Spectrum of PAH gene variants in Jordanian patients with phenylalanine hydroxylase deficiency

Phenylketonuria (PKU) is an autosomal recessive metabolic disorder caused by pathogenic variants in the phenylalanine hydroxylase (PAH) gene. PKU is considered as one of the most common autosomal recessive diseases in Jordan; however, the spectrum of gene variants is yet to be determined. The present study aimed to identify the PAH genetic variants in a cohort of Jordanian children diagnosed with PKU. A total of 77 affected patients from 50 families were enrolled in the present study. All exons as well as exon-intron boundaries of the PAH gene were analyzed by Sanger sequencing. Segregation analysis was performed on the available family members. A total of 23 distinct PAH variants were identified with a detection rate of 100%. All variants were either pathogenic or likely pathogenic. These variants included 9 missense (39.1%), 6 splice site (26.1%), 4 frameshift (17.4%), 2 nonsense (8.7%) and 2 in-frame deletion (8.7%) variants. Among these variants, one was novel [c.781del; p.(Arg261Glufs80)]. The present study highlighted the wide spectrum of disease-causing variants in the PAH gene among Jordanian patients. The findings also underscore the importance of establishing region-specific genetic screening. Early genetic diagnosis of PKU will facilitate timely treatment and management of affected patients, risk stratification and genetic counseling, thereby reducing the burden of PKU in Jordan.