The distribution of intrafamilial CYP21A2 mutant alleles and investigation of clinical features in Turkish children and their siblings in Southeastern Anatolia
-
Murat Karaoglan
Abstract
Background
The genotype-phenotype relationship shows regional variability in 21-hydroxylase deficiency (21-OHD) caused by mutations in the CYP21A2 gene. This study focuses on the genotype-phenotype compatibility between patients and their siblings in a region where consanguineous marriage is common.
Methods
The most common mutations (I2G-P30L-I172N-V237E-M239K-V281L-Q318X-R356W-F306 + nt) were studied in 60 children with 21-OHD and 40 siblings (12 symptomatic and 28 asymptomatic; mean age 5.89 ± 4.63 and 8.34 ± 2.22 years, respectively). The allele number (patients; 93 siblings; 70 alleles) was counted for each case. Salt wasting (SW; n = 38), simple virilizing (SV; n = 11) and non-classical congenital adrenal hyperplasia (NCCAH; n = 11) types were compared with their genotypes classified into groups Null-AB-C-D-E based on enzyme impairment.
Results
Disease-causing mutations were identified in unrelated alleles: 80 out of 93 alleles (86%) in the patients: SW, 51/56 (91%); SV, 14/16 (87.4%) and NCCAH, 15/21 (71.4%). There were 43 out of 70 alleles (61.4%) in the siblings (asymptomatic, 25/50 [50%]; symptomatic, 18/20 [90%]). The most frequently detected mutations in the patients were: I2G (22%), Q318X-P30L-V281L (13% each). The distribution of the most common mutations by clinical types was: SW: I2G-Q318X (30.2%-19.6%), SV: I172NI2G (37.5%-18.7%), NCCAH: V281L-P30L (33.3%-28.5%). In patients and symptomatic siblings, the concordance percentages by genotype groups were: Null (100%-100%), A (85%-60%), B (100%-Not applicable), C (41.6%-50%). Eleven out of 28 asymptomatic siblings had disease-causing mutations (four, severe; one, moderate; six, mild). The distribution of genotypes by phenotypes were: SW: Null-A (88%), SV: B-A (50%-41.6%), NCCAH: C (100%).
Conclusions
This study showed that the most common alleles were IN2G-Q381X-R356W-P30L-V281L in the children with 21-OHD and asymptomatic siblings, and that the phenotype can be predicted from the genotype except for the P30L-V281L. This result suggests that the most common mutations in 21-OHD are similar to previous reports, but that the genotype-phenotype compatibility is good except for group C showing regional variability, and that genotyping of siblings discovered new patients.
Author contributions: Karaoglan M designed the study, collected and analysed data, wrote the manuscript.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. New MI, Abraham M, Gonzalez B, Dumic M, Razzaghy-Azar M, et al. Genotype-phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Proc Natl Acad Sci USA 2013;110:2611–6.10.1073/pnas.1300057110Search in Google Scholar PubMed PubMed Central
2. Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2010;95:4133–60.10.1210/jc.2009-2631Search in Google Scholar PubMed PubMed Central
3. Güran T, Tezel B, Gürbüz F, Selver Eklioğlu B, Hatipoğlu N, et al. Neonatal screening for congenital adrenal hyperplasia in Turkey: a pilot study with 38,935 infants. J Clin Res Pediatr Endocrinol 2019;11:13–23.10.4274/jcrpe.galenos.2018.2018.0117Search in Google Scholar PubMed PubMed Central
4. Anastasovska V, Kocova M. Molecular analysis of a family with congenital adrenal hyperplasia – genotype/phenotype discrepancy. BJMG 2007;10:23–8.10.2478/v10034-008-0003-3Search in Google Scholar
5. Yadav S, Birla S, Marumudi E, Sharma A, Khadgawat R, et al. Clinical profile and inheritance pattern of CYP21A2 gene mutations in patients with classical congenital adrenal hyperplasia from 10 families. Indian J Endocrinol Metab 2015;19:644–8.10.4103/2230-8210.163191Search in Google Scholar PubMed PubMed Central
6. Zhang B, Lu L, Lu Z. Molecular diagnosis of Chinese patients with 21-hydroxylase deficiency and analysis of genotype-phenotype correlations. J Int Med Res 2017;45:481–92.10.1177/0300060516685204Search in Google Scholar PubMed PubMed Central
7. Kaplan S, Pinar G, Kaplan B, Aslantekin F, Karabulut E, et al. The prevalence of consanguineous marriages and affecting factors in Turkey: a national survey. J Biosoc Sci 2016;48:616–30.10.1017/S0021932016000055Search in Google Scholar PubMed
8. de Carvalho DF, Miranda MC, Gomes LG, Madureira G, Marcondes JA, et al. Molecular CYP21A2 diagnosis in 480 Brazilian patients with congenital adrenal hyperplasia before newborn screening introduction. Eur J Endocrinol 2016;175:107–16.10.1530/EJE-16-0171Search in Google Scholar PubMed
9. Tukel T, Uyguner O, Wei JQ, Yüksel-Apak M, Saka N, et al. A novel semiquantitative polymerase chain reaction/enzyme digestion–based method for detection of large scale deletions/conversions of the CYP21 gene and mutation screening in Turkish families with 21-hydroxylase deficiency. J Clin Endocrinol Metab 2003;88:5893–7.10.1210/jc.2003-030813Search in Google Scholar PubMed
