Genotype–Phenotype Correlation in Children With Congenital Adrenal Hyperplasia due to 21‐Hydroxylase Deficiency Using Next Generation Sequencing
ABSTRACT Background Although there a well‐known correlation in genotype and phenotype, patients with 21‐OHD caused by severe pathogenic variants have better correlation, whereas inconsistencies are more common in the presence of milder variants. This study aimed to evaluate CYP21A2 genotyping and re...
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2025-06-01
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| Online Access: | https://doi.org/10.1002/mgg3.70110 |
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| author | Nurgul Atas Murat Karaoglan Gülper Nacarkahya |
| author_facet | Nurgul Atas Murat Karaoglan Gülper Nacarkahya |
| author_sort | Nurgul Atas |
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| description | ABSTRACT Background Although there a well‐known correlation in genotype and phenotype, patients with 21‐OHD caused by severe pathogenic variants have better correlation, whereas inconsistencies are more common in the presence of milder variants. This study aimed to evaluate CYP21A2 genotyping and reveal the genotype–phenotype correlation in children diagnosed with 21‐OHD in the South‐eastern Anatolia region, where ethnic diversity and consanguineous marriage rates are high. Methods The patients were divided into three groups: salt wasting (SW), simple virilizing (SV) and non‐classical (NC). Pathogenic variants of the CYP21A2 gene were classified into six groups based on predicted 21‐hydroxylase activity: null‐A‐B‐C‐D‐E. CYP21A2 genotyping was performed by sequence‐specific primer and sequenced with next generation sequencing (NGS), and the expected phenotypes were compared to the observed phenotypes. Results The overall genotype–phenotype concordance was found to be 73.1% (68/93). The expected concordance with the SW form of the null (n = 12) and A (n = 51) groups is 91.6% and 88.2%, respectively. While the percentage of the expected clinical form of SV in patients in group B (n = 5) was 80%, the concordance for the expected clinical form of NC for group C (n = 25) was not strong enough (32%). Conclusion This study demonstrates that children with 21‐hydroxylase deficiency show a good correlation between severe pathogenic variants and predicted clinical phenotypes; however, the correlation is not strong enough between milder variants. The discrepancies could have resulted from the complex characteristics of 21‐OHD genotyping and the limitations of using NGS alone without integrating with other comprehensive methods. |
| format | Article |
| id | doaj-art-28a609d293a44267a3dfa4fa087927d5 |
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| language | English |
| publishDate | 2025-06-01 |
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| spelling | doaj-art-28a609d293a44267a3dfa4fa087927d52025-08-20T02:20:52ZengWileyMolecular Genetics & Genomic Medicine2324-92692025-06-01136n/an/a10.1002/mgg3.70110Genotype–Phenotype Correlation in Children With Congenital Adrenal Hyperplasia due to 21‐Hydroxylase Deficiency Using Next Generation SequencingNurgul Atas0Murat Karaoglan1Gülper Nacarkahya2Department of Pediatric Endocrinology Gaziantep University Faculty of Medicine Gaziantep TurkeyDepartment of Pediatric Endocrinology Gaziantep University Faculty of Medicine Gaziantep TurkeyDepartment of Molecular Biology Gaziantep University Faculty of Medicine Gaziantep TurkeyABSTRACT Background Although there a well‐known correlation in genotype and phenotype, patients with 21‐OHD caused by severe pathogenic variants have better correlation, whereas inconsistencies are more common in the presence of milder variants. This study aimed to evaluate CYP21A2 genotyping and reveal the genotype–phenotype correlation in children diagnosed with 21‐OHD in the South‐eastern Anatolia region, where ethnic diversity and consanguineous marriage rates are high. Methods The patients were divided into three groups: salt wasting (SW), simple virilizing (SV) and non‐classical (NC). Pathogenic variants of the CYP21A2 gene were classified into six groups based on predicted 21‐hydroxylase activity: null‐A‐B‐C‐D‐E. CYP21A2 genotyping was performed by sequence‐specific primer and sequenced with next generation sequencing (NGS), and the expected phenotypes were compared to the observed phenotypes. Results The overall genotype–phenotype concordance was found to be 73.1% (68/93). The expected concordance with the SW form of the null (n = 12) and A (n = 51) groups is 91.6% and 88.2%, respectively. While the percentage of the expected clinical form of SV in patients in group B (n = 5) was 80%, the concordance for the expected clinical form of NC for group C (n = 25) was not strong enough (32%). Conclusion This study demonstrates that children with 21‐hydroxylase deficiency show a good correlation between severe pathogenic variants and predicted clinical phenotypes; however, the correlation is not strong enough between milder variants. The discrepancies could have resulted from the complex characteristics of 21‐OHD genotyping and the limitations of using NGS alone without integrating with other comprehensive methods.https://doi.org/10.1002/mgg3.7011021 hydroxylase deficiencyCYP21A2 gene mutationgenotype–phenotype correlation |
| spellingShingle | Nurgul Atas Murat Karaoglan Gülper Nacarkahya Genotype–Phenotype Correlation in Children With Congenital Adrenal Hyperplasia due to 21‐Hydroxylase Deficiency Using Next Generation Sequencing Molecular Genetics & Genomic Medicine 21 hydroxylase deficiency CYP21A2 gene mutation genotype–phenotype correlation |
| title | Genotype–Phenotype Correlation in Children With Congenital Adrenal Hyperplasia due to 21‐Hydroxylase Deficiency Using Next Generation Sequencing |
| title_full | Genotype–Phenotype Correlation in Children With Congenital Adrenal Hyperplasia due to 21‐Hydroxylase Deficiency Using Next Generation Sequencing |
| title_fullStr | Genotype–Phenotype Correlation in Children With Congenital Adrenal Hyperplasia due to 21‐Hydroxylase Deficiency Using Next Generation Sequencing |
| title_full_unstemmed | Genotype–Phenotype Correlation in Children With Congenital Adrenal Hyperplasia due to 21‐Hydroxylase Deficiency Using Next Generation Sequencing |
| title_short | Genotype–Phenotype Correlation in Children With Congenital Adrenal Hyperplasia due to 21‐Hydroxylase Deficiency Using Next Generation Sequencing |
| title_sort | genotype phenotype correlation in children with congenital adrenal hyperplasia due to 21 hydroxylase deficiency using next generation sequencing |
| topic | 21 hydroxylase deficiency CYP21A2 gene mutation genotype–phenotype correlation |
| url | https://doi.org/10.1002/mgg3.70110 |
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