The Genetic Landscape and Epidemiology of Phenylketonuria
- Autores
- Hillert, Alicia; Anikster, Yair; Belanger Quintana, Amaya; Burlina, Alberto; Burton, Barbara K.; Carducci, Carla; Chiesa, Ana Elena; Christodoulou, John; Dordevic, Maja; Desviat, Lourdes R.; Eliyahu, Aviva; Evers, Roeland A.F.; Fajkusova, Lena; Feillet, Francois; Bonfim Freitas, Pedro E.; Gizewska, María; Gundorova, Polina; Karall, Daniela; Kneller, Katya; Kutsev, Sergey I.; Leuzzi, Vincenzo; Levy, Harvey L.; Lichter Koneck, Uta; Muntau, Ania C.; Namour, Fares; Oltarzewsk, Mariusz; Paras, Andrea; Perez, Belén; Polak, Emil; Polyakov, Alexander V.; Porta, Francesco; Rohrbach, Marianne; Scholl Bürgi, Sabine; Spécola, Norma; Stojiljkovic, 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
- Año de publicación
- 2020
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- 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"; Argentina
Fil: 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; - Materia
-
BH4
HYPERPHENYLALANINEMIA
PAH DEFICIENCY
PHENYLALANINE
PKU
TETRAHYDROBIOPTERIN - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/142868
Ver los metadatos del registro completo
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The Genetic Landscape and Epidemiology of PhenylketonuriaHillert, AliciaAnikster, YairBelanger Quintana, AmayaBurlina, AlbertoBurton, Barbara K.Carducci, CarlaChiesa, Ana ElenaChristodoulou, JohnDordevic, MajaDesviat, Lourdes R.Eliyahu, AvivaEvers, Roeland A.F.Fajkusova, LenaFeillet, FrancoisBonfim Freitas, Pedro E.Gizewska, MaríaGundorova, PolinaKarall, DanielaKneller, KatyaKutsev, Sergey I.Leuzzi, VincenzoLevy, Harvey L.Lichter Koneck, UtaMuntau, Ania C.Namour, FaresOltarzewsk, MariuszParas, AndreaPerez, BelénPolak, EmilPolyakov, Alexander V.Porta, FrancescoRohrbach, MarianneScholl Bürgi, SabineSpécola, NormaStojiljkovic, MajaShen, NanSantana da Silva, Luiz C.Skouma, Anastasiavan Spronsen, FrancjanStoppioni, VeraThöny, BeatTrefz, Friedrich K.Vockley, JerryYu, YoungguoZschocke, JohannesHoffmann, Georg F.Garbade, Sven F.Blau, NenadBH4HYPERPHENYLALANINEMIAPAH DEFICIENCYPHENYLALANINEPKUTETRAHYDROBIOPTERINhttps://purl.org/becyt/ford/3.3https://purl.org/becyt/ford/3Phenylketonuria (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;Cell Press2020-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/142868Hillert, Alicia; Anikster, Yair; Belanger Quintana, Amaya; Burlina, Alberto; Burton, Barbara K.; et al.; The Genetic Landscape and Epidemiology of Phenylketonuria; Cell Press; American Journal Of Human Genetics; 107; 2; 8-2020; 234-2500002-9297CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.ajhg.2020.06.006info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:17:22Zoai:ri.conicet.gov.ar:11336/142868instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:17:22.655CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
The Genetic Landscape and Epidemiology of Phenylketonuria |
title |
The Genetic Landscape and Epidemiology of Phenylketonuria |
spellingShingle |
The Genetic Landscape and Epidemiology of Phenylketonuria Hillert, Alicia BH4 HYPERPHENYLALANINEMIA PAH DEFICIENCY PHENYLALANINE PKU TETRAHYDROBIOPTERIN |
title_short |
The Genetic Landscape and Epidemiology of Phenylketonuria |
title_full |
The Genetic Landscape and Epidemiology of Phenylketonuria |
title_fullStr |
The Genetic Landscape and Epidemiology of Phenylketonuria |
title_full_unstemmed |
The Genetic Landscape and Epidemiology of Phenylketonuria |
title_sort |
The Genetic Landscape and Epidemiology of Phenylketonuria |
dc.creator.none.fl_str_mv |
Hillert, Alicia Anikster, Yair Belanger Quintana, Amaya Burlina, Alberto Burton, Barbara K. Carducci, Carla Chiesa, Ana Elena Christodoulou, John Dordevic, Maja Desviat, Lourdes R. Eliyahu, Aviva Evers, Roeland A.F. Fajkusova, Lena Feillet, Francois Bonfim Freitas, Pedro E. Gizewska, María Gundorova, Polina Karall, Daniela Kneller, Katya Kutsev, Sergey I. Leuzzi, Vincenzo Levy, Harvey L. Lichter Koneck, Uta Muntau, Ania C. Namour, Fares Oltarzewsk, Mariusz Paras, Andrea Perez, Belén Polak, Emil Polyakov, Alexander V. Porta, Francesco Rohrbach, Marianne Scholl Bürgi, Sabine Spécola, Norma Stojiljkovic, 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 |
