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
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/142868

id CONICETDig_5188ca6f423a6bc78ef676c2bb1a5bd9
oai_identifier_str oai:ri.conicet.gov.ar:11336/142868
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling 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
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