Mutational Characterization of Steroid 21-Hydroxylase Gene in Portuguese patients with Congenital Adrenal Hyperplasia

Marques, C. Joana; Pignatelli, Duarte; Carvalho, Berta; Barceló, Juana; Almeida, Ana Cristina; Fernandes, Susana; Witchel, Selma F.; Sousa, Mário; Oliveira, Maria João; Freitas, Paula; Fontoura, Manuel; Carvalho, Davide; Barros, Alberto; Carvalho, Filipa

doi:10.1055/s-0029-1237363

Cited by 11 publications

(9 citation statements)

References 24 publications

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“…This approach is designed to detect the most common pathogenic variants described above. A number of different methods and strategies have been described that cover a variable range of pathogenic variants (87, 88).…”

Section: Targeted Pathogenic Variant Analysismentioning

confidence: 99%

The Complexities in Genotyping of Congenital Adrenal Hyperplasia: 21-Hydroxylase Deficiency

et al. 2019

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The deficiency of 21-hydroxylase due to CYP21A2 pathogenic variants is a rather frequent disease with serious consequences, going from a real mortality risk to infertility and to milder symptoms, nevertheless important for affecting the patients' self-esteem. In the most severe cases life-threatening adrenal salt wasting crises may occur. Significant morbidity including the possibility of mistaken gender determination, precocious puberty, infertility and growth arrest with consequent short stature may also affect these patients. In the less severe cases milder symptoms like hirsutism will likely affect the image of the self with strong psychological consequences. Its diagnosis is confirmed by 17OH-progesterone dosages exceeding the cut-off value of 10/15 ng/ml but genotyping is progressively assuming an essential role in the study of these patients particularly in confirming difficult cases, determining some aspects of the prognosis and allowing a correct genetic counseling. Genotyping is a difficult process due to the occurrence of both a gene and a highly homologous pseudo gene. However, new tools are opening new possibilities to this analysis and improving the chances of a correct diagnosis and better understanding of the underlying mechanisms of the disease. Beyond the 10 classic pathogenic variants usually searched for in most laboratories, a correct analysis of 21OH-deficiency cases implies completely sequencing of the entire gene and the determination of gene duplications. These are now recognized to occur frequently and can be responsible for some false positive cases. And finally, because gene conversions can include several pathogenic variants one cannot be certain of identifying that both alleles are affected without studying parental DNA samples. A complete genotype characterization should be considered essential in the preparation for pregnancy, even in the case of parents with milder forms of the disease, or even just carriers, since it has been reported that giving birth to progeny with the severe classic forms occurs with a much higher frequency than expected.

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Section: Targeted Pathogenic Variant Analysismentioning

confidence: 99%

The Complexities in Genotyping of Congenital Adrenal Hyperplasia: 21-Hydroxylase Deficiency

et al. 2019

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“…Two previous smaller studies analyzed the CYP21A2 mutational spectrum in Portuguese CAH patients [15, 16]. However, these studies, like many others, included a small number of patients and represented single centers.…”

Section: Introductionmentioning

confidence: 99%

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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“…Importa salientar que a nossa amostra apenas incluiu doentes até aos 18 anos de idade e que muitas formas não clássicas apenas são diagnosticadas na idade adulta por infertilidade. 26 Foi também evidente o predomínio do sexo feminino, o que está de acordo com a literatura. Como se trata de uma patologia autossómica recessiva, ocorre igualmente nos dois sexos.…”

Section: Discussionunclassified

Hiperplasia Congénita da Suprarrenal por Deficiência de 21-Hidroxílase: Correlação Genótipo-Fenótipo

et al. 2015

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Introduction: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is one of the most frequent inborn conditions. It is caused by distinct mutations in the CYP21A2 gene and in the majority of cases the disease’s severity correlates with CYP21A2 allelic variation Our aim was to describe the mutational spectrum of CYP21A2 and evaluate genotype-phenotype correlation in a cohort of portuguese patients with 21-hydroxylase deficiency. Material and Methods: Retrospective study of 22 patients with clinical diagnosis of 21-hydroxylase deficiency. Molecular analysis of CYP21A2 was performed and genotype-phenotype correlation was then established. Results: Genotyping was performed in 22 unrelated patients: 5 with classic salt-wasting (average age of diagnosis 10,2 days; minimum 1, maximum 20 days), 7 with classic simple virilizing (average age of diagnosis 3,5 years; minimum 0 days, maximum 7 years) and 10 with nonclassical form (average age of diagnosis 5,7 years; minimum 4 years, maximum 8 years). The most frequent genetic defects in the classic forms were I2 splice (24%) and I172N (24%), followed by Q318X (16%) and gene deletions (16%) and in the nonclassical form, the V281L (80%). The overall concordance between genotype and phenotype was 81,8%. Genotype accurately predicted phenotype in 83,3%, 100% and 90% of patients with classic salt-wasting, classic simple virilizing and nonclassical mutations, respectively. Discussion: The frequency of genetic defects in our patients was comparable to similar studies. In most cases there was a good correlation between genotype and phenotype. Conclusions: Molecular analysis of CYP21A2 provides useful information in terms of prediction of disease severity, genetic and prenatal counseling. Keywords: Adrenal Hyperplasia, Congenital; Genotype; Phenotype; Steroid 21-Hydroxylase.

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Mutational Characterization of Steroid 21-Hydroxylase Gene in Portuguese patients with Congenital Adrenal Hyperplasia

Cited by 11 publications

References 24 publications

The Complexities in Genotyping of Congenital Adrenal Hyperplasia: 21-Hydroxylase Deficiency

The Complexities in Genotyping of Congenital Adrenal Hyperplasia: 21-Hydroxylase Deficiency

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

Hiperplasia Congénita da Suprarrenal por Deficiência de 21-Hidroxílase: Correlação Genótipo-Fenótipo

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