CYP21A2mutation update: Comprehensive analysis of databases and published genetic variants

Simonetti, Leandro; Bruque, Carlos David; Fernández, Carolina; Benavides‐Mori, Belén; Delea, Marisol; Kolomenski, Jorge E.; Espeche, Lucía D.; Buzzalino, Noemí; Nadra, Alejandro D.; Daín, Liliana

doi:10.1002/humu.23351

Cited by 80 publications

(80 citation statements)

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“…Patients 11–14, carried the c.293-13A/C>G splice variant, which can be “leaky” such that a small amount of the normal transcript is made resulting in phenotypic heterogeneity [49]. Thus, despite the classification of CAH into 3 different clinical forms, the disease represents a continuous phenotypic spectrum [1]. …”

Section: Discussionmentioning

confidence: 99%

“…Disease-causing pathogenic variants were divided into 5 groups according to the expected 21-hydroxylase activity, a strategy described previously [1, 3, 9, 11, 13, 14, 23-28], as summarized in Table 1. Group D included the new variants detected in 2 patients, with unknown in vitro influence on enzymatic activity.…”

Section: Methodsmentioning

confidence: 99%

“…21OHD results in defective conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol and leads to hypocortisolism and hyperandrogenism due to accumulation of precursor steroid hormones. Although 3 major clinical forms are described (classic salt-wasting [SW], classic simple virilizing [SV], and non-classic [NC]), this disorder represents a continuous phenotypic spectrum [1]. …”

Section: Introductionmentioning

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: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

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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“…CYP21A2 is located on chromosome 6 within the HLA (human leukocyte antigen) locus. It encodes 21hydroxylase enzyme, a member of the cytochrome P450 (CYP450) superfamily [39]. 21-hydroxylase enzyme is necessary to the synthesis of cortisol and aldosterone, the latter regulates the amount of salt retained by the kidneys and then affects blood volume of body and BP.…”

Section: Discussionmentioning

confidence: 99%

Functional polymorphisms in the MED13L and SLC4A7 genes are associated with pregnancy-induced hypertension

Zhou

et al. 2019

Preprint

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Background: Pregnancy-induced hypertension (PIH), including gestational hypertension (GH) and preeclampsia (PE), might share pathophysiologic mechanisms and genetic risk factors with hypertension. This study aimed to investigate whether genetic risk factors for hypertension also been associated with PIH. Methods: This is a case control candidate gene association study. A total of 84 cases with GH, 108 cases with PE, and 192 age-matched (±1 year) controls were recruited from the Liuyang Municipal Hospital of Maternal and Child Health, Hunan Province of China. Three candidate single nucleotide polymorphisms (SNPs) which have been found to be associated with hypertension or blood pressure (BP) were chosen. The associations between SNPs and GH and PE were analyzed by multiple logistic regression models after adjusting for fetal sex and primipara. Results: GG genotype at mediator complex subunit 13-like (MED13L) rs11067763 was a protective factor for developing GH (GG vs. AA + AG, OR = 0.376, 95%CI = 0.158-0.892) and PE (GG vs. AA + AG, OR = 0.489, 95%CI = 0.245-0.979) in recessive model. AA genotype at solute carrier family 4 member 7 (SLC4A7) rs820430 was a risk factor for developing GH (AA vs. GG + AG, OR = 3.562, 95%CI = 1.343-9.447) and PE (AA vs. GG + AG, OR = 3.351, 95%CI = 1.352-8.303) in recessive model. But no significant association was observed between cytochrome P450 family 21 subfamily A member 2 (CYP21A2) rs2021783 and the GH/PE groups. Conclusions: PIH and hypertension are likely to share genetic risk factors. The associations both between variants of MED13L rs11067763 and GH/PE and between variants of SLC4A7 rs820430 and GH/PE were significant.

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“…This high sequence identity causes this chromosomal region to sometimes misalign, causing gene deletions and/or duplications or transference of sequences from the pseudogene to the gene by gene conversion 11,13 . Although most of the patients had pseudogene‐derived pathogenic variants, an increasing number of novel and rare allelic variants have been found in disease‐causing alleles 14 …”

Section: Introductionmentioning

confidence: 99%

Genetic characterization of a large cohort of Argentine 21‐hydroxylase Deficiency

Fernández

Taboas

Bruque

et al. 2020

Clinical Endocrinology

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Context 21‐hydroxylase deficiency is the most common cause of Congenital Adrenal Hyperplasia. It presents as severe or classical forms—salt wasting and simple virilizing—and a mild or nonclassical (NC). Several studies have reported the frequency of pathogenic variants in different populations, although few of them included a large number of NC patients. Objective To analyse the CYP21A2 gene defects in a large cohort of Argentine patients. Design Molecular characterization of 628 patients (168 classical, 460 nonclassical, representing 1203 nonrelated alleles), 398 relatives, 126 partners. Methods Genetic variants were assessed by allele‐specific PCR, PCR‐RFLP or direct sequencing. Deletions, duplications and large gene conversions (LGC) were studied by Southern blot/MLPA or long‐range PCR. Biological implications of novel variants were analysed by structure‐based in silico studies. Results The most frequent pathogenic variants were p.V282L (58%) in NC alleles and c.293‐13C>G (31.8%) and p.I173N (21.1%) in classical. Deletions and LGC were found at low frequency (6.2%), 57 alleles had rare pathogenic variants, and 3 had novel variants: p.(S166F); p.(P189R), p.(R436L). Genotype‐phenotype correlation was observed in 98.6% of the cases, 11 asymptomatic first‐degree relatives had pathogenic variants in both alleles, and 21/126 partners were carriers. Conclusions We conducted a comprehensive genetic characterization of the largest cohort of 21‐hydroxylase patients from the region. In particular, we add to the molecular characterization of a large number of NC patients and to the estimation of the disease carrier's frequency in our population.

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CYP21A2mutation update: Comprehensive analysis of databases and published genetic variants

Cited by 80 publications

References 138 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

Functional polymorphisms in the MED13L and SLC4A7 genes are associated with pregnancy-induced hypertension

Genetic characterization of a large cohort of Argentine 21‐hydroxylase Deficiency

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