Congenital adrenal hyperplasia due to two rare CYP21A2 variant alleles, including a novel attenuated CYP21A1P/CYP21A2 chimera
Open accessAbstract
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.
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CYP21A2 genotyping may be complicated by large deletions and gene conversions that generate TNXA/TNXB or CYP21A1P/CYP21A2 chimeric alleles through non-allelic homologous recombination.
“Beyond the effect of individual variants, CYP21A2 genotyping may be complicated by large deletions and gene conversions that generate TNXA/TNXB or CYP21A1P/CYP21A2 chimeric alleles through non-allelic homologous recombination.”
From Evolution of molecular diagnostic strategies for 21-hydroxylase deficiency: from classical methods to advanced genomic techniques (2026) · cites this paper as [96]
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Krone, N., Braun, A., Roscher, A. A., Knorr, D., & Schwarz, H. P. (2000) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.85.3.6441 · Cited by 397 · see citing works
Finkielstain, G. P., Chen, W., Mehta, S. P., Fujimura, F. K., Hanna, R. M., Van Ryzin, C., McDonnell, N. B., & Merke, D. P. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2010-0319 · Cited by 192 · see citing works
Self-citationJunction Site Analysis of Chimeric CYP21A1P/CYP21A2 Genes in 21-Hydroxylase Deficiency
Chen, W., Xu, Z., Sullivan, A., Finkielstain, G. P., Van Ryzin, C., Merke, D. P., & McDonnell, N. B. (2012) · Clinical Chemistry · doi:10.1373/clinchem.2011.174037 · Cited by 86 · see citing works
Self-citationMerke, D. P., Chen, W., Morissette, R., Xu, Z., Van Ryzin, C., Sachdev, V., Hannoush, H., Shanbhag, S. M., Acevedo, A. T., Nishitani, M., et al. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-3148 · Cited by 82 · see citing works
Self-citationAraujo, R. S., Billerbeck, A. E. C., Madureira, G., Mendonca, B. B., & Bachega, T. A. S. S. (2005) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2005.02184.x · Cited by 42 · see citing works
Genes and Pseudogenes: Complexity of the RCCX Locus and Disease
Carrozza, C., Foca, L., De Paolis, E., & Concolino, P. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.709758 · Cited by 37 · see citing works
Linking the degree of virilization in females with congenital adrenal hyperplasia to genotype
Gurgov, S., Bernabé, K. J., Stites, J., Cunniff, C. M., Lin‐Su, K., Felsen, D., New, M. I., & Poppas, D. P. (2017) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.13370 · Cited by 17 · see citing works
Flagged first, then by citations
Research works printed but not linked: 12
- Baumgartner‐Parzer, S., Witsch‐Baumgartner, M., & Hoeppner, W. (2020). EMQN best practice guidelines for molecular genetic testing and reporting of 21‐hydroxylase deficiency. European Journal of Human Genetics, 28(10), 1341– 1367. 10.1038/s41431-020-0653-5 32616876 PMC7609334 · DOI · Paper page
- Coeli, F. B., Soardi, F. C., Bernardi, R. D., de Araújo, M., Paulino, L. C., Lau, I. F., Petroli, R. J., de Lemos‐Marini, S. H. V., Baptista, M. T. M., Guerra‐Júnior, G., & de‐Mello, M. P. (2010). Novel deletion alleles carrying CYP21A1P/A2chimeric genes in Brazilian patients with 21‐hydroxylase deficiency. BMC Medical Genetics, 11(1), 104. 10.1186/1471-2350-11-104 20587039 PMC3161346 · DOI
- Falhammar, H., Frisén, L., Hirschberg, A. L., Nordenskjöld, A., Almqvist, C., & Nordenström, A. (2019). Increased risk of autoimmune disorders in 21‐hydroxylase deficiency: A Swedish population‐based National Cohort Study. Journal of the Endocrine Society, 3(5), 1039– 1052. 10.1210/js.2019-00122 31065621 PMC6497917 · DOI
- Hannah‐Shmouni, F., Morissette, R., Sinaii, N., Elman, M., Prezant, T. R., Chen, W., Pulver, A., & Merke, D. P. (2017). Revisiting the prevalence of nonclassic congenital adrenal hyperplasia in US Ashkenazi Jews and Caucasians. Genetics in Medicine, 19(11), 1276– 1279. 10.1038/gim.2017.46 28541281 PMC5675788 · DOI · Paper page
