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Cited by 192Sexual Differentiation and DisordersAdrenal Hormones and DisordersMetabolism and Genetic Disorders

Comprehensive genetic analysis of 182 unrelated families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

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Finkielstain, Gabriela P., Chen, Wuyan, Mehta, Sneha P., Fujimura, Frank K., Hanna, Reem M., Van Ryzin, Carol, McDonnell, Nazli B., Merke, Deborah P.·2011·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jc.2010-0319PMC PMC3038490
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Abstract

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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  • The pathogenic IVS2-13A/C > G comprises 20 to 25% of CYP21A2 mutant alleles and translates to the most severe SW forms of the disease when inherited in homozygosity.

    “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]

    The Genotype-phenotype correlation section places patients homozygous for IVS2-13A/C>G in group A and identifies salt-wasting (SW) disease as that group's expected phenotype. The Mutation analysis section reports allele frequencies for deletions and single-point mutations overall, but the passages found do not establish that this specific variant comprises 20–25% of mutant alleles or confirm that frequency across the populations named in the citing sentence. (LLM, conf=0.83)

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  • All subjects had previously completed comprehensive genetic analysis related to 21-hydroxylase deficiency, including targeted PCR-based CYP21A2 mutation analysis and screening for 30-Kb deletion; samples testing positive for 30-Kb deletion underwent a validated Sanger sequencing test to identify CYP21 chimeras.

    “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]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • Approximately 30% of classic CAH mutations are 30-Kb deletions.

    “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]

    The Mutation analysis section (page unavailable) reports that gene deletions accounted for 30.5% of alleles in the study cohort. Table 3 (Discussion; page unavailable) lists 30-kb deletions but also distinguishes them from other deletions. The paper does not establish that approximately 30% of mutations in classic CAH specifically are 30-kb deletions. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The salt-wasting form generally results from combinations of two severe alleles (groups 0 or A); the simple-virilizing form arises in patients homozygous for group B variants or compound heterozygous for group B with null/A; the nonclassical phenotype usually manifests in carriers of two mild alleles (group C) or combinations of mild and severe variants.

    “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]

  • Most affected individuals are compound heterozygotes, and clinical outcome is typically determined by the allele that maintains the highest residual enzyme activity.

    “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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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
DOI
10.1210/jc.2010-0319
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
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
  • 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 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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