ABSTRACT
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