Spectrum of PAH gene mutations and genotype-phenotype correlation in patients with phenylalanine hydroxylase deficiency from Turkey

J Pediatr Endocrinol Metab. 2022 Mar 30;35(5):639-647. doi: 10.1515/jpem-2022-0047. Print 2022 May 25.


Objectives: The aim of our study was to define the genotype-phenotype correlations of mutations in the PAH gene among the Turkey's Central Anatolian region.

Methods: Demographic characteristics of 108 patients with hyperphenylalaninemia (HPA) and 94 patients whose diagnosis was confirmed by PAH gene analysis (Sanger DNA Sequence Analysis and Next-Generation Sequencing) were determined retrospectively. Blood phenylalanine levels were analyzed using the high-performance liquid chromatography method.

Results: Mild HPA-not-requiring-treatment (NT) was found in 50.9% of the patients, and a classical phenylketonuria (PKU) phenotype was found in 25.9%. Forty-seven types of variants were identified. The predominant variants were p.Ala403Val (9.9%), p.Ala300Ser (9.4%), and c.1066-11G>A (splicing) (9.4%). Missense mutations accounted for 68% of mutations and attenuated the clinical impact; splice variations were found in 14.8% of cases with severe features. The p.Thr380Met allele was specific to the mild HPA-NT group. The c.1066-11G>A (splicing) allele was associated with classical PKU, whereas the p.Arg408Trp allele was linked to severe symptoms. Three variations of unknown clinical significance were discovered: c.706+4A>T (splicing), c.843-5T>C (splicing), and p.Thr323=. Of these variants, the patient who was homozygous for the c.843-5T>C (splicing) allele related to the classical PKU phenotype. 70% of the patients who underwent tetrahydrobiopterin (BH4) test were responsive. Phenotypes that responded to BH4 treatment were mostly mild phenotypes.

Conclusions: The PAH genotype is the main factor that determines the phenotype of PKU. Establishing the relationship between the identified genetic mutations and phenotypic characteristics will provide very important data for each patient in terms of the specific management style.

Keywords: genotype–phenotype correlation; hyperphenylalaninemia; phenylketonuria.

MeSH terms

  • Biopterin / therapeutic use
  • Genetic Association Studies
  • Genotype
  • Humans
  • Mutation
  • Organic Anion Transport Protein 1 / metabolism*
  • Phenotype
  • Phenylalanine Hydroxylase* / genetics
  • Phenylketonurias* / diagnosis
  • Retrospective Studies
  • Turkey / epidemiology


  • Organic Anion Transport Protein 1
  • Biopterin
  • Phenylalanine Hydroxylase