Clinical applications of molecular genetics: the model of congenital adrenal hyperplasia

ABSTRACT

Spectacular advances in molecular genetics have enabled the molecular characterisation of many genetic disorders. The clinical applications include (i) identification of pre-symptomatic and symptomatic affected individuals (monogenic diseases), allowing for early treatment and prevention of complications, (ii) carrier testing for genetic counselling, (iii) pharmacogenetic testing to guide medical treatment, and (iv) susceptibility testing (in polygenic diseases) to determine the risk of developing future disease. Using the model of congenital adrenal hyperplasia (CAH), direct mutational analysis can be applied to (i) confirm the diagnosis when hormone assays have been equivocal, which would allow for early treatment and prevention of adrenal crisis, (ii) prenatal diagnosis and prenatal treatment in affected females to prevent or reduce prenatal virilisation, (iii) heterozygote carrier identification for genetic counselling, (iv) novel therapeutic applications to optimise treatment, including adjusting the steroid dose based on consistent genotype-phenotype correlations, so as to reduce the incidence of growth-inhibiting effects of steroid excess. However, molecular analysis can occasionally be complicated by multiple mutations on one allele, which may potentially affect genotype-phenotype correlations. Hence, molecular genetic analysis of CAH may eventually be adopted as a second tier confirmation of the disease, but is unlikely to replace the current first tier screening assays of precursor steroid metabolites proximal to the enzyme deficiency.