Predisposition for de novo gene aberrations in the offspring of mothers with a duplicated CYP21A2 gene
ABSTRACT Although CYP21A2 de novo mutations are assumed to account for 1 to 2% of congenital adrenal hyperplasia (CAH) alleles and CYP21 genotyping has been done worldwide, there are only a few well-documented cases of CYP21A2 de novo mutations. The majority of these are deletions resulting from unequal crossings over owing to misalignment of homologous chromosomes during meiosis. Whereas so far, only heterozygous deletions of the CYP21A1P pseudogene were seen as premutations for de novo aberrations, the present report addresses such a predisposing role for parental duplicated CYP21A2 genes.
As part of routine diagnostic procedures, CYP21 genotyping has been performed in two unrelated female CAH index patients and in their clinically asymptomatic parents and siblings.
Both patients have inherited the paternal Intron2splice mutation and have harbored a de novo gene aberration (large deletion and I271N/exon 4) on their maternal haplotype. Surprisingly, both mothers were carriers of rare duplicated CYP21A2 haplotypes carrying CAH alleles, which were not detected in the daughters. Among 133 CAH alleles that were detected in patients and that could be traced to the respective family members by genotyping, these two de novo aberrations (representing 1.5% of 133 traced CAH alleles) were the only ones identified.
Because both de novo CYP21A2 gene aberrations so far identified in our laboratory occurred in the gametes of mothers carrying rare duplicated CYP21A2 haplotypes, we hypothesize that duplicated CYP21A2 genes could predispose for de novo mutations in the offspring, which is of relevance for prenatal CYP21 genotyping and genetic counseling.
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ABSTRACT: The systematic study of the human genome indicates that the inter-individual variability is greater than expected and it is not only related to sequence polymorphisms but also to gene copy number variants (CNVs). Congenital Adrenal Hyperplasia due to 21-hydroxylase deficiency (21OHD) is the most common autosomal recessive disorder with a carrier frequency of 1:25 to 1:10. The gene that encodes 21-hydroxylase enzyme, CYP21A2, is considered to be one of the most polymorphic human genes. Copy number variations, such as deletions, which are severe mutations common in 21OHD patients, or gene duplications, which have been reported as rare events, have also been described. The correct characterization of 21OHD alleles is important for disease carrier detection and genetic counselling CYP21A2 genotyping by sequencing has been performed in a random sample of the Spanish population, where 144 individuals recruited from university students and employees of the hospital were studied. The frequency of CYP21A2 mutated alleles in our sample was 15.3% (77.3% were mild mutations, 9% were severe mutations and 13.6% were novel variants). Gene dosage assessment was also performed when CYP21A2 gene duplication was suspected. This analysis showed that 7% of individuals bore a chromosome with a duplicated CYP21A2 gene, where one of the copies was mutated. As far as we know, the present study has shown the highest frequency of 21OHD carriers reported by a genotyping analysis. In addition, a high frequency of alleles with CYP21A2 duplications, which could be misinterpreted as 21OHD alleles, was found. Moreover, a high frequency of novel genetic variations with an unknown effect on 21-hydroxylase activity was also found. The high frequency of gene duplications, as well as novel variations, should be considered since they have an important involvement in carrier testing and genetic counseling.PLoS ONE 02/2008; 3(5):e2138. DOI:10.1371/journal.pone.0002138 · 3.53 Impact Factor
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ABSTRACT: Congenital adrenal hyperplasia (CAH) is a family of autosomal recessive disorders caused by mutations in genes encoding the enzymes involved in one of the 5 steps of adrenal steroid synthesis or the electron donor P450 oxidoreductase (POR) enzyme. Steroid 21-hydroxylase deficiency (21-OHD), the principal focus of this review, accounts for about 90-95% of all CAH cases, and its biochemical and clinical severity depends on the underlying CYP21A2 gene disruption. Molecular genetic advancements have been achieved in recent years, and the aim of this review is to attempt to highlight its contribution to the comprehension and management of the disease. When possible, we will try to achieve this goal also by providing some results from our personal experience regarding: some aspects of CYP21A2 gene analysis, with basic genotype/phenotype relationships; its crucial role in both genetic counselling and in prenatal diagnosis and treatment in families at risk for 21-OHD; its help in the comprehension of the severity of the disease in patients diagnosed by neonatal screening and possibly treated before an evident salt-loss crisis or before performing adequate blood sampling; its usefulness in the definition of post ACTH 17-hydroxyprogesterone values, discriminating between non-classic, heterozygote and normal subjects; and finally the contribution of genes other than CYP21A2 whose function or dysfunction could influence 21-hydroxylase activity and modify the presentation or management of the disease.Sexual Development 09/2010; 4(4-5):233-48. DOI:10.1159/000315959 · 1.76 Impact Factor
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ABSTRACT: Genetic analysis is commonly performed in patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. The objective of the study was to describe comprehensive CYP21A2 mutation analysis in a large cohort of CAH patients. Targeted CYP21A2 mutation analysis was performed in 213 patients and 232 parents from 182 unrelated families. Complete exons of CYP21A2 were sequenced in patients in whom positive mutations were not identified by targeted mutation analysis. Copy number variation and deletions were determined using Southern blot analysis and PCR methods. Genotype was correlated with phenotype. In our heterogeneous U.S. cohort, targeted CYP21A2 mutation analysis did not identify mutations on one allele in 19 probands (10.4%). Sequencing identified six novel mutations (p.Gln262fs, IVS8+1G>A, IVS9-1G>A, p.R408H, p.Gly424fs, p.R426P) and nine previously reported rare mutations. The majority of patients (79%) were compound heterozygotes and 69% of nonclassic (NC) patients were compound heterozygous for a classic and a NC mutation. Duplicated CYP21A2 haplotypes, de novo mutations and uniparental disomy were present in 2.7% of probands and 1.9 and 0.9% of patients from informative families, respectively. Genotype accurately predicted phenotype in 90.5, 85.1, and 97.8% of patients with salt-wasting, simple virilizing, and NC mutations, respectively. Extensive genetic analysis beyond targeted CYP21A2 mutational detection is often required to accurately determine genotype in patients with CAH due to the high frequency of complex genetic variation.The Journal of Clinical Endocrinology and Metabolism 10/2010; 96(1):E161-72. DOI:10.1210/jc.2010-0319 · 6.31 Impact Factor