Genotype-Phenotype Correlations in Phenylketonuria and Hyperphenylalaninemia: A Single-Center Study

Phenylketonuria (PKU) is an inherited metabolic disease associated with pathogenic variants in the phenylalanine hydroxylase (PAH) gene. We aimed to investigate the effect of allelic variants in the PAH gene on the chemical phenotype in patients with PKU and hyperphenylalaninemia (HPA) in our center.

We reviewed the medical files of patients diagnosed with PKU and HPA between 2013 and 2022 who had PAH gene analysis. Based on their Phe concentrations at the time of diagnosis, the metabolic phenotypes were classified as follows: classic PKU (cPKU; Phe = 1200 μmol/L), mild PKU (mPKU; Phe = 600-1200 μmol/L), and HPA (Phe = 120-600 μmol/L). We used the allelic phenotype values in the BIOPKUdb to examine the effect of the genotypic findings on the phenotype (0 = cPKU; 5 = mPKU; 10 = HPA). According to their genotypic phenotype values (GPVs), patients were further divided into cPKU, mPKU, and HPA groups. Patients with known BH4 responsiveness were analyzed within groups.

We identified 59 types of variants. A fair but statistically significant compatibility was observed between phenotype classification and the GPV classification (kappa statistic = 0.38, p < 0.001, accuracy rate = 0.594). BH4 unresponsiveness was higher in cPKU groups.

Our findings demonstrate that genotype-phenotype correlation in PKU and HPA is complex and influenced by both genetic variability and metabolic response. The significant association between BH4 responsiveness and genotype highlights the value of molecular testing in guiding individualized treatment. Identification of novel PAH variants further broadens the genetic spectrum and supports the need for continuous genetic characterization in clinical practice.