Identification of three mutatons in the cyp21 gene in Vietnamese patients having signs of congenital adrenal hyperplasia

More than 90% of the cases of congenital adrenal hyperplasia are caused by mutations of the CYP21 gene. Approximately 75% of the defective CYP21 genes are generated through intergenic recombination, termed apparent gene conversion, from the neighboring CYP21P pseudogene. Among them, mutation of the aberrant splicing donor site of IVS2 –12A/C>G at nucleotide (nt) 655 is believed to be a result derived from this mechanism and is the most prevalent case among all ethnic groups. However, mutation of 707–714delGAGACTAC rarely exists alone, although this locus is a distance of 53 nt away from IVS2 –12A/C>G. From the molecular characterization of the mutation of IVS2 –12A/C>G combined with 707–714delGAGACTAC in patients with congenital adrenal hyperplasia, we found that it appeared to be in a 3.2-rather than a 3.7-kb fragment generated by Taq I digestion in a PCR product of the CYP21 gene. Interestingly, the 5′ end region of such a CYP21 haplotype had CYP21P-specific sequences. Our results indicate that the coexistence of these two mutations is caused by deletion of the CYP21P, XA, RP2, and C4B genes and intergenic recombination in the C4-CYP21 repeat module. Surprisingly, this kind of the haplotype of the mutated CYP21 gene has not been reported as a gene deletion.

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Study of a Kindred with Classic Congenital Adrenal Hyperplasia: Diagnostic Challenge due to Phenotypic Variance1

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.83.6.4887 ◽

1998 ◽

Vol 83 (6) ◽

pp. 1940-1945

Author(s):

Daisy Chin ◽

Phyllis W. Speiser ◽

Julianne Imperato-McGinley ◽

Naznin Dixit ◽

Naveen Uli ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Newborn Screening ◽

Point Mutation ◽

Phenotypic Expression ◽

Variable Degree ◽

Adrenal Hyperplasia ◽

Cyp21 Gene ◽

Classic Congenital Adrenal Hyperplasia ◽

Genital Ambiguity ◽

21 Hydroxylase Deficiency

We sought to determine the concordance of the phenotype and genotype in a kindred with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency. The variation in phenotypic expression within this family underscores the difficulty of establishing the diagnosis in the absence of newborn screening, even with a heightened index of suspicion. Steroidogenic profiles were obtained for the three affected siblings. The available clinical history of the two affected aunts was retrieved. Genotyping was performed on several members of the kindred. Detailed sequencing of the entire CYP21 gene of two clinically dissimilar subjects in this family was undertaken to explore the possibility of other mutations or polymorphisms. PCR with ligase detection reaction analysis of CYP21 revealed that the affected family members III-2, III-3, III-4, II-3, and II-4, all were compound heterozygotes carrying the intron 2 point mutation known to interfere with splicing (nucleotide 656 A to G) and the exon 4 point mutation causing a nonconservative substitution of asparagine for isoleucine at codon 172 (I172N). Detailed sequencing of the gene was performed for the two most phenotypically dissimilar subjects. A single silent polymorphism was found in the third nucleotide for codon 248 in patient II-4, but not in patient III-4, and no additional mutations were found. Classic congenital adrenal hyperplasia remains a difficult diagnosis to make in the absence of newborn screening because of the variability of phenotypic expression. Likewise, the variable degree of genital ambiguity in affected females in this family serves to question universal advocacy of prenatal steroid treatment in pregnancies at risk for congenital adrenal hyperplasia. Extensive molecular exploration did not provide an explanation of the phenotypic heterogeneity and supports the possibility of influences other than the CYP21 gene for the observed divergence.

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A Novel 13-bp Deletion in Exon 1 of CYP21 Gene Causing Severe Congenital Adrenal Hyperplasia

Diagnostic Molecular Pathology ◽

10.1097/01.pas.0000177797.81206.eb ◽

2005 ◽

Vol 14 (4) ◽

pp. 250-252 ◽

Cited By ~ 4

Author(s):

Maher Kharrat ◽

V??ronique Tardy ◽

Ridha M??Rad ◽

Faouzi Maazoul ◽

Yves Morel ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Adrenal Hyperplasia ◽

Cyp21 Gene ◽

Exon 1

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Characterization of a novel DNA polymorphism in the human CYP21 gene and application for DNA diagnosis of congenital adrenal hyperplasia

Clinical Endocrinology ◽

10.1046/j.1365-2265.2000.01090.x ◽

2000 ◽

Vol 53 (4) ◽

pp. 419-422 ◽

Cited By ~ 2

Author(s):

Yong-Ho Lee ◽

Eun-Sook Park ◽

Shin-Hye Kang ◽

Hogeun Kim ◽

Jin-Yong Lee ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Dna Polymorphism ◽

