A Novel Variant in the PAH Gene Causing Phenylketonuria in an Iranian Pedigree

Background: Phenylalanine hydroxylase (PAH) gene is the well-known causative gene for classic Phenylketonuria (PKU) (OMIM#261600) disease, with more than 500 reported mutations. Through this study, a novel mutation in the PAH gene in an Iranian pedigree with phenylketonuria was introduced. Methods: A consanguineous family with a 10-year old affected girl was referred for genetic analysis. Mutation screening of all exons and exon-intron boundaries was performed by Sanger sequencing, and mini haplotype analysis was carried out by genotyping of Short Tandem Repeat (STR) and Variable Number Tandem Repeat (VNTR) alleles. Results: Mutation analysis revealed a novel homozygous insertion of a single adenine nucleotide at position 335 in exon 3 of the PAH gene. Based on the American College of Medical Genetics and Genomics (ACMG) guidelines, the change is interpreted as a pathogenic mutation which produces a premature termination signal (TAA) at codon 113 according to in silico assessments. The mini haplotype analysis showed that this mutation was linked to STR (15) –VNTR (3). Conclusion: In this study, a novel mutation was reported in a patient who had PKU symptoms without any previously reported mutations in the PAH gene (NM_000277.1 :p.Asp112Glufs*2) that can be responsible for the classical PKU phenotype in the Iranian population. Detection of novel mutations indicates notable allelic heterogeneity of the PAH locus among this population.