Congenital adrenal hyperplasia due to two rare CYP21A2 variant alleles, including a novel attenuated CYP21A1P/CYP21A2 chimera

• Published in: Molecular genetics & genomic medicine Vol. 11; no. 7; pp. e2195 - n/a
• Main Authors: Lao, Qizong, Burkardt, Deepika D., Kollender, Sarah, Faucz, Fabio R., Merke, Deborah P.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.07.2023; John Wiley and Sons Inc; Wiley
• Subjects: 21‐hydroxylase deficiency; Aldosterone; Alleles; Biosynthesis; CAH; chimera; Chimeras; Clinical Report; Clinical Reports; Cloning; congenital adrenal hyperplasia; CYP21A2; Genes; Genetic screening; Genotype & phenotype; Genotypes; Haplotypes; Hormones; Hyperplasia; Laboratories; Medical screening; Phenotypes; Recombination; chimera; 21-hydroxylase deficiency; CAH; CYP21A2; congenital adrenal hyperplasia
• ISSN: 2324-9269; 2324-9269
• DOI: 10.1002/mgg3.2195

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. CYP21A1P/CYP21A2 chimeric genes caused by recombination between CYP21A2 and its highly homologous CYP21A1P pseudogene are common in congenital adrenal hyperplasia (CAH) due to 21‐hydroxylase (21OH) deficiency and typically are associated with severe salt‐wasting (SW) CAH. We describe a 22‐year‐old female with non‐SW CAH and two rare CYP21A1P/CYP21A2 chimeras, including a novel CAH chimera (named CH‐10) which is expected to retain partial 21OH activity explaining the individual's mild phenotype.