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A Novel Variant in the PAH Gene Causing Phenylketonuria in an Iranian Pedigree
Elaheh Alavinejad1, Seyede Zahra Sajedi2,3, Masoumeh Razipour1
1Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Insights
A novel mutation in the Phenylalanine hydroxylase (PAH) gene was identified in an Iranian family with phenylketonuria (PKU). This discovery highlights the genetic diversity of PKU in this population.
Area of Science:
- Genetics
- Molecular Biology
- Human Disease
Background:
- The Phenylalanine hydroxylase (PAH) gene is associated with classic Phenylketonuria (PKU).
- Over 500 mutations in the PAH gene have been documented.
- This study focuses on a novel mutation within the Iranian population.
Purpose of the Study:
- To identify the genetic cause of phenylketonuria in an Iranian family.
- To characterize a novel mutation in the PAH gene.
Main Methods:
- Genetic analysis of a consanguineous family with an affected child.
- Sanger sequencing for mutation screening of PAH gene exons and boundaries.
- Mini haplotype analysis using Short Tandem Repeat (STR) and Variable Number Tandem Repeat (VNTR) alleles.
Main Results:
- A novel homozygous single adenine nucleotide insertion at PAH gene position 335 in exon 3 was discovered.
- This pathogenic mutation creates a premature termination signal at codon 113.
- The mutation was linked to STR (15) -VNTR (3) alleles.
Conclusions:
- A novel PAH gene mutation (NM_000277.1:p.Asp112Glufs*2) was identified in an Iranian PKU patient.
- This finding contributes to understanding the allelic heterogeneity of the PAH locus in the Iranian population.
- The novel mutation is responsible for the classical PKU phenotype in the studied family.
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.
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