10. Baş F, Kayserili H, Darendeliler F, Uyguner O, Günöz H, et al. CYP21A2 gene mutations in congenital adrenal hyperplasia: genotype-phenotype correlation in Turkish children. J Turk Pediatr Endocrinol Diabetes Soc 2009;1:116–28.10.4008/jcrpe.v1i3.49Search in Google Scholar PubMed PubMed Central
11. Rabbani B, Mahdieh N, Ashtiani MT, Larijani B, Akbari MT, et al. Mutation analysis of the CYP21A2 gene in the Iranian population. Genet Test Mol Biomarkers 2012;16:82–90.10.1089/gtmb.2011.0099Search in Google Scholar PubMed PubMed Central
12. Al-Obaidi RG, Al-Musawi BM, Al-Zubaidi MA, Oberkanins C, Németh S, et al. Molecular analysis of CYP21A2 gene mutations among Iraqi patients with congenital adrenal hyperplasia. Enzyme Res 2016;2016:9040616. Published online 2016 Sep 29.10.1155/2016/9040616Search in Google Scholar PubMed PubMed Central
13. Kharrat M, Tardy V, M’Rad R, Maazoul F, Jemaa LB, et al. Molecular genetic analysis of Tunisian patients with a classical form of 21-hydroxylase deficiency: identification of four novel mutations and high prevalence of Q318X mutation. J Clin Endocrinol Metab 2004;89:368–74.10.1210/jc.2003-031056Search in Google Scholar PubMed
14. Anastasovska V, Kocova M. Genotype-phenotype correlation in CAH patients with severe CYP21A2 point mutations in the Republic of Macedonia. J Pediatr Endocrinol Metab 2010;23:921–6.10.1515/jpem.2010.147Search in Google Scholar PubMed
15. Ishii T, Anzo M, Adachi M, Onigata K, Kusuda S. Guidelines for diagnosis and treatment of 21-hydroxylase deficiency (2014 revision). Clin Pediatr Endocrinol 2015;24:77–105.10.1297/cpe.24.77Search in Google Scholar PubMed PubMed Central
16. Riedl S, Röhl FW, Bonfig W, Brämswig J, Richter-Unruh A, et al. Genotype/phenotype correlations in 538 congenital adrenal hyperplasia patients from Germany and Austria: discordances in milder genotypes and in screened versus prescreening patients. Endocrinol Connect 2019;8:86–94.10.1530/EC-18-0281Search in Google Scholar PubMed PubMed Central
17. Yoo Y, Chang MS, Lee J, Cho SY, Park SW, et al. Genotype-phenotype correlation in 27 pediatric patients in congenital adrenal hyperplasia due to 21-hydroxylase deficiency in a single center. Ann Pediatr Endocrinol Metab 2013;18:128–34.10.6065/apem.2013.18.3.128Search in Google Scholar PubMed PubMed Central
18. Wilson RC, Mercado AB, Cheng KC, New MI. Steroid 21-hydroxylase deficiency: genotype may not predict phenotype. J Clin Endocrinol Metab 1995;80:2322–9.10.1210/jcem.80.8.7629224Search in Google Scholar PubMed
19. Torres N, Mello MP, Germano CM, Elias LL, Moreira AC, et al. Phenotype and genotype correlation of the microconversion from the CYP21A1P to the CYP21A2 gene in congenital adrenal hyperplasia. Braz J Med Biol Res 2003;36:1311–8. Epub 2003 Sep 16.10.1590/S0100-879X2003001000006Search in Google Scholar PubMed
20. Hong G, Park HD, Choi R, Jin DK, Kim JH, et al. CYP21A2 mutation analysis in Korean patients with congenital adrenal hyperplasia using complementary methods: sequencing after long-range PCR and restriction fragment length polymorphism analysis with multiple ligation-dependent probe amplification assay. Ann Lab Med 2015;35:535–9.10.3343/alm.2015.35.5.535Search in Google Scholar PubMed PubMed Central
21. Kolahdouz M, Mohammadi Z, Kolahdouz P, Tajamolian M, Khanahmad H. Pitfalls in molecular diagnosis of 21-hydroxylase deficiency in congenital adrenal hyperplasia. Adv Biomed Res 2015;4:189.Search in Google Scholar PubMed
22. Vrzalová Z, Hrubá Z, St’ahlová Hrabincová E, Pouchlá S, Votava F, et al. Identification of CYP21A2 mutant alleles in Czech patients with 21-hydroxylase deficiency. Int J Mol Med 2010;26:595–603.10.3892/ijmm_00000504Search in Google Scholar PubMed
23. Araujo RS, Billerbeck AE, Madureira G, Mendonca BB, Bachega TA. Substitutions in the CYP21A2 promoter explain the simple-virilizing form of 21-hydroxylase deficiency in patients harbouring a P30L mutation. Clin Endocrinol (Oxf) 2005;62:132–6.10.1111/j.1365-2265.2005.02184.xSearch in Google Scholar PubMed
24. Rabbania B, Akbaria MT, Mahdieha N, Zaridust E. Homozygous complete deletion of CYP21A2 causes a simple virilizing phenotype in an Azeri child. Asian Biomedicine 2011;5:889–92.Search in Google Scholar
25. Kurtoğlu S, Hatipoğlu N. Non-classical congenital adrenal hyperplasia in childhood. J Clin Res Pediatr Endocrinol 2017;9:1–7.10.4274/jcrpe.3378Search in Google Scholar PubMed PubMed Central
©2019 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Mini Review
- Can preimplantation genetic diagnosis be used for monogenic endocrine diseases?
