Article

Predisposition for de novo gene aberrations in the offspring of mothers with a duplicated CYP21A2 gene.

Department of Internal Medicine III, Division of Endocrinology and Metabolism, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
Journal of Clinical Endocrinology &amp Metabolism (impact factor: 6.5). 04/2007; 92(3):1164-7. DOI:10.1210/jc.2006-2189 pp.1164-7
Source: PubMed

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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    Silvia Parajes, Celsa Quinteiro, Fernando Domínguez, Lourdes Loidi
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    PLoS ONE 02/2008; 3(5):e2138. · 4.09 Impact Factor
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    [show abstract] [hide abstract]
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    The Journal of clinical endocrinology and metabolism 10/2010; 96(1):E161-72. · 6.50 Impact Factor
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Keywords

clinically asymptomatic parents
 
congenital adrenal hyperplasia
 
CYP21 genotyping
 
CYP21A2 de novo mutations
 
CYP21A2 haplotypes
 
de novo aberrations
 
de novo CYP21A2 gene aberrations
 
de novo gene aberration
 
de novo mutations
 
duplicated CYP21A2 genes
 
genetic counseling
 
maternal haplotype
 
paternal Intron2splice mutation
 
prenatal CYP21 genotyping
 
present report addresses
 
respective family members
 
routine diagnostic procedures
 
two de novo aberrations
 
unequal crossings
 
unrelated female CAH index patients