Identification of Variants Underlying Phenylalanine Hydroxylase Deficiency in Saudi Arabia.

Background: Deleterious mutations in the human gene phenylalanine hydroxylase (PAH) encoding the phenylalanine hydroxylase enzyme give rise to classic phenylketonuria and hyperphenylalaninemia. Our study was designed to characterize the spectrum of variants in the PAH gene in Saudi patients. Materials and Methods: We screened a cohort of 72 Saudi patients with clinical and biochemical diagnoses of hyperphenylalaninemia at the largest tertiary care center in Saudi Arabia; the King Faisal Specialist Hospital and Research Center (KFSH&RC), Riyadh. All patient's charts were reviewed under an approved study by Institutional Review Board. Results: Twenty-one different PAH variants were identified among the 144 PAH alleles assessed by targeted gene sequencing. Within the studied cohort, 60 of 72 patients had homozygous mutations with the the remaining 12 being compound heterozygotes. The most prevalent of the disease alleles identified in this study was the p.(Arg252Trp) mutation, which accounted for 38 of 144 alleles (26.4%). With the high incidence of genetic disorders in the population, religiously permissible preventive reproductive measures are a priority in our practice. Prenatal diagnoses carried out on four fetuses revealed two that were homozygous for PAH pathogenic variants. In addition, pre-implantation genetic diagnoses were initiated for 19 families. Eight of these families completed more than one full cycle of treatment, from which one healthy newborn was delivered. Conclusions: This study describes the spectrum of PAH variants in the Saudi population and highlights the molecular heterogeneity underlying phenylketonuria and hyperphenylalaninemia. These results add to the existing knowledge about PAH variants in Middle Eastern Countries. These results can be further translated to provide: informed counseling; cascade carrier testing in extended family members; and pre-marital screening.