Adrenal Hyperplasia ◽

Dna Diagnosis ◽

Cyp21 Gene

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Mutational spectrum of congenital adrenal hyperplasia in Slovenian patients: a novel Ala15Thr mutation and Pro30Leu within a larger gene conversion associated with a severe form of the disease

Acta Endocrinologica ◽

10.1530/eje.0.1490137 ◽

2003 ◽

pp. 137-144 ◽

Cited By ~ 22

Author(s):

V Dolzan ◽

M Stopar-Obreza ◽

M Zerjav-Tansek ◽

K Breskvar ◽

C Krzisnik ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Gene Conversion ◽

Promoter Region ◽

Southern Blotting ◽

Point Mutations ◽

Rational Approach ◽

Adrenal Hyperplasia ◽

Mutational Spectrum ◽

Cyp21 Gene ◽

Gene Conversions

OBJECTIVE: To analyse the mutational spectrum, the associated haplotypes and the genotype-phenotype correlation, and to design a reliable and rational approach for CYP21 mutation detection in Slovenian congenital adrenal hyperplasia (CAH) patients. DESIGN: Molecular analysis of the CYP21 gene was performed in 36 CAH patients and 79 family members. METHODS: Southern blotting, sequence-specific PCR amplification (PCR-SSP), sequence-specific oligonucleotide hybridisation (PCR-SSO) and sequencing were used to detect CYP21 gene deletions, conversions and point mutations. RESULTS: CYP21 gene deletion was the most frequent mutation (36.4%). Large gene conversions detectable only by Southern blotting represented 12.1%, and gene conversions involving the promoter region represented 7.6% of the mutated alleles. The most frequent point mutations were: intron 2 splice mutation 16.7%, Ile172Asn mutation 7.6%, Gln318Stop 7.5% and Pro30Leu 12.2% of alleles. A correlation between the genotype and the clinical phenotype similar to those described for large populations was observed. The finding of Pro30Leu mutation linked to a gene conversion could explain the simple virilising (SV) phenotype in compound heterozygotes for the Pro30Leu and a severe mutation. In two siblings with a salt wasting form of CAH (SW-CAH), a novel mutation Ala15Thr was found on the allele characterised by Pro30Leu mutation and gene conversion involving the promoter region. CONCLUSIONS: Our genotyping approach allowed reliable diagnosis of CAH in the Slovenian population. The high frequency of CYP21 gene aberrations on Pro30Leu positive alleles justified systematic searching for a gene conversion in the promoter region using the PCR-SSP reaction.

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Two Cases of Simple Virilizing Congenital Adrenal Hyperplasia with Compound Heterozygous Mutations of CYP21 Gene

Journal of Korean Endocrine Society ◽

10.3803/jkes.2007.22.4.299 ◽

2007 ◽

Vol 22 (4) ◽

pp. 299

Author(s):

Koon Soon Kim ◽

Yun Sun Choi ◽

Youn Sun Bai ◽

So Young Rha ◽

Young Suk Jo ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Compound Heterozygous ◽

Adrenal Hyperplasia ◽

Cyp21 Gene ◽

Compound Heterozygous Mutations ◽

Simple Virilizing

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Phenotype-Genotype Correlation in 56 Women with Nonclassical Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.86.1.7131 ◽

2001 ◽

Vol 86 (1) ◽

pp. 207-213 ◽

Cited By ~ 58

Author(s):

Catherine Deneux ◽

Véronique Tardy ◽

Anne Dib ◽

Etienne Mornet ◽

Line Billaud ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Phenotypic Expression ◽

Complete Analysis ◽

Primary Amenorrhea ◽

Adrenal Hyperplasia ◽

Hydroxylase Deficiency ◽

Cyp21 Gene ◽

Severe Mutation ◽

21 Hydroxylase Deficiency ◽

Genotype Correlation

Complete analysis of the CYP21 gene was performed in 56 unrelated French women with symptomatic nonclassical congenital adrenal hyperplasia. The mutational spectrum and the phenotype-genotype correlation were examined. The overall predominant mutation was V281L, which was present on 51% of alleles and in 80% of women. Three novel mutations were found: L317M, R435C, and a 5′-end gene conversion. Sixty-three percent of the women were carrying a severe mutation of the CYP21 gene, and hence risk giving birth to children with a classical form of the disease. In such cases, screening for heterozygosity in the partner is crucial. Potential genotype/phenotype correlations were examined by classifying the patients into three groups according to the CYP21 allelic combinations: A (mild/mild), B (mild/severe), and C (severe/severe). Primary amenorrhea was more frequent, and mean basal and stimulated 17-hydroxyprogesterone levels were higher in compound heterozygotes for mild and severe mutations (group B) compared with women with two mild mutations (group A), but there was a considerable overlap for individual values. Surprisingly, in two women, a severe mutation was found on both alleles (group C). Therefore, the phenotype cannot be accurately predicted from the genotype. Variability in phenotypic expression may be conditioned by mechanisms other than genetic heterogeneity at the CYP21 locus.

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