GENETIC FEATURES OF CONGENITAL DYSFUNCTION OF THE ADRENAL CORTEX CAUSED BY 21-HYDROXYLASE DEFICIENCY IN PERSONS OF KAZAKH NATIONALITY
Introduction. 21-hydroxylase (21-OHD) deficiency caused by mutations in the CYP21A2 gene accounts for more than 90-95% of cases of congenital adrenal hyperplasia.
Objective: to study the most well-known mutations of the CYP21A2 gene in children of Kazakh nationality with the classical form of 21-OHD.
Materials and research methods. A one-stage cohort study was conducted with congenital adrenal hyperplasia with classical forms of 75 children in the period 2019-2021, of which 50 children underwent genetic testing. The DNA of 35 children with the classic form of CAH, living in 7 regions of Kazakhstan, was studied. To determine the 12 most common mutations in the CYP21A2 gene, long-range PCR was used, followed by nested PCR for target gene regions and direct automatic sequencing according to Sangeroy.
Statistical processing of the obtained data was carried out using the Statistica application package (StatSoft Inc., USA, version 13.0). The correlation between phenotype and mutations in the CYP21A2 gene was studied using a well-known technique (Speiser et al., 1992; Wedell et al., 1994)
Results: Overall, I172N (37.7%) and I2splice (26.2%) mutations were the most common, followed by Δ8bp (11.5%) and Q318X (9.8%) lesions. In the salt-wasting form, I2splice, Q318X, and Δ8bp mutations of the studied alleles were found in 81.3%. In patients with a simple virile form, the most frequent point mutations were I172N and I2G, which were detected in 82.6% of alleles. The genotype and phenotype correlated well in 88% of patients with 21-OHD, and in 12% the clinical variant did not match the detected genotype. A high phenotype-genotype correlation was found in the zero, A and B groups, in the C group there was a large clinical variability.
Conclusions. It was revealed that in children of Kazakh nationality with CAH caused by 21-hydroxylase deficiency, I172N and I2splice mutations are most common. A high correlation was found. Thus, the frequency of CYP21A2 mutations in CAH in our study was somewhat different from those found in other populations. The study will be useful for organizing and conducting early diagnosis of 21-hydroxylase deficiency.
Tamara U. Ermakhanova1, https://orcid.org/0000-0003-1216-3408
Rimma B. Bazarbekova1, https://orcid.org/0000-0002-0470-7594
Ainur K. Dosanova1, https://orcid.org/0000-0002-0565-9651
Aigerim А. Zhakebaeva1, https://orcid.org/0000-0003-3207-797Х
Zhazira А. Nurlykaimova1, https://orcid.org/0009-0009-3723-9879
Rita А. Kasymalieva1, https://orcid.org/0009-0003-2158-5802
1 NGEI "Kazakh-Russian Medical University", Almaty, Republic of Kazakhstan.
1. Chen W., Xu Z., Nishitani M., et al. Complement component 4 copy number variation and CYP21A2 genotype associations in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency // Hum Genet. 2012. 131. P.1889–94.
2. Chen W., Xu Z., Sullivan A., et al. Junction site analysis of chimeric CYP21A1P/ CYP21A2 genes in 21-hydroxylase deficiency //Clin Chem. 2012. 58. P.421–30.
3. De Carvalho D.F., Miranda M.C., Gomes L.G., Madureira G., Marcondes J.A., Billerbeck A.E., Rodrigues A.S., Presti P.F., Kuperman H., Damiani D., et al. Molecular CYP21A2 diagnosis in 480 Brazilian patients with congenital adrenal hyperplasia before newborn screening introduction// European Journal of Endocrinology. 2016. 175. Р.107–116.
4. El-Maouche D., Arlt W., Merke D.P. Congenital adrenal hyperplasia // The Lancet. 2017. 390(10108). P. 2194–2210.
5. Han T.S., Walker B.R., Arlt W., Ross R.J. Treatment and health outcomes in adults with congenital adrenal hyperplasia // Nat Rev Endocrinol. 2014. 10(2). P.115-124.
6. Hannah-Shmouni F., Chen W., Merke D.P. Genetics of Congenital Adrenal Hyperplasia // Endocrinology and Metabolism Clinics of North America. 2017. 46(2). P.435–458.
7. Jenkins-Jones S., Parviainen L., Porter J. et al. Poor compliance and increased mortality, depression and healthcare costs in pаtients with congenital adrenal hyperplasia // Eur J Endocrinol. 2018. 178(4). P.309-320.
