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The Spectrum of Molecular Defects of the CYP21 Gene in the Hellenic Population: Variable Concordance between Genotype and Phenotype in the Different Forms of Congenital Adrenal Hyperplasia¹

Endocrine Unit, Choremis Research Laboratory, A’ Pediatric Department, Athens University Medical School, Aghia Sophia Children’s Hospital, Athens 11527, Greece

Address all correspondence and requests for reprints to: Dr. M. Dracopoulou-Vabouli, Endocrine Unit, Choremis Research Laboratory, A’ Pediatric Department, Athens University Medical School, Aghia Sophia Children’s Hospital, Athens 11527, Greece.

Abstract

Defective steroid synthesis due to 21-hydroxylase deficiency is the most common form of congenital adrenal hyperplasia. Knowledge of the molecular defects causing 21-hydroxylase deficiency in different populations is of both theoretical and practical interest. The types and the relative frequencies of molecular defects and the correlation between the genotype and the phenotype were examined in the Hellenic population. We searched for deletions, conversions, and 11 of the most frequent mutations of the CYP21 gene by Southern blot and allele-specific PCR in 222 chromosomes from 111 unrelated subjects and their parents. The most frequent molecular defects were 1) in the salt wasting form, I₂ splice (42.9%), deletions and conversions (24.5%), and Q318stop (14.3%); 2) in the simple virilizing form, I172N (35.3%), I₂ splice (29.4%), and P30L (19.1%); and 3) in the nonclassical form, V281L (41.1%), P30L (21.4%), and P453S (14.3%). Compared with other populations, Greek patients had a higher frequency of Q318stop in the salt-wasting form, of P30L in both simple virilizing and nonclassical forms and of P453S in the nonclassical form. The concordance of genotype to phenotype in the total sample was 87%. However, the concordance rate was different in the three forms of the disease. Thus, complete concordance was detected in the genotypes predicting the salt-wasting phenotype, a slightly lower concordance (95.2%) was detected in the genotypes predicting the simple virilizing phenotype, and the lowest concordance (67.6%) was observed in genotypes predicting the nonclassical phenotype. In conclusion, the concordance between genotype and phenotype decreases as the severity of the disease diminishes. This should be taken into consideration in genetic counseling and antenatal intervention.

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