fall partly in the same places as the Congenital adrenal hyperplasia variants (37 disease-causing).
• Deficiency of steroid 17-alpha-monooxygenase is also caused by CYP17A1 variants; they fall mostly in different places as the Congenital adrenal hyperplasia variants (40 disease-causing).
• 17-alpha-hydroxylase/17,20-lyase deficiency, combined complete is also caused by CYP17A1 variants; they fall partly in the same places as the Congenital adrenal hyperplasia variants (3 disease-causing).
• Deficiency of steroid 11-beta-monooxygenase is also caused by CYP11B1 variants; they fall partly in the same places as the Congenital adrenal hyperplasia variants (33 disease-causing).
• Glucocorticoid-remediable aldosteronism is also caused by CYP11B1 variants; they fall partly in the same places as the Congenital adrenal hyperplasia variants (20 disease-causing).
• 3 beta-Hydroxysteroid dehydrogenase deficiency is also caused by HSD3B2 variants; they fall mostly in different places as the Congenital adrenal hyperplasia variants (17 disease-causing).
• Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis is also caused by POR variants; they fall mostly in different places as the Congenital adrenal hyperplasia variants (7 disease-causing).
• Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency is also caused by POR variants; they fall mostly in different places as the Congenital adrenal hyperplasia variants (7 disease-causing).

Diseases related to Congenital adrenal hyperplasia

• Differences in sex development, also linked to CYP11B1, CYP17A1 and POR
• Deficiency of steroid 17-alpha-monooxygenase, also linked to CYP17A1
• 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia, also linked to CYP21A2
• Deficiency of steroid 11-beta-monooxygenase, also linked to CYP11B1
• Glucocorticoid-remediable aldosteronism, also linked to CYP11B1
• 3 beta-Hydroxysteroid dehydrogenase deficiency, also linked to HSD3B2
• Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency, also linked to POR
• Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis, also linked to POR
• Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis, also linked to POR
• Prostate cancer, also linked to CYP17A1
• 17-alpha-hydroxylase/17,20-lyase deficiency, combined complete, also linked to CYP17A1
• Hypospadias, also linked to HSD3B2

Frequently asked questions

Which genes are linked to Congenital adrenal hyperplasia?

In CATVariant, Congenital adrenal hyperplasia is linked to 5 analyzed proteins: CYP21A2 (Steroid 21-hydroxylase), CYP17A1 (Steroid 17-alpha-hydroxylase/17,20 lyase), CYP11B1 (Cytochrome P450 11B1, mitochondrial), HSD3B2 (3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2) and POR (NADPH--cytochrome P450 reductase).

How many genetic variants are linked to Congenital adrenal hyperplasia?

81 variants: 49 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 9 are of uncertain significance or have conflicting reports.

Which uncertain variants in Congenital adrenal hyperplasia look disease-causing?

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

Which variant effect predictor works best for Congenital adrenal hyperplasia?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.98, based on 42 disease-causing and 28 harmless variants).

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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