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.