The Genetic Landscape and Epidemiology of Phenylketonuria

Am J Hum Genet. 2020 Aug 6;107(2):234-250. doi: 10.1016/j.ajhg.2020.06.006. Epub 2020 Jul 14.


Phenylketonuria (PKU), caused by variants in the phenylalanine hydroxylase (PAH) gene, is the most common autosomal-recessive Mendelian phenotype of amino acid metabolism. We estimated that globally 0.45 million individuals have PKU, with global prevalence 1:23,930 live births (range 1:4,500 [Italy]-1:125,000 [Japan]). Comparing genotypes and metabolic phenotypes from 16,092 affected subjects revealed differences in disease severity in 51 countries from 17 world regions, with the global phenotype distribution of 62% classic PKU, 22% mild PKU, and 16% mild hyperphenylalaninemia. A gradient in genotype and phenotype distribution exists across Europe, from classic PKU in the east to mild PKU in the southwest and mild hyperphenylalaninemia in the south. The c.1241A>G (p.Tyr414Cys)-associated genotype can be traced from Northern to Western Europe, from Sweden via Norway, to Denmark, to the Netherlands. The frequency of classic PKU increases from Europe (56%) via Middle East (71%) to Australia (80%). Of 758 PAH variants, c.1222C>T (p.Arg408Trp) (22.2%), c.1066-11G>A (IVS10-11G>A) (6.4%), and c.782G>A (p.Arg261Gln) (5.5%) were most common and responsible for two prevalent genotypes: p.[Arg408Trp];[Arg408Trp] (11.4%) and c.[1066-11G>A];[1066-11G>A] (2.6%). Most genotypes (73%) were compound heterozygous, 27% were homozygous, and 55% of 3,659 different genotypes occurred in only a single individual. PAH variants were scored using an allelic phenotype value and correlated with pre-treatment blood phenylalanine concentrations (n = 6,115) and tetrahydrobiopterin loading test results (n = 4,381), enabling prediction of both a genotype-based phenotype (88%) and tetrahydrobiopterin responsiveness (83%). This study shows that large genotype databases enable accurate phenotype prediction, allowing appropriate targeting of therapies to optimize clinical outcome.

Keywords: BH4; PAH deficiency; PKU; hyperphenylalaninemia; phenylalanine; tetrahydrobiopterin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Biopterin / analogs & derivatives
  • Biopterin / genetics
  • Europe
  • Gene Frequency / genetics
  • Genetic Association Studies / methods
  • Genetic Predisposition to Disease / genetics*
  • Genotype
  • Homozygote
  • Humans
  • Mutation / genetics
  • Phenotype
  • Phenylalanine / blood
  • Phenylalanine Hydroxylase / genetics
  • Phenylketonurias / blood
  • Phenylketonurias / epidemiology*
  • Phenylketonurias / genetics*


  • Biopterin
  • Phenylalanine
  • Phenylalanine Hydroxylase
  • sapropterin