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: BH4; PAH deficiency; PKU; hyperphenylalaninemia; phenylalanine; tetrahydrobiopterin.

Figure 1

Prevalence of PKU (All Phenotypes) in 64 Countries from 6 World Regions For exact prevalence numbers see Table S1.

Figure 2

Relationship between Blood Phenylalanine, Phenotype, and Genotypic Phenotype Value (GPV) (A) Boxplot (median, 25^th–75^th percentile, 1.5) of the maximal pretreatment blood Phe concentrations for three metabolic phenotypes in 6,369 PKU subjects. The circles in the cPKU bar represent ordinary high blood Phe concentrations, since cPKU doesn’t have an upper Phe limit for its classification. (B) Contour plot of two-dimensional densities of pretreatment blood Phe concentrations and corresponding genotypic phenotype values (GPV) for 6,115 PKU subjects.

Figure 3

World Map with Relative Frequency (%) of PKU and the Corresponding Most Common Variants for Classic PKU (cPKU), Mild PKU (mPKU), and Mild Hyperphenylalaninemia (MHP) Exact frequencies and additional genotypic phenotype values (GPV) for Europe and other world regions are presented in a more granular form in Figure S4. AF, allele frequency; APV, allelic phenotype value (cPKU = 0–2.6; mPKU = 2.7–6.6; MHP = 6.7–10). The accession number for the PAH is RefSeq: ENSG00000171759; GeneBank: NM_000277.1. ^ac.611A>G reported as Ex6−96A>G splice variant.

Figure 4

Relationship between Genotypic Phenotype Value (GPV) and BH₄ Responsiveness (A) Boxplot (median, 25^th–75^th percentile, 1.5) of GPV in 2,246 BH₄ non-responder and 1,755 responder PKU subjects (for 2,114 out of 6,115 subjects GVP was not known). (B) Boxplot (median, 25^th–75^th percentile, 1.5) of GPV (APV_max) for 11,584 PKU subjects with a known genotype, but not tested for BH₄ responsiveness. Horizontal gray bar: separation area between GPVs for predicted BH₄ responsiveness (3.8–10) and non-responsiveness (0–3.3).

Figure 5

Patterns of Common PAH Variants Possibly Associated with Migration in Europe