Research ExplorerPublicationsThe Genetic Landscape and Epidemiology of Phenylketonuria

The Genetic Landscape and Epidemiology of Phenylketonuria

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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; 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.

In: AM J HUM GENET, Vol. 107, No. 2, 06.08.2020, p. 234-250.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Hillert, A, Anikster, Y, Belanger-Quintana, A, Burlina, A, Burton, BK, Carducci, C, Chiesa, AE, Christodoulou, J, Đorđević, M, Desviat, LR, Eliyahu, A, Evers, RAF, Fajkusova, L, Feillet, F, Bonfim-Freitas, PE, Giżewska, M, Gundorova, P, Karall, D, Kneller, K, Kutsev, SI, Leuzzi, V, Levy, HL, Lichter-Konecki, U, Muntau, AC, Namour, F, Oltarzewski, M, Paras, A, Perez, B, Polak, E, Polyakov, AV, Porta, F, Rohrbach, M, Scholl-Bürgi, S, Spécola, N, Stojiljković, M, Shen, N, Santana-da Silva, LC, Skouma, A, van Spronsen, F, Stoppioni, V, Thöny, B, Trefz, FK, Vockley, J, Yu, Y, Zschocke, J, Hoffmann, GF, Garbade, SF & Blau, N 2020, 'The Genetic Landscape and Epidemiology of Phenylketonuria', AM J HUM GENET, vol. 107, no. 2, pp. 234-250. https://doi.org/10.1016/j.ajhg.2020.06.006

APA

Hillert, A., Anikster, Y., Belanger-Quintana, A., Burlina, A., Burton, B. K., Carducci, C., Chiesa, A. E., Christodoulou, J., Đorđević, M., Desviat, L. R., Eliyahu, A., Evers, R. A. F., Fajkusova, L., Feillet, F., Bonfim-Freitas, P. E., Giżewska, M., Gundorova, P., Karall, D., Kneller, K., ... Blau, N. (2020). The Genetic Landscape and Epidemiology of Phenylketonuria. AM J HUM GENET, 107(2), 234-250. https://doi.org/10.1016/j.ajhg.2020.06.006

Vancouver

Hillert A, Anikster Y, Belanger-Quintana A, Burlina A, Burton BK, Carducci C et al. The Genetic Landscape and Epidemiology of Phenylketonuria. AM J HUM GENET. 2020 Aug 6;107(2):234-250. https://doi.org/10.1016/j.ajhg.2020.06.006

Bibtex

@article{53d222ff7beb4573ab08701d52f5f030,
title = "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.",
keywords = "Alleles, Biopterin/analogs & derivatives, Europe, Gene Frequency/genetics, Genetic Association Studies/methods, Genetic Predisposition to Disease/genetics, Genotype, Homozygote, Humans, Mutation/genetics, Phenotype, Phenylalanine/blood, Phenylalanine Hydroxylase/genetics, Phenylketonurias/blood",
author = "Alicia Hillert and Yair Anikster and Amaya Belanger-Quintana and Alberto Burlina and Burton, {Barbara K} and Carla Carducci and Chiesa, {Ana E} and John Christodoulou and Maja {\D}or{\d}evi{\'c} and Desviat, {Lourdes R} and Aviva Eliyahu and Evers, {Roeland A F} and Lena Fajkusova and Fran{\c c}ois Feillet and Bonfim-Freitas, {Pedro E} and Maria Gi{\.z}ewska and Polina Gundorova and Daniela Karall and Katya Kneller and Kutsev, {Sergey I} and Vincenzo Leuzzi and Levy, {Harvey L} and Uta Lichter-Konecki and Muntau, {Ania C} and Fares Namour and Mariusz Oltarzewski and Andrea Paras and Belen Perez and Emil Polak and Polyakov, {Alexander V} and Francesco Porta and Marianne Rohrbach and Sabine Scholl-B{\"u}rgi and Norma Sp{\'e}cola and Maja Stojiljkovi{\'c} and Nan Shen and {Santana-da Silva}, {Luiz C} and Anastasia Skouma and {van Spronsen}, Francjan and Vera Stoppioni and Beat Th{\"o}ny and Trefz, {Friedrich K} and Jerry Vockley and Youngguo Yu and Johannes Zschocke and Hoffmann, {Georg F} and Garbade, {Sven F} and Nenad Blau",
note = "Copyright {\textcopyright} 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.",
year = "2020",
month = aug,
day = "6",
doi = "10.1016/j.ajhg.2020.06.006",
language = "English",
volume = "107",
pages = "234--250",
journal = "AM J HUM GENET",
issn = "0002-9297",
publisher = "Cell Press",
number = "2",

}

RIS

TY - JOUR

T1 - The Genetic Landscape and Epidemiology of Phenylketonuria

AU - Hillert, Alicia

AU - Anikster, Yair

AU - Belanger-Quintana, Amaya

AU - Burlina, Alberto

AU - Burton, Barbara K

AU - Carducci, Carla

AU - Chiesa, Ana E

AU - Christodoulou, John

AU - Đorđević, Maja

AU - Desviat, Lourdes R

AU - Eliyahu, Aviva

AU - Evers, Roeland A F

AU - Fajkusova, Lena

AU - Feillet, François

AU - Bonfim-Freitas, Pedro E

AU - Giżewska, Maria

AU - Gundorova, Polina

AU - Karall, Daniela

AU - Kneller, Katya

AU - Kutsev, Sergey I

AU - Leuzzi, Vincenzo

AU - Levy, Harvey L

AU - Lichter-Konecki, Uta

AU - Muntau, Ania C

AU - Namour, Fares

AU - Oltarzewski, Mariusz

AU - Paras, Andrea

AU - Perez, Belen

AU - Polak, Emil

AU - Polyakov, Alexander V

AU - Porta, Francesco

AU - Rohrbach, Marianne

AU - Scholl-Bürgi, Sabine

AU - Spécola, Norma

AU - Stojiljković, Maja

AU - Shen, Nan

AU - Santana-da Silva, Luiz C

AU - Skouma, Anastasia

AU - van Spronsen, Francjan

AU - Stoppioni, Vera

AU - Thöny, Beat

AU - Trefz, Friedrich K

AU - Vockley, Jerry

AU - Yu, Youngguo

AU - Zschocke, Johannes

AU - Hoffmann, Georg F

AU - Garbade, Sven F

AU - Blau, Nenad

N1 - Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

PY - 2020/8/6

Y1 - 2020/8/6

N2 - 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.

AB - 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.

KW - Alleles

KW - Biopterin/analogs & derivatives

KW - Europe

KW - Gene Frequency/genetics

KW - Genetic Association Studies/methods

KW - Genetic Predisposition to Disease/genetics

KW - Genotype

KW - Homozygote

KW - Humans

KW - Mutation/genetics

KW - Phenotype

KW - Phenylalanine/blood

KW - Phenylalanine Hydroxylase/genetics

KW - Phenylketonurias/blood

U2 - 10.1016/j.ajhg.2020.06.006

DO - 10.1016/j.ajhg.2020.06.006

M3 - SCORING: Journal article

C2 - 32668217

VL - 107

SP - 234

EP - 250

JO - AM J HUM GENET

JF - AM J HUM GENET

SN - 0002-9297

IS - 2

ER -