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Comprehensive Genetic Analysis of 182 Unrelated Families with Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency
Open accessAbstract
Background: Genetic analysis is commonly performed in patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. Study Objective: The objective of the study was to describe comprehensive CYP21A2 mutation analysis in a large cohort of CAH patients. Methods: Targeted CYP21A2 mutation analysis was performed in 213 patients and 232 parents from 182 unrelated families. Complete exons of CYP21A2 were sequenced in patients in whom positive mutations were not identified by targeted mutation analysis. Copy number variation and deletions were determined using Southern blot analysis and PCR methods. Genotype was correlated with phenotype. Results: In our heterogeneous U.S. cohort, targeted CYP21A2 mutation analysis did not identify mutations on one allele in 19 probands (10.4%). Sequencing identified six novel mutations (p.Gln262fs, IVS8+1G>A, IVS9-1G>A, p.R408H, p.Gly424fs, p.R426P) and nine previously reported rare mutations. The majority of patients (79%) were compound heterozygotes and 69% of nonclassic (NC) patients were compound heterozygous for a classic and a NC mutation. Duplicated CYP21A2 haplotypes, de novo mutations and uniparental disomy were present in 2.7% of probands and 1.9 and 0.9% of patients from informative families, respectively. Genotype accurately predicted phenotype in 90.5, 85.1, and 97.8% of patients with salt-wasting, simple virilizing, and NC mutations, respectively. Conclusions: Extensive genetic analysis beyond targeted CYP21A2 mutational detection is often required to accurately determine genotype in patients with CAH due to the high frequency of complex genetic variation.
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“Several reports in European, Mediterranean, Middle Eastern, and Chinese populations confirmed a high frequency of the pathogenic IVS2-13A/C > G and found it to comprise 20 to 25% of the CYP21A2 mutant alleles and to translate to the most severe SW forms of the disease when inherited in homozygosity [1, 4, 27, 39–43].”
From Salt-wasting congenital adrenal hyperplasia phenotype as a result of the TNXA/TNXB chimera 1 (CAH-X CH-1) and the pathogenic IVS2-13A/C > G in CYP21A2 gene (2023) · cites this paper as [39]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“All subjects had previously completed comprehensive genetic analysis related to 21-hydroxylase de fi ciency at the time of study, including a targeted PCR-based CYP21A2 mutation analysis of 12 common CYP21A2 mutations and screening for the presence of a 30-Kb deletion based on 12 single-nucleotide polymorphic markers (Esoterix Laboratory Services, Calabasas Hills, CA). Samples testing positive for”
From High-Throughput Screening for CYP21A1P-TNXA/TNXB Chimeric Genes Responsible for Ehlers Danlos Syndrome in Patients with Congenital Adrenal Hyperplasia. (2019) · cites this paper as [7]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Given that approximately 30% of classic CAH mutations are 30-Kb deletions 7”
From High-Throughput Screening for CYP21A1P-TNXA/TNXB Chimeric Genes Responsible for Ehlers Danlos Syndrome in Patients with Congenital Adrenal Hyperplasia. (2019) · cites this paper as [7]
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“Consequently, the SW form generally results from combinations of two severe alleles (groups 0 or A), whereas the SV form arises in patients homozygous for group B variants, or compound heterozygous of group B variants with groups null or A. The NC phenotype usually manifests in carriers of two mild alleles (group C) or combinations of mild and severe (groups null, A or B) variants (22, 26, 47, 48)”
From Evolution of molecular diagnostic strategies for 21-hydroxylase deficiency: from classical methods to advanced genomic techniques (2026) · cites this paper as [26]
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“Most affected individuals are compound heterozygotes, and the clinical outcome is typically determined by the allele that maintains the highest residual enzyme activity.”
From Evolution of molecular diagnostic strategies for 21-hydroxylase deficiency: from classical methods to advanced genomic techniques (2026) · cites this paper as [26]
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“In 21-OHD, a strong correlation between genotype and phenotype has been consistently reported across multiple populations (22, 26, 46, 47).”