- Original Articles
- The distribution of intrafamilial CYP21A2 mutant alleles and investigation of clinical features in Turkish children and their siblings in Southeastern Anatolia
- 3-Methylcrotonyl-CoA carboxylase deficiency newborn screening in a population of 536,008: is routine screening necessary?
- Long non-coding RNA HCP5 serves as a ceRNA sponging miR-17-5p and miR-27a/b to regulate the pathogenesis of childhood obesity via the MAPK signaling pathway
- Once-weekly supervised combined training improves neurocognitive and psychobehavioral outcomes in young patients with type 1 diabetes mellitus
- Associations between thyroid-stimulating hormone, blood pressure and adiponectin are attenuated in children and adolescents with overweight or obesity
- Mental health of both child and parents plays a larger role in the health-related quality of life of obese and overweight children
- Near final adult height, and body mass index in overweight/obese and normal-weight children with idiopathic central precocious puberty and treated with gonadotropin-releasing hormone analogs
- Effects of vitamin D and estrogen receptor polymorphisms on bone mineral density in adolescents with anorexia nervosa
- Case Reports
- Whole exome sequencing identified a heterozygous KCNJ2 missense variant underlying autosomal dominant familial hypokalemic periodic paralysis in a Pakistani family
- Infantile cerebral infarction caused by severe diabetic ketoacidosis in new-onset type 1 diabetes mellitus
- Gallstone formation due to rapid weight loss through hyperthyroidism
- A neonate with mucolipidosis II and transient secondary hyperparathyroidism
- Zoledronate-responsive calcitriol-mediated hypercalcemia in a 5-year-old case with squamous cell carcinoma on the background of xeroderma pigmentosum
Articles in the same Issue
- Frontmatter
- Mini Review
- Can preimplantation genetic diagnosis be used for monogenic endocrine diseases?
- Original Articles
- The distribution of intrafamilial CYP21A2 mutant alleles and investigation of clinical features in Turkish children and their siblings in Southeastern Anatolia
- 3-Methylcrotonyl-CoA carboxylase deficiency newborn screening in a population of 536,008: is routine screening necessary?
- Long non-coding RNA HCP5 serves as a ceRNA sponging miR-17-5p and miR-27a/b to regulate the pathogenesis of childhood obesity via the MAPK signaling pathway
- Once-weekly supervised combined training improves neurocognitive and psychobehavioral outcomes in young patients with type 1 diabetes mellitus
- Associations between thyroid-stimulating hormone, blood pressure and adiponectin are attenuated in children and adolescents with overweight or obesity
- Mental health of both child and parents plays a larger role in the health-related quality of life of obese and overweight children
- Near final adult height, and body mass index in overweight/obese and normal-weight children with idiopathic central precocious puberty and treated with gonadotropin-releasing hormone analogs
- Effects of vitamin D and estrogen receptor polymorphisms on bone mineral density in adolescents with anorexia nervosa
- Case Reports
- Whole exome sequencing identified a heterozygous KCNJ2 missense variant underlying autosomal dominant familial hypokalemic periodic paralysis in a Pakistani family
- Infantile cerebral infarction caused by severe diabetic ketoacidosis in new-onset type 1 diabetes mellitus
- Gallstone formation due to rapid weight loss through hyperthyroidism
- A neonate with mucolipidosis II and transient secondary hyperparathyroidism
- Zoledronate-responsive calcitriol-mediated hypercalcemia in a 5-year-old case with squamous cell carcinoma on the background of xeroderma pigmentosum
