Assesment of pathogenic variants in the PAH gene and genotype-phenotype correlation in Phenylketonuria patients from Turkey.

Abstract This study aims to determine the allele and genotype frequency, evaluate genotype-phenotype correlation, and contribute to the spectrum of pathogenic variants in the PAH gene. Ninety-three individuals diagnosed with PKU were included in the study. Next-generation sequencing was utilized for detecting variants in the PAH gene. Copy Number Variations in patients without biallelic pathogenic variant were investigated by Multiplex Ligation-dependent Probe Amplification method. Genotype-phenotype correlations and genotype-based phenotype predictions were examined by comparing molecular test results with BIOPKUdb database. The clinical distributions of the patients were as follows: classic PKU 21% (n=19), mild PKU 3% (n=3) and mild hyperphenylalaninemia 76% (n=71), respectively. Thirty-nine distinct variants and 70 distinct genotypes were found in patients. The most frequently observed variant was p.Ala300Ser (15%) and the most frequently observed genotype was p.Ala300Ser)/p.Ala300Ser (5,4%). Compound heterozygous genotypes (%69) were more prevalent than homozygous genotypes. Two novel variants, c.1089G>C and c.441+4A>C, were observed. Predicted metabolic phenotypes in the database showed consistency with patient phenotypes (n=33/41). BH4 responsiveness showed partial consistency with database predictions (n=13/25). Establishing genotype-phenotype correlations can facilitate personalized management approaches. Overall, this study contributes to understanding the genetic basis and clinical course of PKU.