Molecular Genetic Analysis of Tunisian Patients with a Classic Form of 21-Hydroxylase Deficiency: Identification of Four Novel Mutations and High Prevalence of Q318X Mutation

Kharrat, Maher; Tardy, Véronique; Mrad, Ridha; Mâazoul, Faouzi; Jemaa, Lamia Ben; Refai, M.; Morel, Yves; Chaâbouni, Habiba

doi:10.1210/jc.2003-031056

Cited by 81 publications

(65 citation statements)

References 34 publications

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“…Gene deletions and chimeric genes encompass 31.8% of all gene mutations. The I2G has been mentioned as the most frequent mutation in western European cohorts (White and Speiser, 2000); but with an exception, the Q318X mutation was frequent in our study, which corresponds to Tunisia (Kharrat et al, 2004) and confirms the previous study in Iran (Vakili et al, 2005). By far, the I172N mutation is associated with the SV form.…”

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confidence: 89%

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Mutation Analysis of theCYP21A2Gene in the Iranian Population

Rabbani

Mahdieh

Ashtiani

et al. 2012

Genetic Testing and Molecular Biomarkers

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Background: Defects in the CYP21A2 gene cause steroid 21-hydroxylase deficiency, which is the most frequent cause of congenital adrenal hyperplasia. Forty four affected families were investigated to identify the mutation spectrum of the CYP21A2 gene. Methods: Families were subjected to clinical, biochemical, and molecular analyses. Allele-specific polymerase chain reaction amplification was used for eight common mutations followed by dosage analysis to exclude CYP21A2 deletions. Results: The most frequent mutations detected were gene deletions and chimera (31.8%). Other mutation frequencies were as follows: Q318X, 15.9%; I2G, 14.8%; I172N, 5.8%; gene duplication, 5.7%; R356W, 8%; and E6 cluster mutations, 2.3%. Direct sequencing of the CYP21A2 gene revealed R316X, P453S, c.484insT, and a change at the start codon. Different modules carried by patients were classified into five different haplotypes. The genotype phenotype correlation (positive predictive value) for group null, A, B, and C were 92.3%, 85.7%, 100%, and 0, respectively. Conclusions: Methods used will be helpful for carrier detection and antenatal diagnosis, especially with inclusion of the multiplex ligation probe dependent amplification technique, which is easier for routine tests in comparison with other methods. Mutation frequencies indicate that Iranians are possible descendants of Asians and Europeans.

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confidence: 89%

“…The PCR products were purified by ethanol precipitation protocols. Primers used were P1, P2, P5, P6, P10, (Kharrat et al, 2004) 3na, 4 ns, and 7na (Wilson et al, 1995b). Combination of these primers covered the whole coding and intronic sequences.…”

Section: Direct Sequencingmentioning

confidence: 99%

Mutation Analysis of theCYP21A2Gene in the Iranian Population

Rabbani

Mahdieh

Ashtiani

et al. 2012

Genetic Testing and Molecular Biomarkers

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“…8 More than half of our female subjects showed Prader score III virilization. Similar to our study, Bajpai et al 18 reported Prader score III virilization in 52.7% of subjects, Kharrat et al 19 reported Prader score III and Prada score IV in 22 and 45% of the subjects respec-A. Deletion/LGC Figure 2.…”

Section: Discussionsupporting

confidence: 89%

“…The highest incidence of consanguinity that had ever been reported was in Tunisian population. 19 On the contrary, Koyama et al 16 reported that there were no consanguinity in CAH family in Japan. These facts emphasized that CYP21 gene and its pseudo gene are susceptible to genomic alteration due to adjacent structures and highly recombination events.…”

Section: Discussionmentioning

confidence: 99%

Phenotype and genotype characteristics of Indonesian 21-hydroxylase deficient patients

