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Cited by 15Sexual Differentiation and DisordersAdrenal Hormones and DisordersMetabolism and Genetic Disorders

Characteristics of In2G Variant in Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency

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Kocova, Mirjana, Concolino, Paola, Falhammar, Henrik·2022·Frontiers in Endocrinology
DOI 10.3389/fendo.2021.788812PMC PMC8818746
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Abstract

Substantial research has been performed during the last decades on the clinical and genetic variability of congenital adrenal hyperplasia (CAH) and its most common form, 21-hydroxylase deficiency (21OHD). CAH is one of the most prevalent autosomal recessive diseases in humans, and it can be divided into classic—further subdivided into salt wasting (SW) and simple virilizing (SV)—and non-classic (NC) forms. Pathogenic variants of CYP21A2 gene, encoding the 21-hydroxylase enzyme, have been reported with variable prevalence in different populations. NM_000500.9:c.293-13C/A>G (In2G) variant represents the most common CYP21A2 gene changes related to the classic 21OHD form. However, the phenotype of In2G carriers is variable depending on the variant homozygous/heterozygous status and combination with other CYP21A2 pathogenic variants. In addition, identical genotypes, harboring the homozygous In2G variant, can present with variable phenotypes including the SW and SV or rarely NC form of the disease. Here, we analyze and present the clinical aspects, genotype/phenotype correlations, and other characteristics related to the CYP21A2 In2G variant.

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  • The c.293-13C>G (I2 splice) variant is the most prevalent pathogenic allele, accounting for approximately 20-25% of reported genotypes.

    “Across global cohorts, the c.293-13C>G (I2 splice) variant consistently emerges as the most prevalent pathogenic allele, accounting for approximately 20–25% of reported genotypes (24).”

    From Evolution of molecular diagnostic strategies for 21-hydroxylase deficiency: from classical methods to advanced genomic techniques (2026) · cites this paper as [24]

    The CYP21A2 In2G Variant section calls In2G the most common CAH mutation in the majority of countries and ethnicities, but explicitly notes exceptions. It reports prevalence of 20.6%–30.3% in selected studies, while Table 1 shows a wider range across countries and labels its counts as alleles, not genotypes. Thus the source does not support a consistent global figure of 20%–25% of reported genotypes. (LLM, conf=0.88)

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  • The intron-2 splice variant (c.293-13C>G) reduces correct splicing by strengthening a cryptic acceptor and promoting aberrant exon-3 inclusion/skipping, normally leading to severe disease; however, clinical presentation can vary from SW to SV and rarely NC.

    “The intron-2 splice variant (c.293-13C>G, “I2 splice”), one of the most common variants among different populations, reduces correct splicing by strengthening a cryptic acceptor and promoting aberrant exon-3 inclusion/skipping, normally leading to severe disease; however, the clinical presentation can vary from the SW form, through the SV form and rarely the NC form.”

    From Evolution of molecular diagnostic strategies for 21-hydroxylase deficiency: from classical methods to advanced genomic techniques (2026) · cites this paper as [24]

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Authors
Kocova, M., Concolino, P., & Falhammar, H.
Affiliations
  • Agostino Gemelli University Polyclinic (IT)
  • Karolinska University Hospital (SE)
ORCID
Venue
Frontiers in Endocrinology
Publisher
Frontiers Media SA
Published
2022-01-24
Volume
12
Pages
788812-788812
ISSN
1664-2392 (ISSN-L)
DOI
10.3389/fendo.2021.788812
PMC
PMC8818746
OpenAlex
W4206999530
Cited by
15
References
106
Citations by year
2026: 3 · 2025: 6 · 2024: 2 · 2023: 3 · 2022: 1
FWCI
0.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Endocrinology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Magnus Bergvalls Stiftelse
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, splice site mutation, genotype-phenotype correlation, salt wasting, non-classical congenital adrenal hyperplasia, autosomal recessive inheritance, mutation carriers
MeSH terms
Adrenal Hyperplasia, Congenital, Genotype, Humans, Introns, Phenotype, Steroid 21-Hydroxylase

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