Identification of non-amplifying CYP21 genes when using PCR-based diagnosis of 21-hydroxylase deficiency in congenital adrenal hyperplasia (CAH) affected pedigrees

Darren J. Day, Phyllis W. Speiser, Egbert Schulze, M. Bettendorf, Jodene Fitness, Francis Barany, Perrin C. White

Research output: Contribution to journalArticlepeer-review

117 Scopus citations

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 and drogens, and a severe form of con genital 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.

Original languageEnglish (US)
Pages (from-to)2039-2048
Number of pages10
JournalHuman molecular genetics
Volume5
Issue number12
DOIs
StatePublished - Dec 1996

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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