- Keen‐Kim, D., Redman, J. B., Alanes, R. U., Eachus, M. M., Wilson, R. C., New, M. I., Nakamoto, J. M., & Fenwick, R. G. (2005). Validation and clinical application of a locus‐specific polymerase chain reaction‐ and minisequencing‐based assay for congenital adrenal hyperplasia (21‐hydroxylase deficiency). The Journal of Molecular Diagnostics, 7(2), 236– 246. 10.1016/s1525-1578(10)60550-8 15858147 PMC1867523 · DOI
- l'Allemand, D., Tardy, V., Grüters, A., Schnabel, D., Krude, H., & Morel, Y. (2000). How a patient homozygous for a 30‐kb deletion of the C4‐CYP 21 genomic region can have a nonclassic form of 21‐hydroxylase deficiency. The Journal of Clinical Endocrinology & Metabolism, 85(12), 4562– 4567. 10.1210/jcem.85.12.7018 11134109 · DOI · Paper page
- Merke, D. P., & Auchus, R. J. (2020). Congenital adrenal hyperplasia due to 21‐hydroxylase deficiency. The New England Journal of Medicine, 383(13), 1248– 1261. 10.1056/NEJMra1909786 32966723 · DOI · Paper page
- Miller, W. L. (2020). Tenascin‐X‐discovery and early research. Frontiers in Immunology, 11, 612497. 10.3389/fimmu.2020.612497 33505400 PMC7829301 · DOI · Paper page
- Pignatelli, D., Carvalho, B. L., Palmeiro, A., Barros, A., Guerreiro, S. G., & Macut, D. (2019). The complexities in genotyping of congenital adrenal hyperplasia: 21‐hydroxylase deficiency. Frontiers in Endocrinology, 10, 432. 10.3389/fendo.2019.00432 31333583 PMC6620563 · DOI · Paper page
- Tolba, A., Mandour, I., Musa, N., Elmougy, F., Hafez, M., Abdelatty, S., Ibrahim, A., Soliman, H., Labib, B., Elshiwy, Y., Ramzy, T., & Elsharkawy, M. (2022). Copy number variations in genetic diagnosis of congenital adrenal hyperplasia children. Frontiers in Genetics, 13, 785570. 10.3389/fgene.2022.785570 35309130 PMC8924405 · DOI · Paper page
- Tsai, L. P., & Lee, H. H. (2012). Analysis of CYP21A1P and the duplicated CYP21A2 genes. Gene, 506(1), 261– 262. 10.1016/j.gene.2012.06.045 22771554 · DOI
- Xu, Z., Chen, W., Merke, D. P., & McDonnell, N. B. (2013). Comprehensive mutation analysis of the CYP21A2 gene: An efficient multistep approach to the molecular diagnosis of congenital adrenal hyperplasia. The Journal of Molecular Diagnostics, 15(6), 745– 753. 10.1016/j.jmoldx.2013.06.001 24071710 PMC5803549 · DOI · Paper page
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Sorted by citations
Miranda, M. C. D., Oliveira, A. C. M. D., Soares, G. J., Batatinha, J. A. P., Latronico, A. C., Mendonca, B. B., & Bachega, T. A. S. S. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1770274 · Cited by 2 · see citing works
Claps, A., Kolomenski, J. E., Fernández, F., Macchiaroli, N., Ingravidi, M. L., Delea, M., Fernández, C., Castro, T., Laiseca, J., Kamenetzky, L., et al. (2025) · Scientific Reports · doi:10.1038/s41598-025-03799-7 · Cited by 3 · see citing works
- Authors
- Lao, Q., Burkardt, D. D., Kollender, S., Faucz, F. R., & Merke, D. P.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Merke, Deborah P.
- Venue
- Molecular Genetics & Genomic Medicine
- Publisher
- Wiley
- Published
- 2023-05-08
- Volume
- 11
- Issue
- 7
- Pages
- e2195-e2195
- ISSN
- 2324-9269 (ISSN-L)
- PMC
- PMC10337281
- OpenAlex
- W4375956175
- Cited by
- 8
- References
- 7
- Citations by year
- 2026: 2 · 2025: 4 · 2023: 2
- FWCI
- 0.71
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Genetics & Genomic Medicine (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- congenital adrenal hyperplasia, 21-hydroxylase deficiency, CYP21A2, simple virilizing CAH, salt-wasting CAH, genotype-phenotype correlation
- MeSH terms
- Adrenal Hyperplasia, Congenital, Alleles, Female, Genetic Testing, Humans, Steroid 21-Hydroxylase, Young Adult
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