Oswari¹,

Tridjaja²,

Setianingsih³

et al. 2007

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C ongenital adrenal hyperplasia (CAH) is a frequent autosomal recessive disorder which is caused by the loss or severely decreased activity of one of five steroidogenic enzymes necessary for cortisol biosynthesis. [1][2][3][4][5][6][7][8] This disease is known to be the most common cause of ambiguous genitalia in children (60-70%) 9,10 and 21-hydroxylase deficiency (CAH-21OH) is considered to be responsible for 90-95% cases. 1-3 Clinical manifestations of CAH-21OH vary from mild to severe, depend on the residual activity of 21-hydroxylase. It is classified into three forms: salt-wasting (SW) form, simple virilization (SV) form and non-classic (NC) form. [1][2][3][4][5][6][7][8] In severe impaired steroidogenesis, the affected female will experience intrauterine virilization therefore presenting ambiguous genitalia at birth. Aldosterone deficiency will result in postnatal salt losing and cortisol deficiency will cause inadequate response to stress. These problems will put the affected infants into life threatening condition. 11,12 In partial impaired AbstractBackground Congenital adrenal hyperplasia (CAH) is the most common cause of ambiguous genitalia in children and 90-95% cases show 21-hydroxylase deficiency. More than 100 mutations have been described and of these, four mutations have been frequently reported in Asia. Those mutations are deletion/large gene conversion (LGC), intron2 splice mutation (I2 splice), point mutations at codon 172 (I172N) and codon 356 (R356W). Genotyping is very valuable since close correlation observed between genotype and phenotype. Objective To identify phenotype and genotype characteristics of CAH due to 21-hydroxylase deficiency (CAH-21OH) and correlation between them. Methods From June to November 2006 we analyzed 37 confirmed CAH-21OH patients treated at the Department of Child Health, Cipto Mangunkusumo Hospital during the period of 1990-2006. Polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP) analysis or amplification-created restriction site (ACRS) were performed. We first identified deletion/ LGC and I172N mutation that had been mostly reported in salt wasting (SW) and simple virilizing (SV) form patients respectively. Results There were 37 patients, consisted of 6 males and 31 females with the ratio 1:5.2. Of those, 25, 10, 2 patients were SW, SV and non-classic (NC) form, respectively. PCR-RFLP or ACRS was performed to detect two mutations in 32 patients (64 alleles). Deletion/LGC was found in 6 alleles while I172N mutations in two. All deletion alleles showed SW phenotype but I172 mutated alleles showed SW and SV phenotype. Conclusion There is a consistent close association between genotype and phenotype in our CAH-21OH patients. [Paediatr Indones 2007;47:189-195].

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“…The previously described mutations p.G424S, p.R408C, IVS2-2A>G, p.Ser170fs, p.R426H, p.H365Y, and p.W19X were observed in 35 nonrelated patients (23,24,25,26) (Table 2). Among them, the most frequent were the IVS2-2A>G, p.G424S, and p.R426H mutations.…”

Section: Mutations Not Derived From Gene Conversion Eventsmentioning

confidence: 80%

Molecular CYP21A2 diagnosis in 480 Brazilian patients with congenital adrenal hyperplasia before newborn screening introduction

Carvalho¹,

Miranda²,

Gomes³

et al. 2016

European Journal of Endocrinology

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Background: Most congenital adrenal hyperplasia (CAH) patients carry CYP21A2 mutations derived from conversion events involving the pseudogene, and the remaining carry new mutations. Objective: To review causal mutations and genotype-phenotype correlation in 480 Brazilian patients. Methods: DNA was extracted from 158 salt-wasters (SWs), 116 simple virilizing (SV), and 206 nonclassical (NC) patients. Fourteen point mutations were screened by allele-specific PCR, large rearrangements by Southern blotting/ MLPA, and sequencing was performed in those with incomplete genotype. The gene founder effect was analyzed by microsatellite studies. Patients were divided into six genotypes (Null; A: <2%; B: 3-7%; C: >20% of residual enzymatic activity (EA); D: unknown EA; E: incomplete genotype). Results: Targeted methodologies defined genotype in 87.6% of classical and in 80% of NC patients and the addition of sequencing in 100 and 83.5%, respectively. The most frequent mutations were p.V281L (26.6% of alleles), IVS2-13A/C>G (21.1%), and p.I172N (7.5%); seven rare mutations and one novel mutation (p.E351V) were identified. Gene founder effect was observed in all but one (p.W19X) mutation. Null, A, B, and C genotypes correlated with SW (88%), SW (70%), SV (98%), and NC forms (100%), respectively. In group D, the p.E351V mutation correlated with classical form and group E comprised exclusively NC-patients. ACTH-stimulated 17OHP level of 44.3 ng/mL was the best cutoff to identify NC-patients carrying severe mutations. Conclusions: We identified a good genotype-phenotype correlation in CAH, providing useful data regarding prediction of disease´s severity; moreover, we suggest that ACTH-stimulated 17OHP levels could predict carrier status for severe mutations. Sequencing is essential to optimize molecular diagnosis in Brazilian CAH patients.

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Molecular Genetic Analysis of Tunisian Patients with a Classic Form of 21-Hydroxylase Deficiency: Identification of Four Novel Mutations and High Prevalence of Q318X Mutation

Cited by 81 publications

References 34 publications

Mutation Analysis of theCYP21A2Gene in the Iranian Population

Mutation Analysis of theCYP21A2Gene in the Iranian Population

Phenotype and genotype characteristics of Indonesian 21-hydroxylase deficient patients

Molecular CYP21A2 diagnosis in 480 Brazilian patients with congenital adrenal hyperplasia before newborn screening introduction

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