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. 2020 Aug 6;107(2):234-250.
doi: 10.1016/j.ajhg.2020.06.006. Epub 2020 Jul 14.

The Genetic Landscape and Epidemiology of Phenylketonuria

Alicia Hillert  1 , Yair Anikster  2 , Amaya Belanger-Quintana  3 , Alberto Burlina  4 , Barbara K Burton  5 , Carla Carducci  6 , Ana E Chiesa  7 , John Christodoulou  8 , Maja Đorđević  9 , Lourdes R Desviat  10 , Aviva Eliyahu  2 , Roeland A F Evers  11 , Lena Fajkusova  12 , François Feillet  13 , Pedro E Bonfim-Freitas  14 , Maria Giżewska  15 , Polina Gundorova  16 , Daniela Karall  17 , Katya Kneller  2 , Sergey I Kutsev  16 , Vincenzo Leuzzi  18 , Harvey L Levy  19 , Uta Lichter-Konecki  20 , Ania C Muntau  21 , Fares Namour  13 , Mariusz Oltarzewski  22 , Andrea Paras  5 , Belen Perez  10 , Emil Polak  23 , Alexander V Polyakov  16 , Francesco Porta  24 , Marianne Rohrbach  25 , Sabine Scholl-Bürgi  17 , Norma Spécola  26 , Maja Stojiljković  27 , Nan Shen  28 , Luiz C Santana-da Silva  14 , Anastasia Skouma  29 , Francjan van Spronsen  11 , Vera Stoppioni  30 , Beat Thöny  25 , Friedrich K Trefz  1 , Jerry Vockley  20 , Youngguo Yu  31 , Johannes Zschocke  32 , Georg F Hoffmann  1 , Sven F Garbade  33 , Nenad Blau  34
Affiliations

The Genetic Landscape and Epidemiology of Phenylketonuria

Alicia Hillert et al. Am J Hum Genet. .

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.

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Conflict of interest statement

N.B. has received honoraria and/or consulting fees from BioMarin Pharmaceuticals, Censa, Nestle Pharmaceuticals, and Homology Medicines. A.B. has received advisory board honoraria, speaker fees, and travel support from Biomarin Pharmaceuticals, Nutricia, Cambrooke, PIAM, APR, Sanofi Genzyme, and Takeda. B.K.B. has received honoraria and/or consulting fees from BioMarin, Shire (a Takeda company), Sanofi Genzyme, Ultragenyx, Alexion, Horizon, Denali, JCR Pharma, Regenxbio, Inventiva, Chiesi, Homology Medicines, Aeglea, Agios, and Moderna. G.F.H. received lecture fees from Takeda. J.V. received research funding from Biomarin Pharmaceuticals, Homology Pharmaceuticals, American Gene Technologies, Nestle Pharmaceuticals, Rubius Pharmaceuticals, and Synlogic Pharmaceuticals.

All other authors have no conflicts of interests and nothing to disclose.

Figures

Figure 1
Figure 1
Prevalence of PKU (All Phenotypes) in 64 Countries from 6 World Regions For exact prevalence numbers see Table S1.
Figure 2
Figure 2
Relationship between Blood Phenylalanine, Phenotype, and Genotypic Phenotype Value (GPV) (A) Boxplot (median, 25th–75th 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
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
Figure 4
Relationship between Genotypic Phenotype Value (GPV) and BH4 Responsiveness (A) Boxplot (median, 25th–75th 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, 25th–75th percentile, 1.5) of GPV (APVmax) 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
Figure 5
Patterns of Common PAH Variants Possibly Associated with Migration in Europe
See this image and copyright information in PMC

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