Differences in sex development

Gene: CYP11A1

Green List (high evidence)

Comment on mode of inheritance: There are only two potentially plausible reports of heterozygous CYP11A1 variants and adrenal insufficiency / differences in sex development (PMIDs: 29995203, 11502818). In contrast, there are at least 44 biallelic CYP11A1 cases with adrenal insufficiency and/or differences in sex development. Studies have shown that severe CYP11A1 LOF variants in conjunction with common, 'likely benign' variants (e.g., rs6161 in European populations) may underlie unsolved cases of PAI (PMID:30620006). Hence, the mode of inheritance should be changed to BIALLELIC, autosomal or pseudoautosomal, for Differences in sex development.

Created: 21 Jan 2026, 11:44 a.m. | Last Modified: 21 Jan 2026, 11:44 a.m.

Panel Version: 4.12

PMID: 39457196 - 2024 literature review: 4 het individuals (described below) and 44 biallelic cases of P450scc deficiency

PMID: 29995203 - het CYP11A1 c.235G>A, p.Val79Ile - 3 family members with transient adrenal insufficiency and life-threatening failure to thrive - variant has MAF 0.006202 in gnomAD (European pop), 24 homozygotes - unlikely to be pathogenic?

PMID: 11502818 - heterozygous CYP11A1 c.809_814dup; p.Asp271_Val272insGlyAsp - female with clitoromegaly and adrenal insufficiency, onset at 4 years (not congenital?); variant not reported in gnomAD

Additional evidence:
PMID: 35418949 - possible digenic, tri-allelic inheritance - patient with compound heterozygous variants in STAR, c.465+1G>A and p.(E99K), plus a heterozygous c.940G>A (p.Glu314Lys) change in CYP11A1 (MAF 0.004798, 18 homozygotes total in gnomAD).

PMID: 30620006 - 'Predicted Benign and Synonymous Variants in CYP11A1 Cause Primary Adrenal Insufficiency Through Missplicing' - showed that rs6161 - CYP11A1 c.940G>A (p.Glu314Lys) - alters splicing of the pre-mRNA sequence, and may be responsible for a substantial proportion of unsolved PAI in conjunction with another LOF allele

https://abstracts.eurospe.org/hrp/0092/hrp0092p2-260 - poster - het case with CYP11A1 c.835delA p.(lle279Tyrfs*1) - normally pathogenic in recessive state - may contribute but not explain the phenotype. Patient phenotype: hypoglycaemia, perineal hypospadias, chordee and cryptorchidism.

CYP11A1 is associated with Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM: 613743 - MOI not specified (OMIM accessed 21st Jan 2026).

Created: 21 Jan 2026, 11:42 a.m. | Last Modified: 21 Jan 2026, 11:42 a.m.

Panel Version: 4.12

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM: 613743; Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency, MONDO:0013400

Publications

• 11502818
• 29995203
• 30620006
• 35418949
• 39457196

The mode of inheritance of this gene has been updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.

Created: 31 Jan 2023, 4:46 p.m. | Last Modified: 31 Jan 2023, 4:46 p.m.

Panel Version: 3.2

Comment on mode of inheritance: Homozygous, compound heterozygous, and heterozygous (although most rare) variants in the CYP11A1 gene have all been associated with disease. Therefore, MOI should be updated to 'Both mono- and biallelic' at the next GMS panel update.

Created: 7 Jun 2022, 11:01 a.m. | Last Modified: 7 Jun 2022, 11:01 a.m.

Panel Version: 2.60

Green List (high evidence)

As discussed in the GMS Endocrinology Specialist Test Group webex call 28th Jan 2019: The Specialist Test Group agreed that there is enough evidence to rate this gene green.

Created: 29 Apr 2019, 9:46 a.m.

Comment when marking as ready: Associated with phenotype in OMIM, not in G2P / DD. At least nine variants reported

Created: 8 Sep 2016, 2:22 p.m.

Green List (high evidence)

Severe loss associated with underandrogenization (46,XY) and primary salt losing adrenal insufficiency. Milder variants may cause hypospadias or normal genitalia with milder adrenal insufficiency.

Created: 4 Feb 2016, 12:14 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
DSD; primary adrnal insufficiency

Phenotypes from UKGTN and OMIM.

Created: 11 Jan 2016, 10:52 a.m.