Genetic approach to prenatal diagnosis in urea cycle defects

To demonstrate the feasibility of prenatal diagnosis by molecular genetics in all urea cycle defects in order to improve and standardize the current approaches.

Deceased index patients who had suffered from a urea cycle disorder were investigated for mutations of the biochemically most likely affected gene. If no material of index patients was available, parental DNA was studied for obligate carrier status. Fetal cells of 15 pregnancies, either chorionic villi or amniotic fluid cells, were used for direct sequence analysis of the respective mutations. Thirteen families were investigated, of which two were affected by N-acetylglutamate synthase deficiency, four by carbamoylphosphate synthetase 1 deficiency, one by ornithine transcarbamylase deficiency, three by argininosuccinate synthetase deficiency, two by argininosuccinate lyase deficiency, and one by arginase deficiency.

Molecular genetics allowed the determination of the fetal status in all cases. Besides 14 known mutations, we detected the novel mutation c.544delC of the N-acetylglutamate synthase gene, the novel missense mutation c.721G>A (E241K) of the argininosuccinate lyase gene, and the novel double mutated allele comprising the known mutation c.703G>A (G235R) and the novel insertion c.712ins[GGACC](2) (254X) of the arginase 1 gene.

Direct genetic analysis of chorionic villi or amniotic fluid cells is feasible, fast, and specific, and can be regarded as the method of choice for prenatal diagnosis in urea cycle disorders.