The Genetic Landscape and Epidemiology of Phenylketonuria

Hillert, A., Anikster, Y., Belanger-Quintana, A., Burlina, A., Burton, B. K., Carducci, C., Chiesa, A. E., Christodoulou, J., Dordevic, M., Desviat, L. R., Eliyahu, A., Evers, R. A. F., Fajkusova, L., Feillet, F., Bonfim-Freitas, P. E., Gizewska, M., Gundorova, P., Karall, D., Kneller, K., Kutsev, S., Leuzzi, V., Levy, H. L., Lichter-Konecki, U., Muntau, A. C., Namour, F., Oltarzewski, M., Paras, A., Perez, B., Polak, E., Polyakov, A., Porta, F., Rohrbach, M., Scholl-Burgi, S., Specola, N., Stojiljkovic, M., Shen, N., Santana-da Silva, L. C., Skouma, A., van Spronsen, F., Stoppioni, V., Thony, B., Trefz, F. K., Vockley, J., Yu, Y., Zschocke, J., Hoffmann, G. F., Garbade, S. F. & Blau, N., 6-Aug-2020, In : American Journal of Human Genetics. 107, 2, p. 234-250 17 p.

Research output: Contribution to journalArticleAcademicpeer-review

Copy link to clipboard


  • The Genetic Landscape and Epidemiology of Phenylketonuria

    Final publisher's version, 2.03 MB, PDF document

    Request copy


  • Alicia Hillert
  • Yair Anikster
  • Amaya Belanger-Quintana
  • Alberto Burlina
  • Barbara K. Burton
  • Carla Carducci
  • Ana E. Chiesa
  • John Christodoulou
  • Maja Dordevic
  • Lourdes R. Desviat
  • Aviva Eliyahu
  • Roeland A. F. Evers
  • Lena Fajkusova
  • Francois Feillet
  • Pedro E. Bonfim-Freitas
  • Maria Gizewska
  • Polina Gundorova
  • Daniela Karall
  • Katya Kneller
  • Sergey Kutsev
  • Vincenzo Leuzzi
  • Harvey L. Levy
  • Uta Lichter-Konecki
  • Ania C. Muntau
  • Fares Namour
  • Mariusz Oltarzewski
  • Andrea Paras
  • Belen Perez
  • Emil Polak
  • Alexander Polyakov
  • Francesco Porta
  • Marianne Rohrbach
  • Sabine Scholl-Burgi
  • Norma Specola
  • Maja Stojiljkovic
  • Nan Shen
  • Luiz C. Santana-da Silva
  • Anastasia Skouma
  • Francjan van Spronsen
  • Vera Stoppioni
  • Beat Thony
  • Friedrich K. Trefz
  • Jerry Vockley
  • Youngguo Yu
  • Johannes Zschocke
  • Georg F. Hoffmann
  • Sven F. Garbade
  • Nenad Blau

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.

Original languageEnglish
Pages (from-to)234-250
Number of pages17
JournalAmerican Journal of Human Genetics
Issue number2
Publication statusPublished - 6-Aug-2020



ID: 133222451