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Cited by 98Sexual Differentiation and DisordersAdrenal Hormones and DisordersMetabolism and Genetic Disorders

Steroid 21‐hydroxylase gene mutational spectrum in 454 Argentinean patients: genotype–phenotype correlation in a large cohort of patients with congenital adrenal hyperplasia

Marino, Roxana, Ramirez, Pablo, Galeano, Jesica, Perez Garrido, Natalia, Rocco, Carlos, Ciaccio, Marta, Warman, Diana M., Guercio, Gabriela +8 more·2011·Clinical Endocrinology
DOI 10.1111/j.1365-2265.2011.04123.x
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Abstract

Objective To report genotype–phenotype correlation in a large cohort of patients. Context Study of the CYP21A2 gene in 866 unrelated chromosomes of 21‐hydroxylase deficiency in Argentinean patients with classic and nonclassic (NC) forms of congenital adrenal hyperplasia (CAH). Methods Eleven most common mutations were analysed by allele‐specific polymerase chain reaction, restriction fragment length polymorphism (RFLP) or southern blot analysis. Gene sequencing was performed when no mutation was detected in one allele or the genotype–phenotype correlation was lacking. Results The 11‐most‐common‐mutation screening allowed for the detection of 88·1% of affected alleles (80·3% in the NC and 95·2% in the classic forms). p.V281L, IVS2‐13A/C>G (In2) and gene deletions and large gene conversions were the most prevalent mutations. In2 (35·2%) in salt wasting (SW), p.I172N (37·3%) in simple virilizing and p.V281L (54·1%) in NC CAH were the most prevalent mutations within the clinical forms. In 7/15 p.P30L mutation alleles, a chimeric CYP21A1P/CYP21A2 gene [PromCYP21A1P; p.P30L] was detected, while 6/15 represented a single‐nucleotide substitution, and in 2/15 linkage with mutations, p.[P30L; V281L] and [p.P30L; IVS2‐13A/C > G; p.Q318X] was found. In two SW patients, a novel nonsense mutation, p.Q41X, was observed. In three p.V281L mutation patients, the phenotype was more severe than predicted by genotype. Sequence analysis revealed an intronic alteration in the allele carrying the p.V281L mutation [IVS2 + 5G > A; p.V281L]. An aberrant splicing in this p.V281L mutated allele explains the clinical phenotype. Conclusions A high percentage of CYP21A2 affected alleles is detected by the 11‐mutation screening study. Genotype–phenotype correlation was high, but when the phenotype is more severe than predicted by genotype, presence of two alterations in one allele should be ruled out.

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  • In a large Brazilian cohort, nine novel or rare variants were identified, several of which exhibited clear founder effects and shared haplotypes with Spanish and Portuguese patients.

    “In a large Brazilian cohort, nine novel or rare variants were identified, several of which (p.(Arg408Cys), c.1450_1451insC, p.(His365Tyr), c.293-2C>G, p.(Gly424Ser) exhibited clear founder effects and shared haplotypes with Spanish and Portuguese patients, reflecting the historical Iberian contribution to Brazilian ancestry (22, 27, 40, 41).”

    From Evolution of molecular diagnostic strategies for 21-hydroxylase deficiency: from classical methods to advanced genomic techniques (2026) · cites this paper as [27]

  • In most populations, targeted genotyping methods achieve a detection rate of approximately 90-95% of known pathogenic alleles.

    “In most populations, these methods achieve a detection rate of approximately 90-95% of known pathogenic alleles, providing a balance between analytical precision, efficiency and reproducibility, making it suitable for detecting recurrent CYP21A2 variants in diagnostic laboratories during the 1990s and early 2000s (27, 31, 47, 71, 72).”

    From Evolution of molecular diagnostic strategies for 21-hydroxylase deficiency: from classical methods to advanced genomic techniques (2026) · cites this paper as [27]

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Authors
Marino, R., Ramirez, P., Galeano, J., Perez Garrido, N., Rocco, C., Ciaccio, M., Warman, D. M., Guercio, G., Chaler, E., Maceiras, M., Bergadá, I., Gryngarten, M., Balbi, V., Pardes, E., Rivarola, M. A., & Belgorosky, A.
Affiliations
  • Garrahan Hospital (AR)
  • Hospital General de Niños Ricardo Gutierrez (AR)
  • Hospital de Niños Superiora Sor María Ludovica (AR)
  • Hospital Ramos Mejía (AR)
Corresponding author
Belgorosky, Alicia
ORCID
Venue
Clinical Endocrinology
Publisher
Wiley
Published
2011-09-07
Volume
75
Issue
4
Pages
427-435
ISSN
  • 0300-0664 (ISSN-L)
  • 1365-2265
DOI
10.1111/j.1365-2265.2011.04123.x
OpenAlex
W1488201200
Cited by
98
References
34
Citations by year
2026: 1 · 2025: 6 · 2024: 1 · 2023: 15 · 2022: 7 · 2021: 19 · 2020: 5 · 2019: 8 · 2018: 3 · 2017: 5 · 2016: 9 · 2015: 3 · 2014: 4 · 2013: 7 · 2012: 5
FWCI
2.07
Type
journal article
Language
en
Open access
closed
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Clinical Endocrinology (publishedVersion)
  • PubMed (publishedVersion)
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, mutation spectrum, genotype-phenotype correlation, non-classical congenital adrenal hyperplasia, salt wasting, aberrant splicing
MeSH terms
Adrenal Hyperplasia, Congenital, Argentina, DNA Mutational Analysis, Female, Genotype, Humans, Male, Mutation, Phenotype, Steroid 21-Hydroxylase

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