The Genetic Landscape and Epidemiology of PhenylketonuriaHillert, 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 journal › Article › Academic › peer-review
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.
|Number of pages||17|
|Journal||American Journal of Human Genetics|
|Publication status||Published - 6-Aug-2020|
- PHENYLALANINE-HYDROXYLASE DEFICIENCY, GENOTYPE-PHENOTYPE CORRELATIONS, MOLECULAR CHARACTERIZATION, PAH GENE, MUTATIONS, HYPERPHENYLALANINEMIA, DIAGNOSIS, PATIENT, ORIGINS, STATE