The Genetic Landscape and Epidemiology of Phenylketonuria

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.Fil: Hillert, Alicia. No especifíca;Fil: Anikster, Yair. No especifíca;Fil: Belanger Quintana, Amaya. No especifíca;Fil: Burlina, Alberto. No especifíca;Fil: Burton, Barbara K.. No especifíca;Fil: Carducci, Carla. No especifíca;Fil: Chiesa, Ana Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; ArgentinaFil: Christodoulou, John. No especifíca;Fil: Dordevic, Maja. No especifíca;Fil: Desviat, Lourdes R.. No especifíca;Fil: Eliyahu, Aviva. No especifíca;Fil: Evers, Roeland A.F.. No especifíca;Fil: Fajkusova, Lena. No especifíca;Fil: Feillet, Francois. No especifíca;Fil: Bonfim Freitas, Pedro E.. No especifíca;Fil: Gizewska, María. No especifíca;Fil: Gundorova, Polina. No especifíca;Fil: Karall, Daniela. No especifíca;Fil: Kneller, Katya. No especifíca;Fil: Kutsev, Sergey I.. No especifíca;Fil: Leuzzi, Vincenzo. No especifíca;Fil: Levy, Harvey L.. No especifíca;Fil: Lichter Koneck, Uta. No especifíca;Fil: Muntau, Ania C.. No especifíca;Fil: Namour, Fares. No especifíca;Fil: Oltarzewsk, Mariusz. No especifíca;Fil: Paras, Andrea. No especifíca;Fil: Perez, Belén. No especifíca;Fil: Polak, Emil. No especifíca;Fil: Polyakov, Alexander V.. No especifíca;Fil: Porta, Francesco. No especifíca;Fil: Rohrbach, Marianne. No especifíca;Fil: Scholl Bürgi, Sabine. No especifíca;Fil: Spécola, Norma. No especifíca;Fil: Stojiljkovic, Maja. No especifíca;Fil: Shen, Nan. No especifíca;Fil: Santana da Silva, Luiz C.. No especifíca;Fil: Skouma, Anastasia. No especifíca;Fil: van Spronsen, Francjan. No especifíca;Fil: Stoppioni, Vera. No especifíca;Fil: Thöny, Beat. No especifíca;Fil: Trefz, Friedrich K.. No especifíca;Fil: Vockley, Jerry. No especifíca;Fil: Yu, Youngguo. No especifíca;Fil: Zschocke, Johannes. No especifíca;Fil: Hoffmann, Georg F.. No especifíca;Fil: Garbade, Sven F.. No especifíca;Fil: Blau, Nenad. No especifíca