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Cited by 8Sexual Differentiation and DisordersAdrenal Hormones and DisordersGenetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities

Copy Number Variations in Genetic Diagnosis of Congenital Adrenal Hyperplasia Children

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Tolba, Aisha, Mandour, Iman, Musa, Noha, Elmougy, Fatma, Hafez, Mona, Abdelatty, Sahar, Ibrahim, Amany, Soliman, Hend +4 more·2022·Frontiers in Genetics
DOI 10.3389/fgene.2022.785570PMC PMC8924405
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Abstract

Background: Congenital adrenal hyperplasia (CAH) is a monogenic disorder caused by genetic diversity in the CYP21A2 gene, with 21-hydroxylase deficiency (21-OHD) as the most common type. Early sex assignment and early diagnosis of different genetic variations with a proper technique are important to reduce mortality and morbidity. Proper early sex identification reduces emotional, social, and psychological stress. Aim: Detection of a spectrum of aberrations in the CYP21A2 gene, including copy number variations, gene conversion, chimeric genes, and point variations. Methods: The CYP21A2 gene was screened using MLPA assay in 112 unrelated Egyptian children with 21-OHD CAH (33 males and 79 females). Results: In the studied group, 79.5% were diagnosed within the first month of life. 46.8% of the genetic females were misdiagnosed as males. Among the copy number variation results, large deletions in 15.4% and three types of chimeric genes in 9% (CH-1, CH-7, and CAH-X CH-1) were detected. Regarding gene dosage, one copy of CYP21A2 was found in 5 cases (4.5%), three copies were detected in 7 cases (6.3%), and one case (0.9%) showed four copies. Eight common genetic variants were identified, I2G, large deletions, large gene conversion (LGC), I172N, F306 + T, -113 SNP, 8bp Del, and exon 6 cluster (V237E and M239K) with an allelic frequency of 32.62%, 15.45%, 7.30%, 3.00%, 2.58%, 2.15%, 0.86%, and 0.86%, respectively. Conclusion: High prevalence of copy number variations highlights the added value of using MLPA in routine laboratory diagnosis of CAH patients.

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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 [40]

    The Introduction describes I2G as a common mutation, and Table 2 in the Discussion reports salt-wasting disease in 18 of 25 patients homozygous for I2G. But the paper gives 28%, not 20–25%, for I2G among deleterious mutations, and Table 2 also records simple-virilizing disease in 7 of those 25 homozygous patients. It does not establish the claimed frequency across the listed populations or that homozygosity invariably produces salt-wasting disease. (LLM, conf=0.88)

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Authors
Tolba, A., Mandour, I., Musa, N., Elmougy, F., Hafez, M., Abdelatty, S., Ibrahim, A., Soliman, H., Labib, B., Elshiwy, Y., Ramzy, T., & Elsharkawy, M.
Affiliations
  • Cairo University (EG)
  • Royal College of Surgeons in Ireland - Bahrain (BH)
Corresponding author
Elsharkawy, Marwa
ORCID
Venue
Frontiers in Genetics
Publisher
Frontiers Media SA
Published
2022-03-02
Volume
13
Pages
785570-785570
ISSN
1664-8021 (ISSN-L)
DOI
10.3389/fgene.2022.785570
PMC
PMC8924405
OpenAlex
W4214870971
Cited by
8
References
4
Citations by year
2026: 3 · 2024: 1 · 2023: 3 · 2022: 1
FWCI
0.41
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Genetics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
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 › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
Keywords
congenital adrenal hyperplasia, 21-hydroxylase deficiency, CYP21A2 gene, copy number variation, gene conversion, fusion genes, gene dosage, genetic diagnosis, multiplex ligation-dependent probe amplification, Egyptian children

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