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.

Ann and Robert H Lurie Children's Hospital of Chicago Chicago IL 60611 USA

Centre of Molecular Biology and Gene Therapy University Hospital Brno 62500 Brno Czech Republic

Centro de Diagnóstico de Enfermedades Moleculares Centro de Biología Molecular CSIC UAM Universidad Autónoma de Madrid CIBERER IdiPAz 28049 Madrid Spain

Centro Screening Neonatale Regione Marche Azienda Ospedaliera Ospedali Riuniti Marche Nord 61032 Fano Italy

Clinic of Pediatrics Division of Inherited Metabolic Disorders Medical University of Innsbruck 6020 Innsbruck Austria

Comenius University Faculty of Natural Sciences Department of Molecular Biology 84215 Bratislava 4 Slovak Republic

Department of Experimental Medicine Sapienza University of Rome 00185 Rome Italy

Department of Human Neuroscience Sapienza University of Rome 00185 Rome Italy

Department of Infectious Diseases Shanghai Children's Medical Center Shanghai Jiao Tong University School of Medicine 2000025 Shanghai China

Department of Pediatric Endocrinology Genetics Xinhua Hospital Shanghai Jiao Tong University School of Medicine Shanghai Institute for Pediatric Research 2000025 Shanghai China

Department of Pediatrics AOU Citta' della Salute e della Scienza di Torino 10126 Torino Italy

Department of Pediatrics Endocrinology Diabetology Metabolic Diseases and Cardiology Pomeranian Medical University 71 252 Szczecin Poland

Department of Screening and Metabolic Diagnostics Institute of Mother and Child 01 211 Warsaw Poland

Division of Child Neurology and Metabolic Medicine Centre for Child and Adolescent Medicine Clinic 1 University Hospital Heidelberg 69120 Heidelberg Germany

Division of Child Neurology and Metabolic Medicine Centre for Child and Adolescent Medicine Clinic 1 University Hospital Heidelberg 69120 Heidelberg Germany; Division of Metabolism University Children's Hospital 8032 Zürich Switzerland

Division of Genetics and Genomics Boston Children's Hospital Harvard Medical School Boston MA 02115 USA

Division of Inherited Metabolic Diseases Department of Woman's and Child's Health University Hospital 35129 Padua Italy

Division of Metabolism University Children's Hospital 8032 Zürich Switzerland

Fundación de Endocrinología Infantil C1425 Buenos Aires Argentina

Institute of Child Health 11526 Athens Greece

Institute of Human Genetics Medical University Innsbruck 6020 Innsbruck Austria

Institute of Molecular Genetics and Genetic Engineering University of Belgrade 11000 Belgrade Serbia

Institute of Mother and Child Healthcare Dr Vukan Čupić 11000 Belgrade Serbia

Laboratory of Inborn Errors of Metabolism Institute of Biological Sciences Federal University of Pará Belém 66075 110 Brazil

Metabolic Disease Unit Edmond and Lily Safra Children's Hospital Sheba Medical Center Tel Aviv University 52621 Tel Aviv Israel

Murdoch Children's Research Institute and Department of Pediatrics University of Melbourne Melbourne VIC 3052 Australia

Reference Center for Inherited Metabolic Diseases University Hospital of Nancy 54511 Vandoeuvre lès Nancy France

Research Centre for Medical Genetics 115522 Moscow Russia

Unidad de Enfermedades Metabolicas Servicio de Pediatria Hospital Ramon y Cajal 28034 Madrid Spain

Unidad de Metabolismo Hospital de Niños Sor Ludovica de La Plata 1904 Buenos Aires Argentina

University Children's Hospital University Medical Center Hamburg Eppendorf 20246 Hamburg Germany

University of Groningen University Medical Center Groningen Beatrix Children's Hospital Section of Metabolic Diseases 9712 CP Groningen the Netherlands

UPMC Children's Hospital of Pittsburgh Pittsburgh PA 15224 USA

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