Allelic phenotype values: a model for genotype-based phenotype prediction in phenylketonuria

Genet Med. 2019 Mar;21(3):580-590. doi: 10.1038/s41436-018-0081-x. Epub 2018 Jul 12.


Purpose: The nature of phenylalanine hydroxylase (PAH) variants determines residual enzyme activity, which modifies the clinical phenotype in phenylketonuria (PKU). We exploited the statistical power of a large genotype database to determine the relationship between genotype and phenotype in PKU.

Methods: A total of 9336 PKU patients with 2589 different genotypes, carrying 588 variants, were investigated using an allelic phenotype value (APV) algorithm.

Results: We identified 251 0-variants encoding inactive PAH, and assigned APVs (0 = classic PKU; 5 = mild PKU; 10 = mild hyperphenylalaninaemia) to 88 variants in PAH-functional hemizygous patients. The genotypic phenotype values (GPVs) were set equal to the higher-APV allele, which was assumed to be dominant over the lower-APV allele and to determine the metabolic phenotype. GPVs for 8872 patients resulted in cut-off ranges of 0.0-2.7 for classic PKU, 2.8-6.6 for mild PKU and 6.7-10.0 for mild hyperphenylalaninaemia. Genotype-based phenotype prediction was 99.2% for classic PKU, 46.2% for mild PKU and 89.5% for mild hyperphenylalaninaemia. The relationships between known pretreatment blood phenylalanine levels and GPVs (n = 4217), as well as tetrahydrobiopterin responsiveness and GPVs (n = 3488), were significant (both P < 0.001).

Conclusions: APV and GPV are powerful tools to investigate genotype-phenotype associations, and can be used for genetic counselling of PKU families.

Keywords: Genotype–phenotype prediction; Locus-specific database; PKU; Tetrahydrobiopterin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Female
  • Gene Frequency / genetics
  • Genetic Association Studies / methods*
  • Genotype
  • Humans
  • Male
  • Mutation
  • Phenotype
  • Phenylalanine Hydroxylase / genetics*
  • Phenylalanine Hydroxylase / physiology
  • Phenylketonurias / diagnosis
  • Phenylketonurias / genetics*


  • Phenylalanine Hydroxylase