The Genetic Landscape and Epidemiology of Phenylketonuria

• Published in: American journal of human genetics Vol. 107; no. 2; pp. 234 - 250
• Main Authors: Hillert, Alicia, Anikster, Yair, Belanger-Quintana, Amaya, Burlina, Alberto, Burton, Barbara K., Carducci, Carla, Chiesa, Ana E., Christodoulou, John, Đorđević, Maja, Desviat, Lourdes R., Eliyahu, Aviva, Evers, Roeland A.F., Fajkusova, Lena, Feillet, François, Bonfim-Freitas, Pedro E., Giżewska, Maria, Gundorova, Polina, Karall, Daniela, Kneller, Katya, Kutsev, Sergey I., Leuzzi, Vincenzo, Levy, Harvey L., Lichter-Konecki, Uta, Muntau, Ania C., Namour, Fares, Oltarzewski, Mariusz, Paras, Andrea, Perez, Belen, Polak, Emil, Polyakov, Alexander V., Porta, Francesco, Rohrbach, Marianne, Scholl-Bürgi, Sabine, Spécola, Norma, Stojiljković, Maja, Shen, Nan, Santana-da Silva, Luiz C., Skouma, Anastasia, van Spronsen, Francjan, Stoppioni, Vera, Thöny, Beat, Trefz, Friedrich K., Vockley, Jerry, Yu, Youngguo, Zschocke, Johannes, Hoffmann, Georg F., Garbade, Sven F., Blau, Nenad
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.08.2020; Elsevier BV; Elsevier
• Subjects: Alleles; BH4; BH4, PAH deficiency, PKU, hyperphenylalaninemia, phenylalanine, tetrahydrobiopterin; Biopterins; Biopterins - analogs & derivatives; Biopterins - genetics; DIAGNOSIS; Europe; Gene Frequency; Gene Frequency - genetics; Genetic Association Studies; Genetic Association Studies - methods; Genetic Predisposition to Disease; Genetic Predisposition to Disease - genetics; Genotype; GENOTYPE-PHENOTYPE CORRELATIONS; Homozygote; https://purl.org/becyt/ford/3; https://purl.org/becyt/ford/3.3; Humans; HYPERPHENYLALANINEMIA; MOLECULAR CHARACTERIZATION; Mutation; Mutation - genetics; MUTATIONS; ORIGINS; PAH DEFICIENCY; PAH GENE; PATIENT; Phenotype; Phenylalanine; Phenylalanine - blood; Phenylalanine Hydroxylase; Phenylalanine Hydroxylase - genetics; PHENYLALANINE-HYDROXYLASE DEFICIENCY; Phenylketonurias; Phenylketonurias - blood; Phenylketonurias - epidemiology; Phenylketonurias - genetics; PKU; STATE; TETRAHYDROBIOPTERIN; Europe; tetrahydrobiopterin; PKU; phenylalanine; hyperphenylalaninemia; PAH deficiency; BH4
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2020.06.006

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.