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The Genetic Landscape and Epidemiology of Phenylketonuria.


ABSTRACT: 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.

SUBMITTER: Hillert A 

PROVIDER: S-EPMC7413859 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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The Genetic Landscape and Epidemiology of Phenylketonuria.

Hillert Alicia A   Anikster Yair Y   Belanger-Quintana Amaya A   Burlina Alberto A   Burton Barbara K BK   Carducci Carla C   Chiesa Ana E AE   Christodoulou John J   Đorđević Maja M   Desviat Lourdes R LR   Eliyahu Aviva A   Evers Roeland A F RAF   Fajkusova Lena L   Feillet François F   Bonfim-Freitas Pedro E PE   Giżewska Maria M   Gundorova Polina P   Karall Daniela D   Kneller Katya K   Kutsev Sergey I SI   Leuzzi Vincenzo V   Levy Harvey L HL   Lichter-Konecki Uta U   Muntau Ania C AC   Namour Fares F   Oltarzewski Mariusz M   Paras Andrea A   Perez Belen B   Polak Emil E   Polyakov Alexander V AV   Porta Francesco F   Rohrbach Marianne M   Scholl-Bürgi Sabine S   Spécola Norma N   Stojiljković Maja M   Shen Nan N   Santana-da Silva Luiz C LC   Skouma Anastasia A   van Spronsen Francjan F   Stoppioni Vera V   Thöny Beat B   Trefz Friedrich K FK   Vockley Jerry J   Yu Youngguo Y   Zschocke Johannes J   Hoffmann Georg F GF   Garbade Sven F SF   Blau Nenad N  

American journal of human genetics 20200714 2


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 phenotyp  ...[more]

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