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21-Hydroxylase deficiency: Mutational spectrum and Genotype-Phenotype relations analyses by next-generation sequencing and multiplex ligation-dependent probe amplification.
Eur J Med Genet. 2020 Apr; 63(4):103782.EJ

Abstract

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is autosomal recessive disorder of cortisol biosynthesis. Genetic defects in CYP21A2 cause 21OHD. The aim of this study was to determine spectrum of mutations in CYP21A2 in a large cohort and analyze the genotype-phenotype correlation to assess predictive characteristics of genotype. We investigated a total of 113 patients with 21OHD. Next-generation sequencing and Multiplex ligation-dependent probe amplification of the CYP21A2 gene were performed in patients and their parents. The genotypes were categorized into Groups 0, A, B, and C according to the residual 21-hydroxylase activities. In this study, the group A was divided into two subgroups as A1 and A2. Three novel variants were found. The genotype-phenotype correlation of the mutation classification was 91.5%. Positive predictivity of subgroups A1 was higher than groups A and subgroups A2. Our study reports genotype-phenotype correlations in the largest 21OHD cohort in Turkey. This correlation sustained when we analyzed our data in combination with metadata from other published studies. This study confirms that CYP21A2 genotyping with next-generation sequencing and MLPA can accurately and reliably confirm the diagnosis of 21OHD. We propose a new classification by dividing group A into two new subgroups to better predict the phenotype. In light of this very high genotype-phenotype correlation, with their ever-increasing availability, declining cost, and turnaround time, we propose that molecular genetic studies can be more economical and practical alternative to the current initial diagnostic laboratory studies based on assays of intermediary steroid metabolites.

Authors+Show Affiliations

Sanlıurfa Training and Research Hospital, Clinic of Pediatric Endocrinology, Sanlıurfa, Turkey.Cukurova University, Faculty of Medicine, Division of Pediatric Endocrinology, Adana, Turkey.Cukurova University, Faculty of Medicine, Division of Medical Biochemistry, Adana, Turkey.Cukurova University, Faculty of Medicine, Division of Pediatric Endocrinology, Adana, Turkey.Cukurova University, Faculty of Medicine, Division of Pediatric Endocrinology, Adana, Turkey.Cukurova University, Faculty of Medicine, Division of Medical Biochemistry, Adana, Turkey.Cukurova University, Faculty of Medicine, Division of Pediatric Endocrinology, Adana, Turkey. Electronic address: byuksel@cu.edu.tr.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31586465

Citation

Turan, Ihsan, et al. "21-Hydroxylase Deficiency: Mutational Spectrum and Genotype-Phenotype Relations Analyses By Next-generation Sequencing and Multiplex Ligation-dependent Probe Amplification." European Journal of Medical Genetics, vol. 63, no. 4, 2020, p. 103782.
Turan I, Tastan M, Boga DD, et al. 21-Hydroxylase deficiency: Mutational spectrum and Genotype-Phenotype relations analyses by next-generation sequencing and multiplex ligation-dependent probe amplification. Eur J Med Genet. 2020;63(4):103782.
Turan, I., Tastan, M., Boga, D. D., Gurbuz, F., Kotan, L. D., Tuli, A., & Yüksel, B. (2020). 21-Hydroxylase deficiency: Mutational spectrum and Genotype-Phenotype relations analyses by next-generation sequencing and multiplex ligation-dependent probe amplification. European Journal of Medical Genetics, 63(4), 103782. https://doi.org/10.1016/j.ejmg.2019.103782
Turan I, et al. 21-Hydroxylase Deficiency: Mutational Spectrum and Genotype-Phenotype Relations Analyses By Next-generation Sequencing and Multiplex Ligation-dependent Probe Amplification. Eur J Med Genet. 2020;63(4):103782. PubMed PMID: 31586465.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 21-Hydroxylase deficiency: Mutational spectrum and Genotype-Phenotype relations analyses by next-generation sequencing and multiplex ligation-dependent probe amplification. AU - Turan,Ihsan, AU - Tastan,Mehmet, AU - Boga,Duygu D, AU - Gurbuz,Fatih, AU - Kotan,Leman D, AU - Tuli,Abdullah, AU - Yüksel,Bilgin, Y1 - 2019/10/02/ PY - 2019/03/19/received PY - 2019/09/17/revised PY - 2019/10/01/accepted PY - 2019/10/6/pubmed PY - 2020/12/2/medline PY - 2019/10/6/entrez KW - 21-Hydroxylase KW - CAH KW - Congenital adrenal hyperplasia KW - cyp21a2 SP - 103782 EP - 103782 JF - European journal of medical genetics JO - Eur J Med Genet VL - 63 IS - 4 N2 - Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is autosomal recessive disorder of cortisol biosynthesis. Genetic defects in CYP21A2 cause 21OHD. The aim of this study was to determine spectrum of mutations in CYP21A2 in a large cohort and analyze the genotype-phenotype correlation to assess predictive characteristics of genotype. We investigated a total of 113 patients with 21OHD. Next-generation sequencing and Multiplex ligation-dependent probe amplification of the CYP21A2 gene were performed in patients and their parents. The genotypes were categorized into Groups 0, A, B, and C according to the residual 21-hydroxylase activities. In this study, the group A was divided into two subgroups as A1 and A2. Three novel variants were found. The genotype-phenotype correlation of the mutation classification was 91.5%. Positive predictivity of subgroups A1 was higher than groups A and subgroups A2. Our study reports genotype-phenotype correlations in the largest 21OHD cohort in Turkey. This correlation sustained when we analyzed our data in combination with metadata from other published studies. This study confirms that CYP21A2 genotyping with next-generation sequencing and MLPA can accurately and reliably confirm the diagnosis of 21OHD. We propose a new classification by dividing group A into two new subgroups to better predict the phenotype. In light of this very high genotype-phenotype correlation, with their ever-increasing availability, declining cost, and turnaround time, we propose that molecular genetic studies can be more economical and practical alternative to the current initial diagnostic laboratory studies based on assays of intermediary steroid metabolites. SN - 1878-0849 UR - https://www.unboundmedicine.com/medline/citation/31586465/21_Hydroxylase_deficiency:_Mutational_spectrum_and_Genotype_Phenotype_relations_analyses_by_next_generation_sequencing_and_multiplex_ligation_dependent_probe_amplification_ DB - PRIME DP - Unbound Medicine ER -