ClinGen - Dosage score is 30 (Gene associated with AR phenotype) for CAH. GenCC - Myriad/LMM/Invitae - Definitive or Strong for CAH. BabySeq - definitive for CAH (PMIDs: 9556656, 9521938, 7629224, 9300201, 18000084, 18323673, 12915679). Given these curations, scoring for gene-disease validity is unnecessary.
Simple virilizing form - Virilization of external genitalia of genetic females. Excess adrenal androgen production. Those who do not receive glucocorticoid replacement therapy develop precocious development of pubic and axillary hair, acne, rapid linear growth, and advanced bone age. Untreated males have progressive penile enlargement and small testes. Untreated females have clitoral enlargement, hirsutism, male pattern baldness, menstrual abnormalities, and reduced fertility.
Salt wasting form - Virilization plus risk for life-threatening salt-wasting crises at birth. Features include poor feeding, weight loss, failure to thrive, vomiting, dehydration, hypotension, hyponatremia, and hyperkalemic metabolic acidosis progressing to adrenal crisis (azotemia, vascular collapse, shock, and death). Males are at particular risk because normal male genitalia at birth does not alert to the dx; females with ambiguous genitalia usually prompts early dx and treatment
CAUSED BY SEVERE VARIANTS ON BOTH ALLELES
Non-classic:
hyperandrogenism
females are not virilized at birth, postnatal symptoms may include hirsutism, frontal baldness, delayed menarche, menstrual irregularities, and infertility.
Males may have early beard growth and an enlarged phallus with relatively small testes.
CAUSED BY TWO MILD/NONCLASSIC VARIANTS OR 1 MILD + 1 SEVERE. Nonclassic variants include p.Pro31Leu, p.Val282Leu, p.Pro454Ser
A nonfunctional pseudogene, CYP21A1P is located ~30kb from the CYP21A2 genes. High sequence homology at ~98% between exons.
A common duplication haplotype consists of the Gln319Ter pathogenic variant co-existing with a duplication on the same chromosome. Individuals with this duplication are at risk of being diagnosed as a carrier when in fact they have two normal functioning alleles.
High structural variability at the locus caused by unequal crossing over, results in deletions, duplications, quadruplications and gene-pseudogene conversions. PMID: 33961029
Gene conversions (which are pathogenic) can include CYP21A1P variants as shown in the two figures below from PMID: 23359698. Review your case in IGV for evidence of these variants, keeping in mind that short read sequencing has significant limitations, and variants may not be called correctly in the CYP21A2 gene due to pseudogene homology.
from PMID: 23359698
from PMID: 23359698
CYP21A1P is transcribed but its mRNA cannot encode a functional protein owing to at least 10 deleterious mutations (143, 144) including 2 frameshifts (8 bp deletion in exon 3, 1 bp insertion in exon 7, a nonsense mutation (p.Gln318stop; Q318X) (150), and a mutation in intron 2 that activates a cryptic splice site and causes an extra 19 nucleotides to be included in the mRNA (151). Missense mutations in the pseudogene include p.Pro30Leu (P30L) (107), p.Ile172Asn (I172N) (152), a cluster of missense mutations in exon 6, p.Ile236Asn, Val237Glu, Met239Lys (I236N, V237E, M239K), p.Val281Leu (V281L) (153), and p.Arg356Trp (R356W).
Genotype-phenotype correlations
Curation Summary
The CYP21A2 gene is associated with autosomal recessive congenital adrenal hyperplasia due to 21--hydroxylase deficiency, which may present as a classic salt-wasting form with virilization in affected females and risk for life-threatening salt-wasting at birth, a simple virilizing form with virilization of external genitalia in genetic females with additional features that may present later in life in untreated individuals, and a non-classic form with hyperandrogenism and postnatal symptoms (PMID: 20301350). Genotype-phenotype correlations have been described. In addition, the CYP21A2 gene shares high homology with the CYP21A1P pseudogene, both of which are located in the Human Leukocyte Antigen (HLA) Class III region on chromosome 6 (PMID: 33961029). The homology with CYP21A1P presents a challenge to molecular diagnostics, and there is high structural variability at this locus caused by unequal crossing over, which results in deletions, duplications, and gene-pseudogene conversions (PMID: 33961029)
