Molecular genetic study of congenital adrenal hyperplasia in Serbia: novel p.Leu129Pro and p.Ser165Pro CYP21A2 gene mutations

Milacic, Iva; Barać, Miroljub B.; Milenković, Tatjana; Ugrin, Milena; Klaassen, Kristel; Skakic, Anita; Jesic, Milos; Joksić, Ivana; Mitrovic, Katarina; Todorović, Sladjana; Vujović, Svetlana; Pavlović, Sonja; Stojiljković, Maja

doi:10.1007/s40618-015-0366-8

Cited by 18 publications

(26 citation statements)

References 39 publications

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“…The percentage of homozygous genotypes observed in the present study (46.7%) is higher than in the majority of the countries (Serbia 13% [38], China 16.1% [6], USA 21% [24], Tunisia 24% [30], the Netherlands 28.3% [39], Croatia 33% [12], Romania 33.3% [40], Brazil 39% [41]), even though not one case of consanguinity was reported. Alleles with multiple pathogenic variants accounted for 8.2% of unrelated alleles.…”

Section: Discussioncontrasting

confidence: 62%

“…Alleles with multiple pathogenic variants accounted for 8.2% of unrelated alleles. The percentage of alleles carrying 2 or more pathogenic variants in cis is very variable in previous publications (6.5% in Serbia [38] to 21.6% in Spain [42]). This is related to the methodology used for the diagnosis and the segregation studies, which are extremely important for genetic counseling.…”

Section: Discussionmentioning

confidence: 99%

“…For both cases, only the 10 most common variants were analyzed, and the evaluation of duplicated genes by multiplex ligation-dependent probe amplification or Southern-blotting was not conducted. The existence of a trimodular haplotype has been reported in many populations [24, 38, 47, 48]. For instance, a random sample of the Spanish population showed that 7% of the individuals carried at least one chromosome with duplicated CYP21A2 [18].…”

Section: Discussionmentioning

confidence: 99%

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CYP21A2 Gene Pathogenic Variants: A Multicenter Study on Genotype–Phenotype Correlation from a Portuguese Pediatric Cohort

et al. 2019

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Background: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is an autosomal recessive disorder characterized by 3 overlapping phenotypes: salt-wasting (SW), simple virilizing (SV), and non-classic (NC). We aimed at conducting a nationwide genotype description of the CAH pediatric patients and to establish their genotype–phenotype correlation. Methods: CAH patients were recruited from Portuguese pediatric endocrinology centers and classified as SW, SV, or NC. Genetic analysis was performed by polymerase chain reaction (sequence specific primer, restriction fragment length polymorphism) or direct Sanger sequencing. Genotypes were categorized into 4 groups (0, A, B, and C), according to their predicted enzymatic activity. In each group, the expected phenotype was compared to the observed phenotype to assess the genotype–phenotype correlation. Results: Our cohort comprises 212 unrelated pediatric CAH patients (29% SW, 11% SV, 60% NC). The most common pathogenic variant was p.(Val282Leu; 41.3% of the 424 alleles analyzed). The p.(Val282Leu) variant, together with c.293-13A/C>G, p.(Ile173Asn), p.(Leu308Thr), p.(Gln319*), and large deletions/conversions were responsible for 86.4% of the mutated alleles. Patients’ stratification by disease subtype revealed that the most frequent pathogenic variants were c.293-13A/C>G in SW (31.1%), p.(Ile173Asn) in SV (46.9%), and p.(Val282Leu) in NC (69.5%). The most common genotype was homozygosity for p.(Val282Leu; 33.0%). Moreover, we found 2 novel variants: p.(Ile161Thr) and p.(Trp202Arg), in exons 4 and 5, respectively. The global genotype-phenotype correlation was 92.4%. Group B (associated with the SV form) showed the lowest genotype–phenotype correlation (80%). Conclusion: Our cohort has one of the largest NC CAH pediatric populations described. We emphasize the high frequency of the p.(Val282Leu) variant and the very high genotype–phenotype correlation observed.

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Section: Discussioncontrasting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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CYP21A2 Gene Pathogenic Variants: A Multicenter Study on Genotype–Phenotype Correlation from a Portuguese Pediatric Cohort

et al. 2019

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“…Using this procedure we predicted the in silico residual enzymatic activity of 32 CYP21A2 mutations20262728293031323334353637383940414243 that lack functional assays and are putatively involved in protein destabilization. The predicted activities were calculated from the linear fit based on the bovine template, which showed a better correlation with the experimental activities (see above).…”

Section: Resultsmentioning

confidence: 99%

Structure-based activity prediction of CYP21A2 stability variants: A survey of available gene variations

Bruque

Delea

Fernández

et al. 2016

Sci Rep

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Congenital adrenal hyperplasia due to 21-hydroxylase deficiency accounts for 90–95% of CAH cases. In this work we performed an extensive survey of mutations and SNPs modifying the coding sequence of the CYP21A2 gene. Using bioinformatic tools and two plausible CYP21A2 structures as templates, we initially classified all known mutants (n = 343) according to their putative functional impacts, which were either reported in the literature or inferred from structural models. We then performed a detailed analysis on the subset of mutations believed to exclusively impact protein stability. For those mutants, the predicted stability was calculated and correlated with the variant’s expected activity. A high concordance was obtained when comparing our predictions with available in vitro residual activities and/or the patient’s phenotype. The predicted stability and derived activity of all reported mutations and SNPs lacking functional assays (n = 108) were assessed. As expected, most of the SNPs (52/76) showed no biological implications. Moreover, this approach was applied to evaluate the putative synergy that could emerge when two mutations occurred in cis. In addition, we propose a putative pathogenic effect of five novel mutations, p.L107Q, p.L122R, p.R132H, p.P335L and p.H466fs, found in 21-hydroxylase deficient patients of our cohort.

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“…Over the past few decades this genetically heterogeneous disorder has been extensively studied worldwide. However, only recently a first report regarding genetic basis of CAH in Serbia has been published (MILACIC et al, 2015). Based on recent investigation, in this paper we discuss genetic approach used in Serbia and propose an optimal molecular diagnostic algorithm for patients affected with CAH in our country.…”

Section: Introductionmentioning

confidence: 99%

Molecular genetic strategy for diagnosis of congenital adrenal hyperplasia in Serbia

et al. 2017

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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 458

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Molecular genetic study of congenital adrenal hyperplasia in Serbia: novel p.Leu129Pro and p.Ser165Pro CYP21A2 gene mutations

Abstract: The first comprehensive molecular genetic study of Serbian CAH patients revealed two novel CYP21A2 mutations. This study will enable genetic counseling in our population and contribute to better understanding of molecular landscape of CAH in Europe.

Cited by 18 publications

References 39 publications

<b><i>CYP21A2</i></b> Gene Pathogenic Variants: A Multicenter Study on Genotype–Phenotype Correlation from a Portuguese Pediatric Cohort

<b><i>CYP21A2</i></b> Gene Pathogenic Variants: A Multicenter Study on Genotype–Phenotype Correlation from a Portuguese Pediatric Cohort

Structure-based activity prediction of CYP21A2 stability variants: A survey of available gene variations

Molecular genetic strategy for diagnosis of congenital adrenal hyperplasia in Serbia

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