From Evolution of molecular diagnostic strategies for 21-hydroxylase deficiency: from classical methods to advanced genomic techniques (2026) · cites this paper as [26]
In the citing paper
“The discovery of POR deficiency in 2004 15,16 provided an explanation for multiple hormonal deficiency initially known as apparent combined 17OH and 21OH deficiency.”
From Congenital adrenal hyperplasia (2017) · cites this paper as [15]
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“Phenotypic classification was determined based on clinical and hormonal criteria and has been previously reported 11.”
From Cortical bone mineral density in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (2015) · cites this paper as [11]
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“Good genotype-phenotype correlation was observed and has been previously reported (5).”
From Clinical characteristics of a cohort of 244 patients with congenital adrenal hyperplasia (2012) · cites this paper as [5]
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“The diagnosis was confirmed with hormonal testing and genotyping (5).”
From Clinical characteristics of a cohort of 244 patients with congenital adrenal hyperplasia (2012) · cites this paper as [5]
In the citing paper
“For NCCAH, almost 70% of diagnosed patients are compound heterozygotes, carrying one allele that causes classic CAH and one that causes NCCAH (171, 246).”
From Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society* Clinical Practice Guideline (2018) · cites this paper as [246]
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Citations
Cites
Congenital Adrenal Hyperplasia
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High frequency of nonclassical steroid 21-hydroxylase deficiency
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Speiser, P. W., Azziz, R., Baskin, L. S., Ghizzoni, L., Hensle, T. W., Merke, D. P., Meyer-Bahlburg, H. F. L., Miller, W. L., Montori, V. M., Oberfield, S. E., et al. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-2631 · Cited by 1,468
Self-citationSpeiser, P. W., Arlt, W., Auchus, R. J., Baskin, L. S., Conway, G. S., Merke, D. P., Meyer-Bahlburg, H. F. L., Miller, W. L., Murad, M. H., Oberfield, S. E., et al. (2018) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2018-01865 · Cited by 1,234
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Self-citationCongenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management
Claahsen - van der Grinten, H. L., Speiser, P. W., Ahmed, S. F., Arlt, W., Auchus, R. J., Falhammar, H., Flück, C. E., Guasti, L., Huebner, A., Kortmann, B. B. M., et al. (2022) · Endocrine Reviews · doi:10.1210/endrev/bnab016 · Cited by 556
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Metadata
- Authors
- Finkielstain, G. P., Chen, W., Mehta, S. P., Fujimura, F. K., Hanna, R. M., Van Ryzin, C., McDonnell, N. B., & Merke, D. P.
- Affiliations
- National Institutes of Health (US)
- National Institute on Aging (US)
- Esoterix, Inc. (F.K.F.), Calabasas Hills, California 91301
- The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Clinical Center (S.P.M., R.M.H., C.V.R., D.P.M.), National Institutes of Health, Bethesda, Maryland 20892
- Corresponding author
- Merke, Deborah P.
- ORCID
- Merke, Deborah P.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2011-01-01
- Volume
- 96
- Issue
- 1
- Pages
- E161-E172
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC3038490
- OpenAlex
- W2117425767
- Cited by
- 192
- References
- 63
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 12 · 2023: 10 · 2022: 12 · 2021: 15 · 2020: 11 · 2019: 15 · 2018: 11 · 2017: 9 · 2016: 11 · 2015: 12 · 2014: 12 · 2013: 17 · 2012: 14
- FWCI
- 5.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- CARES Foundation
- National Institutes of Health
- U.S. Public Health Service
- National Institute of Child Health and Human Development
- NIH Clinical Center
- Eunice Kennedy Shriver National Institute of Child Health and Human Development
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › 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 mutations, novel mutations, compound heterozygosity, copy number variation, uniparental disomy, de novo mutations, genotype-phenotype correlation, salt-wasting CAH, simple virilizing CAH
- MeSH terms
- Adolescent, Adrenal Hyperplasia, Congenital, Adult, Aged, Alleles, Child, Child, Preschool, DNA Mutational Analysis, Female, Genetic Testing, Genotype, Humans, Infant, Male, Middle Aged, Mutation, Phenotype, Steroid 21-Hydroxylase, United States, Blotting, Southern, Reverse Transcriptase Polymerase Chain Reaction, Genetic Association Studies
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