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Updated: Jun 16, 2026
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Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
Genotype-Phenotype Correlations in Phenylketonuria and Hyperphenylalaninemia: A Single-Center Study
Hatice Güneş1,2, Fatih Kardaş1, Murat Erdoğan3
1Division of Metabolism, Department of Pediatrics, Faculty of Medicine, Erciyes University, Kayseri, Türkiye.
Summary
Phenylketonuria (PKU) genotype-phenotype correlation is complex, influenced by genetic variability and metabolic response. Molecular testing and genetic characterization are crucial for guiding individualized PKU treatment.
Area of Science:
- Genetics
- Metabolic Disorders
- Biochemistry
Background:
- Phenylketonuria (PKU) is an inherited metabolic disorder caused by pathogenic variants in the phenylalanine hydroxylase (PAH) gene.
- Investigating the impact of PAH gene allelic variants on the chemical phenotype in PKU and hyperphenylalaninemia (HPA) patients is essential.
Purpose of the Study:
- To analyze the correlation between PAH gene variants and metabolic phenotypes in PKU and HPA patients.
- To assess the influence of genotypic phenotype values (GPVs) on metabolic classification.
- To evaluate the role of BH4 responsiveness in different PKU/HPA groups.
Main Methods:
- Retrospective review of medical files for PKU/HPA patients (2013-2022) with PAH gene analysis.
- Classification of metabolic phenotypes based on phenylalanine (Phe) concentrations: classic PKU (cPKU), mild PKU (mPKU), and HPA.
- Utilized BIOPKUdb for allelic phenotype values and genotypic phenotype values (GPVs) to assess genotype-phenotype correlation, including BH4 responsiveness analysis.
Main Results:
- Identified 59 distinct PAH gene variants.
- A statistically significant, fair compatibility (kappa=0.38, p<0.001) was found between phenotypic and GPV classifications, with an accuracy rate of 59.4%.
- BH4 unresponsiveness was more prevalent in the classic PKU (cPKU) groups.
Conclusions:
- Genotype-phenotype correlation in PKU/HPA is intricate, affected by genetic diversity and patient metabolic response.
- The significant association between BH4 responsiveness and genotype underscores the importance of molecular testing for personalized PKU treatment strategies.
- The discovery of novel PAH variants expands the known genetic spectrum, emphasizing the need for ongoing genetic characterization in clinical practice.
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