The Genetic Landscape and Epidemiology of Phenylketonuria

HILLERT, ALICIA; ANIKSTER, YAIR; BELANGER-QUINTANA, AMAYA; BURLINA, ALBERTO; BURTON, BARBARA K.; CARDUCCI, CARLA; CHIESA, ANA E.; CHRISTODOULOU, JOHN; ?OR?EVI?, MAJA; DESVIAT, LOURDES R.; ELIYAHU, AVIVA; EVERS, ROELAND A.F.; FAJKUSOVA, LENA; FEILLET, FRANÇOIS; BONFIM-FREITAS, PEDRO E.; GI?EWSKA, 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; STOJILJKOVI?, 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

AMERICAN JOURNAL OF HUMAN GENETICS

CELL PRESS

Año: 2020 vol. 107 p. 234 - 250

0002-9297

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.