8. Krone N., Braun A., Roscher A.A., Knorr D., Schwarz H.P. Predicting phenotype in steroid 21-hydroxylase deficiency? Comprehensive genotyping in 155 unrelated, well defined patients from southern Germany // Journal of Clinical Endocrinology and Metabolism. 2000. 85. Р. 1059–1065.
9. Marino R., Ramirez P., Galeano J., Perez Garrido N., Rocco C., Ciaccio M., Warman D.M., Guercio G., Chaler E., Maceiras M. et al. Steroid 21-hydroxylase gene mutational spectrum in 454 Argentinean patients: genotype-phenotype correlation in a large cohort of patients with congenital adrenal hyperplasia // Clinical Endocrinology. 2011. 75. Р. 427–435.
10. Merke D.P., Mallappa A., Arlt W., Perriere A.B., Hirschberg A.L., Juul A., Newell-Price J., Perry C., Prete A., Rees D.A., Reisch N., Stikkelbroeck N., Touraine Ph., Maltby K., Treasure F.P., Porter J., Ross R. Modified-Release Hydrocortisone in Congenital Adrenal Hyperplasia // The Journal of Clinical Endocrinology & Metabolism. 2021. 106. P.2063–2077.
11. Merke D.P., Poppas D.P. Management of adolescents with congenital adrenal hyperplasia // Lancet Diabetes Endocrinol. 2013 Dec. 1(4). Р. 341–352.
12. Merke D.P., Auchus R.J. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency // N Engl J Med. 2020. 383(13). P.1248-1261.
13. New M.I., Abraham M., Gonzalez B., Dumic M., Razzaghy-Azar M., Chitayat D., Sun L., Zaidi M., Wilson R.C., Yuen T. Genotype– phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency // PNAS. 2013. 110. Р.2611–2616.
14. Parsa A.A., New M.I. Steroid 21-hydroxylase deficiency in congenital adrenal hyperplasia // Journal of Steroid Biochemistry and Molecular Biology. 2017. 165. Р.2–11.
15. Podgórski R., Aebisher D., Stompor M., Podgórska D., Mazur A. Congenital adrenal hyperplasia: clinical symptoms and diagnostic methods // Acta Biochimica Polonica. 2018. 65(1). P.25–33.
16. Rushworth R.L., Torpy D.J., Falhammar H. Adrenal crisis // N Engl J Med. 2019. 381(9). P.852-861.
17. Riedl S., Röhl F., Bonfig W., Brämswig J., Richter-Unruh A., Fricke-Otto S., Bettendorf M., Riepe F., Kriegshäuser G., Schönau Е., Even G., Hauffa B., Dörr Н., Holl R.W., Mohnike K. on behalf of the AQUAPE CAH Study Group. Genotype/phenotype correlations in 538 congenital adrenal hyperplasia patients from Germany and Austria: discordances in milder genotypes and in screened versus prescreening patients // Endocrine Connections. 2019. 8. Р. 86–94.
18. Speiser P.W., Arlt W., Auchus R.J., Baskin L.S., Conway G.S., Merke D.P., Meyer-Bahlburg H.L., Miller W.L., Murad M.H. et al. Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society* Clinical Practice Guideline, 2018 // J Clin Endocrinol Metab. - November 2018. 103(11). pp.1–46.
19. Vrzalova Z., Hruba Z., Hrabincova E.S. et al. Chimeric CYP21A1P/CYP21A2 genes identified in Czech patients with congenital adrenal hyperplasia // Eur J Med Genet. 2011. 54. pp.112–7.
20. White P.C., Speiser P.W. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency // Endocrine Reviews. 2000. 21. pp. 245–291.
21. Wang R., Yu Y., Ye J., Han L., Qiu W., Zhang H., Liang L., Gong Z., Wang L. 21-hydroxylase deficiency-induced congenital adrenal hyperplasia in 230 Chinese patients: genotype-phenotype correlation and identification of nine novel mutations // Steroids. 2016. 108. pp. 47-55.
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Ermakhanova T.U., Bazarbekova R.B., Dosanova А.К., Zhakebaeva А.А., Nurlykaimova Zh.А., Каsymalieva R.А. Genetic features of congenital dysfunction of the adrenal cortex caused by 21-hydroxylase deficiency in persons of Kazakh nationality // Nauka i Zdravookhranenie [Science & Healthcare]. 2024, (Vol.26) 1, pp. 15-21. doi 10.34689/SH.2024.26.1.002Related publications:
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