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

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 residu...

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Autores principales: Lao, Qizong, Burkardt, Deepika D., Kollender, Sarah, Faucz, Fabio R., Merke, Deborah P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10337281/
https://www.ncbi.nlm.nih.gov/pubmed/37157918
http://dx.doi.org/10.1002/mgg3.2195
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author Lao, Qizong
Burkardt, Deepika D.
Kollender, Sarah
Faucz, Fabio R.
Merke, Deborah P.
author_facet Lao, Qizong
Burkardt, Deepika D.
Kollender, Sarah
Faucz, Fabio R.
Merke, Deborah P.
author_sort Lao, Qizong
collection PubMed
description 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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spelling pubmed-103372812023-07-13 Congenital adrenal hyperplasia due to two rare CYP21A2 variant alleles, including a novel attenuated CYP21A1P/CYP21A2 chimera Lao, Qizong Burkardt, Deepika D. Kollender, Sarah Faucz, Fabio R. Merke, Deborah P. Mol Genet Genomic Med Clinical Reports 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. John Wiley and Sons Inc. 2023-05-08 /pmc/articles/PMC10337281/ /pubmed/37157918 http://dx.doi.org/10.1002/mgg3.2195 Text en 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. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Clinical Reports
Lao, Qizong
Burkardt, Deepika D.
Kollender, Sarah
Faucz, Fabio R.
Merke, Deborah P.
Congenital adrenal hyperplasia due to two rare CYP21A2 variant alleles, including a novel attenuated CYP21A1P/CYP21A2 chimera
title Congenital adrenal hyperplasia due to two rare CYP21A2 variant alleles, including a novel attenuated CYP21A1P/CYP21A2 chimera
title_full Congenital adrenal hyperplasia due to two rare CYP21A2 variant alleles, including a novel attenuated CYP21A1P/CYP21A2 chimera
title_fullStr Congenital adrenal hyperplasia due to two rare CYP21A2 variant alleles, including a novel attenuated CYP21A1P/CYP21A2 chimera
title_full_unstemmed Congenital adrenal hyperplasia due to two rare CYP21A2 variant alleles, including a novel attenuated CYP21A1P/CYP21A2 chimera
title_short Congenital adrenal hyperplasia due to two rare CYP21A2 variant alleles, including a novel attenuated CYP21A1P/CYP21A2 chimera
title_sort congenital adrenal hyperplasia due to two rare cyp21a2 variant alleles, including a novel attenuated cyp21a1p/cyp21a2 chimera
topic Clinical Reports
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10337281/
https://www.ncbi.nlm.nih.gov/pubmed/37157918
http://dx.doi.org/10.1002/mgg3.2195
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