scholarly journals Current Aspects of Genetic Diagnosis of 21-Hydroxylase Insufficiency

Doctor Ru ◽  
2021 ◽  
Vol 20 (6) ◽  
pp. 73-79
Author(s):  
N.S. Osinovskaya ◽  
◽  
Yu.A. Nasykhova ◽  
M.I. Yarmolinskaya ◽  
O.B. Glavnova ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Congenital Adrenal Hyperplasia ◽  
Genetic Counselling ◽  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Clinical Manifestations ◽  
Adrenal Hyperplasia ◽  
Cyp21a2 Gene ◽  
Gene Sequence Analysis ◽  
Dideoxynucleotide Chain Termination Method

Objective of the Review: To discuss the current peculiarities of 21-hydroxylase insufficiency diagnostics. Key Points. Congenital adrenal hyperplasia (CAH) is a group of autosomal-recessive pathologies, associated with a defective enzyme or transport protein participating in cortisol biosynthesis. Currently, there is information on CAH genetics including information on 21-hydroxylase insufficiency. Neonatal screening, antenatal and postnatal methods to diagnose 21-hydroxylase deficit have been developed. Timely diagnosis and correct therapy have been found to facilitate normal physical and mental development of patients. Molecular genetic testing for CAH associated with 21-hydroxylase deficit is widely used both in Russia and globally and is of importance for differential diagnosis, identification of pathogenic CYP21A2 gene carriers and adequate genetic counselling. The best strategy to diagnose 21-hydroxylase insufficiency is 2-stage CYP21A2 gene analysis. The test should include both gene sequence analysis and identification of point replacements, minor deletions and duplication (e.g., dideoxynucleotide chain-termination method or Next Generation Sequencing), and identification of extended deletions and duplication (multiplex ligation dependent probe amplification, real-time polymerase chain reaction). Such a comprehensive approach can help finding a majority of types of possible changes. Conclusion. Correct genetic testing methods ensure detection of pathogen variants in CYP21A2 gene; evaluation of the possible rate of clinical manifestations of the disease, both during antenatal testing and if an unknown clinical CAH form is encountered; prescribing an adequate therapy; and ensuring genetic counselling in order to develop a management strategy, including when planning for pregnancy in a woman with confirmed CAH. Keywords: congenital adrenal hyperplasia, CYP21A2 gene, genetic counselling, 21-hydroxylase

scholarly journals Molecular genetic strategy for diagnosis of congenital adrenal hyperplasia in Serbia

Genetika ◽  
2017 ◽  
Vol 49 (2) ◽  
pp. 457-467 ◽  
Author(s):  
Milena Ugrin ◽  
Iva Milacic ◽  
Anita Skakic ◽  
Kristel Klaassen ◽  
Jovana Komazec ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Congenital Adrenal Hyperplasia ◽  
Direct Sequencing ◽  
Molecular Genetic ◽  
Gene Rearrangements ◽  
Molecular Genetic Testing ◽  
Adrenal Hyperplasia ◽  
Cyp21a2 Gene ◽  
Classical Form ◽  
Large Gene

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is one of the most common endocrine diseases, yet genetic diagnosis is among the most complicated of all monogenic disorders. It has an overall incidence of 1:10000-1:20000, it is inherited in autosomal recessive pattern and caused by mutations affecting CYP21A2 gene. Based on the phenotypic expression, this disease is categorized into severe, classical form revealed at birth and mild, non-classical form. Although diagnosis could be established based on biochemical tests and distinctive clinical features, molecular genetic testing is crucial for diagnosis confirmation, detection of carriers and asymptomatic patients, disease prognosis, as well as for providing proper genetic counselling and prenatal diagnosis. Based on CYP21A2 mutational spectrum and frequencies in Serbia, in this paper we propose an optimal molecular genetic diagnostic algorithm for CAH and discuss genetic mechanisms underlying the disease. The complete diagnostic procedure combines multiplex minisequencing technique (SNaPshot PCR) as a method for rapid detection of common point mutations, direct sequencing of whole CYP21A2 gene and PCR with sequence specific primers (PCR-SSP) for large gene rearrangements detection (CYP21A1P/CYP21A2 chimeras). While SNaPshot PCR assay analyses ten common mutations (c.290-13A/C>G, p.P30L, p.R356W, p.G110fs, p.V281L, p.Q318X, p.L307fs, p.I172N, Cluster p.[I236N;V237E;M239K] and p.P453S) which account for over 80% of all CYP21A2 mutations in Serbian population, direct sequencing of CYP21A2 gene is needed to identify potential rare or novel mutations present in Serbian population with frequency of 1.8%. Additionally, large gene rearrangements which are present with frequency of 16.7% make PCR-SSP analysis an unavoidable part of molecular characterization of CAH in Serbia. Described molecular genetic strategy is intended to facilitate correct diagnosis assessment in CAH affected individuals and their families in Serbia but it will also contribute to molecular genetic testing of CAH patients across Europe.

