High variability in <i>CYP21A2</i> mutated alleles in Spanish 21‐hydroxylase deficiency patients, six novel mutations and a founder effect

Loidi, Lourdes; Quinteiro, Celsa; Parajes, Silvia; Barreiro, J; Lestón, Domingo G.; Cabezas-Agrícola, José Manuel; Sueiro, Aurelio M.; Araújo‐Vilar, David; Catro-Feijóo, Lidia; Costas, Javier; Pombo, Manuel; Domı́nguez, Fernando

doi:10.1111/j.1365-2265.2006.02465.x

Cited by 54 publications

(38 citation statements)

References 24 publications

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“…Point mutations and copy number variations, such as deletions and duplications, have been described in many populations (20)(21)(22)(23)(24). Using the analysis of the CYP21A2 gene, we confirmed the referral diagnosis in 241 Czech unrelated patients suspected of 21OHD.…”

Section: Discussionmentioning

confidence: 51%

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Identification of CYP21A2 mutant alleles in Czech patients with 21-hydroxylase deficiency

Vrzalová

Hrubá²,

Hrabincová³

et al. 2010

Int J Mol Med

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Abstract. Congenital adrenal hyperplasia (CAH) is comprised of a group of autosomal recessive disorders caused by an enzymatic deficiency which impairs the biosynthesis of cortisol and, in most of the severe cases, also the biosynthesis of aldosterone. Approximately 90-95% of all the CAH cases are due to mutations in the steroid 21-hydroxylase gene (CYP21A2). In this study, the molecular genetic analysis of CYP21A2 was performed in 267 Czech probands suspected of 21-hydroxylase deficiency (21OHD). 21OHD was confirmed in 241 probands (2 mutations were detected). In 26 probands, a mutation was found only in 1 CYP21A2 allele. A set of 30 different mutant alleles was determined. We describe i) mutated CYP21A2 alleles carrying novel point mutations (p.Thr168Asn, p.Ser169X and p.Pro386Arg), ii) mutated CYP21A2 alleles carrying the novel chimeric gene designated as CH-7, which was detected in 21.4% of the mutant alleles, iii) an unusual genotype with a combination of the CYP21A2 duplication, 2 point mutations and the CYP21A2 large-scale gene conversion on the second allele, and (iv) a detailed analysis of the chimeric CYP21A1P/CYP21A2 genes. In conclusion, our genotyping approach allowed for the accurate identification of the CYP21A2 gene mutations in 21OHD patients and their families and provided some useful information on diagnosis and genetic counselling.

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Section: Discussionmentioning

confidence: 51%

“…In both cases, the CYP21A2 duplication was associated with the mutations, p.Ser97fsX12 and p.Gln318X (the same mutant allele has been previously described) (24). Both probands with the CYP21A2 duplication, p.Ser97fsX12 and p.Gln318X on 1 allele have SW-CAH phenotypes.…”

Section: Discussionmentioning

confidence: 92%

Identification of CYP21A2 mutant alleles in Czech patients with 21-hydroxylase deficiency

Vrzalová

Hrubá²,

Hrabincová³

et al. 2010

Int J Mol Med

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“…For instance, the study of the CYP21A2 gene reveals a low SNP density on HapMap, but it can be merged through GDF with the SNP information obtained by direct sequencing of 21-hydroxylase deficiency patients [29] in order to highlight haplotypes associated with this pathology.…”

Section: Resultsmentioning

confidence: 99%

GDF: Dealing with High-throughput Genotyping Multiplatform Data for Medical and Population Genetic Applications

Amigo¹,

Salas²,

Costas³

et al. 2012

JPB

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“…Nevertheless, this method requires large quantities of DNA and is too laborious and time-consuming to be routinely used for 21OHD molecular diagnosis (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28).…”

Section: Discussionmentioning

confidence: 99%

“…The CYP21A2 gene sequencing and the Southern blot for the 24 samples used to develop the assay were carried out as previously described (26 ) and enabled the assessment of the CYP21A2 copy number. Thus, the presence of 2 copies of the CYP21A2 gene was assumed for individuals who were compound heterozygous for mutations or polymorphisms in the gene.…”

Section: Genotyping Of the Samplesmentioning

confidence: 99%

A Simple and Robust Quantitative PCR Assay to Determine CYP21A2 Gene Dose in the Diagnosis of 21-Hydroxylase Deficiency

et al. 2007

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Background: Correct diagnosis of 21-hydroxylase deficiency (21OHD) requires the identification of CYP21A2 gene deletions and CYP21A1P/CYP21A2 chimeric genes, which are disease-causing alleles, and gene duplications, which can lead to false-positive 21OHD allele results. Because lack of suitable CYP21A2 dosage assessment methods hampers correct 21OHD diagnosis, we developed a new assay based on the relative quantification of the CYP21A2 gene using the DSP gene as a reference. Methods: The assay to determine CYP21A2 copy number is based on real-time PCR. The method also detects the presence of the CYP21A1P/CYP21A2 chimeric gene. We used a duplex PCR to coamplify the DSP gene, included as an internal control, along with CYP21A2. The difference in threshold cycles between CYP21A2 and DSP genes (⌬Ct) was used to assess CYP21A2 copy number. Results:The ⌬Ct values obtained from 24 samples used to set up the method clearly differentiated 3 nonoverlapping intervals, which corresponded to the number of CYP21A2 copies: ؊1.35 to ؊0.25 defined 2 gene copies, ؉0.20 to ؉2.00 defined 1 copy, and ؊2.50 to ؊1.50 defined 3 copies. With these intervals we were able to assess the gene copy number in 24 additional samples. Conclusions: This new method for gene copy assessment detects homozygous and heterozygous CYP21A2 gene deletions, CYP21A1P/CYP21A2 chimeric genes, and gene duplications. Moreover, the method is robust, fast, and easy to use in a molecular diagnosis laboratory.

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High variability in CYP21A2 mutated alleles in Spanish 21‐hydroxylase deficiency patients, six novel mutations and a founder effect

Abstract: A great diversity of haplotypes with a large spectrum of mutated alleles was found. The frequency of the V281L mutation was the highest reported and the relatively high frequency of R444X was the result of a founder effect.

Cited by 54 publications

References 24 publications

Identification of CYP21A2 mutant alleles in Czech patients with 21-hydroxylase deficiency

Identification of CYP21A2 mutant alleles in Czech patients with 21-hydroxylase deficiency

GDF: Dealing with High-throughput Genotyping Multiplatform Data for Medical and Population Genetic Applications

A Simple and Robust Quantitative PCR Assay to Determine CYP21A2 Gene Dose in the Diagnosis of 21-Hydroxylase Deficiency

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