Carrier detection and prenatal diagnosis of congenital adrenal hyperplasia must identify 'apparently mild' CYP21A2 alleles which associate neonatal salt-wasting disease

Objective Couples at risk of severe congenital adrenal hyperplasia (CAH) may be offered prenatal treatment or preimplantation diagnosis. However, proper genetic counselling requires the accurate identification of apparently ‘mild alleles’ in partners of CAH‐carriers/patients. Methods CYP21A2 gene an...

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Published in:Prenatal diagnosis 2010-08, Vol.30 (8), p.758-763
Main Authors: Ezquieta, Begoña, Santomé, Luis, Barrio, Raquel, Barrionuevo, Jose L., López-Siguero, Juan P., Oliver, Antonio, Ramírez, Joaquín, Rodríguez, Ildefonso, Muñoz-Pacheco, Rafael
Format: Article
Language:English
Subjects:
Adrenal Hyperplasia, Congenital - diagnosis
Adrenal Hyperplasia, Congenital - enzymology
Adrenal Hyperplasia, Congenital - genetics
Alleles
Biological and medical sciences
carriers in general population
Chromosomes
Computer programs
congenital adrenal hyperplasia
CYP21A2 splice donor site
Delivery. Postpartum. Lactation
DNA
DNA - chemistry
DNA - genetics
Female
Fundamental and applied biological sciences. Psychology
Gene frequency
Genetic Counseling
Genetic counselling
Genetic Variation
Genetics of eukaryotes. Biological and molecular evolution
Gynecology. Andrology. Obstetrics
Heterozygosity
Heterozygote
Humans
Hyperplasia
Infant, Newborn
Male
Medical sciences
Microsatellite Repeats
Molecular and cellular biology
Mutation
Neonates
p.Val282Leu (Val281Leu)
Polymerase Chain Reaction
Polymorphism, Single Nucleotide
Prenatal diagnosis
Prenatal Diagnosis - methods
software
Splicing
Statistics
Steroid 21-Hydroxylase - genetics
steroid 21-hydroxylase deficiency
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Summary:Objective Couples at risk of severe congenital adrenal hyperplasia (CAH) may be offered prenatal treatment or preimplantation diagnosis. However, proper genetic counselling requires the accurate identification of apparently ‘mild alleles’ in partners of CAH‐carriers/patients. Methods CYP21A2 gene analyses were performed in 255 patients with severe 21‐hydroxylase deficiency (21‐OHD), 94 with mild 21‐OHD, 752 parental samples, 233 clinically unaffected partners and 253 historic DNA samples. GENSCAN and ClustalX2.0 software were used for in silico analyses, and Epidat 3.1 software for statistical calculations. Results Twenty‐seven partners were carriers of p.Val282Leu (alias p.Val281Leu, allele frequency 11.7%, 7.4–16.1). ‘Val282Leu alleles’ were detected in 30 patients with salt‐wasting (SW) disease, 21 with other pseudogene‐derived and rare coding cis severe mutations, and 9 without. These CYP21A2 genes were compared to those of 94 fully characterized patients with mild deficiency carrying p.Val282Leu in compound heterozygosity with a severe allele. A rare intronic variant, c.292+5G>A, was detected in the nine ‘severe Val282Leu alleles’ and that was not seen in mild p.Val282Leu alleles, in other deficient alleles or in normal chromosomes. The in silico documented effect on splicing and the clinical association (p < 0.0001) confirmed p.Val282Leu; c.292+5G>A as a severe allele. Conclusion As only severe alleles require clinical intervention, CAH‐carrier detection of p.Val282Leu should be followed by the analysis of c.292+5G>A. Copyright © 2010 John Wiley & Sons, Ltd.
ISSN:0197-3851
1097-0223
1097-0223
DOI:10.1002/pd.2537