scholarly journals Non-Classical Congenital Adrenal Hyperplasia-Causing Alleles in Adolescent Girls with PCOS and in Risk Group for PCOS Development

Diagnostics ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 980
Author(s):  
Lasma Lidaka ◽  
Laine Bekere ◽  
Gunta Lazdane ◽  
Iveta Dzivite-Krisane ◽  
Anda Kivite-Urtane ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Phenotypic Expression ◽  
Clinical Manifestations ◽  
Control Group ◽  
Compound Heterozygous ◽  
Heterozygous State ◽  
Adrenal Hyperplasia ◽  
Cyp21a2 Gene ◽  
Female Population ◽  
Increased Risk

Background: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women. Depending on the diagnostic criteria applied, it occurs in up to 16.6% of the general female population. Congenital adrenal hyperplasia includes a group of autosomal recessive disorders, the most common of which is non-classical congenital adrenal hyperplasia (NCAH) caused by mutations in the CYP21A2 gene. PCOS and NCAH have similar clinical manifestations (hyperandrogenemia, i.e., hirsutism, acne, alopecia, and increased androgen levels in the blood) and potential impact on long-term health (infertility, increased risk of type 2 diabetes, and cardiovascular disease. Consequently, it is thought that NCAH mutations in the heterozygous state may play a role in PCOS development and phenotypic expression. Objective: To determine the prevalence of the most common pathogenic alleles of the CYP21A2 gene in adolescents with PCOS and adolescents at risk of PCOS development, and to compare the results with healthy adolescents matched for gynecological age. Methods: A cross-sectional study was conducted with 55 PCOS patients, 23 risk patients (with hyperandrogenism but a normal menstrual cycle), and 49 healthy adolescents. Genetic variations in the CYP21A2 gene were analyzed using a standard Multiplex Ligation-dependent Probe Amplification test (SALSA MLPA Probemix P050-C1 CAH; MRC Holland). Results: No significant differences were found among the three groups regarding the frequency of carriers of NCAH variations in the heterozygous state. It was found that the I172N carrier in the PCOS group had a significantly higher Global Acne Grading Scale score than PCOS patients without this variation (p = 0.038). Within the control group of healthy adolescents, compound heterozygous carriers (IVS2-12A > G and -113G > A) had a significantly higher body mass index than non-carriers (p = 0.036). Conclusion: We found no differences in the incidence of NCAH-causing variations in the heterozygous state in adolescent PCOS patients, risk adolescents (with hirsutism but normal menstruation), and healthy adolescents. Future studies of larger cohorts and rarer pathogenic CYP21A2 gene variations are required.

scholarly journals Molecular genetic analysis of CYP21A2 gene in patients with congenital adrenal hyperplasia

2012 ◽  
Vol 16 (3) ◽  
pp. 384 ◽  
Author(s):  
AriacheryC Ammini ◽  
Arundhati Sharma ◽  
Rajesh Khadgawat ◽  
Eunice Marumudi ◽  
Bindu Kulshreshtha ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Congenital Adrenal Hyperplasia ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Adrenal Hyperplasia ◽  
Cyp21a2 Gene

scholarly journals Genotype-Phenotype Correlation in Patients with Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency in Cuba

2021 ◽  
Vol 2021 ◽  
pp. 1-6
Author(s):  
Tania Mayvel Espinosa Reyes ◽  
Teresa Collazo Mesa ◽  
Paulina Arasely Lantigua Cruz ◽  
Adriana Agramonte Machado ◽  
Emma Domínguez Alonso ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Point Mutations ◽  
Clinical Manifestations ◽  
Adrenal Hyperplasia ◽  
Phenotype Correlation ◽  
Hydroxylase Deficiency ◽  
Cyp21a2 Gene ◽  
Genotype Phenotype Correlation ◽  
21 Hydroxylase Deficiency ◽  
Cuban Population

Background. There are several studies that show a good genotype-phenotype correlation in congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD). However, there is well-documented evidence of inconsistency in some cases. Objectives. To determine if there is a correlation between the identified mutations and the clinical manifestations of 21OHD in the Cuban population. Methods. A cross-sectional descriptive study of all patients referred for a molecular diagnosis of 21OHD in Cuba from January 2000 to December 2018. The clinical manifestations of each patient were identified and classified according to the phenotype. The CYP21A2 gene was analyzed for the presence of 5 point mutations involved in the pathogenesis of 21OHD (intron 2, deletion of 8bp, I172N, P30L, and Q318X); correlation was sought between the phenotypic characteristics and the frequencies of point mutations in the patients using the Spearman test. Results. A total of 55 patients underwent direct analysis of the CYP21A2 gene in order to determine the presence of the 5 point mutations. Point mutations were identified in 31 patients, which corresponded to 56%. A statistically significant genotype-phenotype correlation was found. Conclusions. The correlation between the detected molecular defect and the clinical expression of 21OHD was reasonable in the Cuban population, which could allow phenotypic predictions to be made from the genotype.

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