The Genetic Landscape and Epidemiology of Phenylketonuria.
BH4
PAH deficiency
PKU
hyperphenylalaninemia
phenylalanine
tetrahydrobiopterin
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
06 08 2020
06 08 2020
Historique:
received:
25
04
2020
accepted:
05
06
2020
pubmed:
16
7
2020
medline:
21
10
2020
entrez:
16
7
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32668217
pii: S0002-9297(20)30194-4
doi: 10.1016/j.ajhg.2020.06.006
pmc: PMC7413859
pii:
doi:
Substances chimiques
Biopterins
0
Phenylalanine
47E5O17Y3R
Phenylalanine Hydroxylase
EC 1.14.16.1
sapropterin
EGX657432I
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
234-250Subventions
Organisme : NIMHD NIH HHS
ID : L60 MD003721
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK117916
Pays : United States
Organisme : NINR NIH HHS
ID : R01 NR016991
Pays : United States
Informations de copyright
Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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