author |
Hillert, Alicia |
author_facet |
Hillert, Alicia Anikster, Yair Belanger Quintana, Amaya Burlina, Alberto Burton, Barbara K. Carducci, Carla Chiesa, Ana Elena Christodoulou, John Dordevic, Maja Desviat, Lourdes R. Eliyahu, Aviva Evers, Roeland A.F. Fajkusova, Lena Feillet, Francois Bonfim Freitas, Pedro E. Gizewska, María Gundorova, Polina Karall, Daniela Kneller, Katya Kutsev, Sergey I. Leuzzi, Vincenzo Levy, Harvey L. Lichter Koneck, Uta Muntau, Ania C. Namour, Fares Oltarzewsk, Mariusz Paras, Andrea Perez, Belén Polak, Emil Polyakov, Alexander V. Porta, Francesco Rohrbach, Marianne Scholl Bürgi, Sabine Spécola, Norma Stojiljkovic, 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 |
author_role |
author |
author2 |
Anikster, Yair Belanger Quintana, Amaya Burlina, Alberto Burton, Barbara K. Carducci, Carla Chiesa, Ana Elena Christodoulou, John Dordevic, Maja Desviat, Lourdes R. Eliyahu, Aviva Evers, Roeland A.F. Fajkusova, Lena Feillet, Francois Bonfim Freitas, Pedro E. Gizewska, María Gundorova, Polina Karall, Daniela Kneller, Katya Kutsev, Sergey I. Leuzzi, Vincenzo Levy, Harvey L. Lichter Koneck, Uta Muntau, Ania C. Namour, Fares Oltarzewsk, Mariusz Paras, Andrea Perez, Belén Polak, Emil Polyakov, Alexander V. Porta, Francesco Rohrbach, Marianne Scholl Bürgi, Sabine Spécola, Norma Stojiljkovic, 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 |
author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
dc.subject.none.fl_str_mv |
BH4 HYPERPHENYLALANINEMIA PAH DEFICIENCY PHENYLALANINE PKU TETRAHYDROBIOPTERIN |
topic |
BH4 HYPERPHENYLALANINEMIA PAH DEFICIENCY PHENYLALANINE PKU TETRAHYDROBIOPTERIN |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/3.3 https://purl.org/becyt/ford/3 |
dc.description.none.fl_txt_mv |
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"; Argentina Fil: 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; |
description |
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. |
publishDate |
2020 |
dc.date.none.fl_str_mv |
2020-08 |
dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
format |
article |
status_str |
publishedVersion |
dc.identifier.none.fl_str_mv |
http://hdl.handle.net/11336/142868 Hillert, Alicia; Anikster, Yair; Belanger Quintana, Amaya; Burlina, Alberto; Burton, Barbara K.; et al.; The Genetic Landscape and Epidemiology of Phenylketonuria; Cell Press; American Journal Of Human Genetics; 107; 2; 8-2020; 234-250 0002-9297 CONICET Digital CONICET |
url |
http://hdl.handle.net/11336/142868 |
identifier_str_mv |
Hillert, Alicia; Anikster, Yair; Belanger Quintana, Amaya; Burlina, Alberto; Burton, Barbara K.; et al.; The Genetic Landscape and Epidemiology of Phenylketonuria; Cell Press; American Journal Of Human Genetics; 107; 2; 8-2020; 234-250 0002-9297 CONICET Digital CONICET |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.ajhg.2020.06.006 |
dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
eu_rights_str_mv |
openAccess |
rights_invalid_str_mv |
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
dc.format.none.fl_str_mv |
application/pdf application/pdf |
dc.publisher.none.fl_str_mv |
Cell Press |
publisher.none.fl_str_mv |
Cell Press |
dc.source.none.fl_str_mv |
reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
reponame_str |
CONICET Digital (CONICET) |
collection |
CONICET Digital (CONICET) |
instname_str |
Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.name.fl_str_mv |
CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.mail.fl_str_mv |
dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
_version_ |
1844614126336212992 |
score |
13.070432 |