Background: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase (21OH) deficiency is an autosomal recessive inborn error of cortisol biosynthesis, with varying degrees of aldosterone production. There is a continuum of phenotypes which generally correlate with genotype and the expected residual 21OH activity of the less severely impaired allele. CYP21A1P/CYP21A2 chimeric genes caused by recombination between CYP21A2 and its highly homologous CYP21A1P pseudogene are common in CAH and typically associated with salt-wasting CAH, the most severe form. Nine chimeras have been described (CH-1 to CH-9).
Aims: The aim of this study was to genetically evaluate two variant alleles carried by a 22-year-old female with the non-salt-wasting simple virilizing form of CAH and biallelic 30-kb deletions.
Methods: The haplotypes of the CYP21A2 heterozygous variants, as well as the chimeric junction sites, were determined by Sanger sequencing TA clones of an allele-specific PCR product.
Results: Genetic testing revealed two rare CYP21A1P/CYP21A2 chimeras: allele 1 matches the previously described CAH CH-1 chimera but without the P30L variant, and allele 2, termed here as novel CAH CH-10, has a junction site between c.293-37 and c.29314, which is expected to retain partial 21OH activity.
Conclusion: These two variant alleles further document the complex nature of RCCX modules and highlight that not all CYP21A1P/CYP21A2 chimera severely impair 21OH activity.
Keywords: CYP21A2; 21-hydroxylase deficiency; CAH; chimera; congenital adrenal hyperplasia.
Published 2023. This article is a U.S. Government work and is in the public domain in the USA. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.