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.

苯丙酮尿症（PKU）由苯丙氨酸羟化酶（PAH）基因的变异引起，是氨基酸代谢中最常见的常染色体隐性孟德尔表型。我们估计全球有45万人患有PKU，全球活产婴儿的比例为1：23,930（范围为：1,4,500 [意大利] –1：125,000 [日本]）。比较来自16,092名受影响受试者的基因型和代谢表型，发现来自17个世界地区的51个国家的疾病严重程度存在差异，全球表型分布为62％经典PKU，22％轻度PKU和16％轻度高苯丙氨酸血症。从东部的经典PKU到西南的轻度PKU，到南部的轻度高苯丙氨酸血症，整个欧洲存在着基因型和表型分布的梯度。c.1241A> G（p.Tyr414Cys）相关基因型可以追溯到北欧到西欧，从瑞典经挪威，到丹麦，再到荷兰。经典PKU的频率从欧洲（56％）通过中东（71％）到澳大利亚（80％）增加。的758PAH变体，c.1222C> T（p.Arg408Trp）（22.2％），c.1066-11G> A（IVS10-11G> A）（6.4％），c.782G> A（p.Arg261Gln）（5.5 ％）是最常见的基因，并负责两种流行的基因型：p。[Arg408Trp]; [Arg408Trp]（11.4％）和c。[1066-11G> A]; [1066-11G> A]（2.6％）。大多数基因型（73％）是复合杂合子，27％是纯合子，3659种不同基因型中有55％仅在一个个体中出现。多环芳烃使用等位基因表型值对变异体进行评分，并与治疗前血液苯丙氨酸浓度（n = 6,115）和四氢生物蝶呤负载测试结果（n = 4,381）相关，从而能够预测基于基因型的表型（88％）和四氢生物蝶呤的反应性（ 83％）。这项研究表明，大型基因型数据库能够进行准确的表型预测，从而能够适当地靶向治疗方法以优化临床结果。