title: Identification of non-amplifying CYP21 genes when using PCR-based diagnosis of 21-hydroxylase deficiency in congenital adrenal hyperplasia (CAH) affected pedigrees.
abstract: Steroid 21-hydroxylase deficiency is among the most common inborn errors of metabolism in man. Characterization of mutations in the 21-hydroxylase gene (CYP21) has permitted genetic diagnosis, facilitated by the polymerase chain reaction (PCR). The most common mutation is conversion of an A or C at nt656 to a G in the second intron causing aberrant splicing of mRNA. Homozygosity for nt656G is associated with profoundly deficient adrenal cortisol and aldosterone synthesis, secondary hypersecretion of adrenal androgens, and a severe form of congenital adrenal hyperplasia (CAH) characterized by ambiguous genitalia and/or sodium wasting in newborns. During the course of genetic analysis of CYP21 mutations in CAH families, we and others have noticed a number of relatives genotyped as nt656G homozygotes, yet showing no clinical signs of disease. A number of lines of evidence have led us to propose that the putative asymptomatic nt656G/G individuals are incorrectly typed due to dropout of one haplotype during PCR amplification of CYP21. For prenatal diagnosis, we recommend that microsatellite typing be used as a supplement to CYP21 genotyping in order to resolve ambiguities at nt656.
authors.affiliation: Victoria University of Wellington, School of Biological Sciences, New Zealand.
authors.forename: D J
authors.initials: DJ
authors.lastname: Day
authors.forename: P W
authors.initials: PW
authors.lastname: Speiser
authors.forename: E
authors.initials: E
authors.lastname: Schulze
authors.forename: M
authors.initials: M
authors.lastname: Bettendorf
authors.forename: J
authors.initials: J
authors.lastname: Fitness
authors.forename: F
authors.initials: F
authors.lastname: Barany
authors.forename: P C
authors.initials: PC
authors.lastname: White
mesh_terms: D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics* / Q000378:metabolism; D000483:Alleles; D005260:Female; D006801:Humans; D008297:Male; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D017421:Sequence Analysis; D013255:Steroid 21-Hydroxylase / Q000235:genetics*
chemical_list: D013255:Steroid 21-Hydroxylase