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Allelic phenotype values: a model for genotype-based phenotype prediction in phenylketonuria


Garbade, Sven F; Shen, Nan; Himmelreich, Nastassja; Haas, Dorothea; Trefz, Friedrich K; Hoffmann, Georg F; Burgard, Peter; Blau, Nenad (2019). Allelic phenotype values: a model for genotype-based phenotype prediction in phenylketonuria. Genetics in Medicine, 21(3):580-590.

Abstract

PURPOSE The nature of phenylalanine hydroxylase (PAH) variants determines residual enzyme activity, which modifies the clinical phenotype in phenylketonuria (PKU). We exploited the statistical power of a large genotype database to determine the relationship between genotype and phenotype in PKU. METHODS A total of 9336 PKU patients with 2589 different genotypes, carrying 588 variants, were investigated using an allelic phenotype value (APV) algorithm. RESULTS We identified 251 0-variants encoding inactive PAH, and assigned APVs (0 = classic PKU; 5 = mild PKU; 10 = mild hyperphenylalaninaemia) to 88 variants in PAH-functional hemizygous patients. The genotypic phenotype values (GPVs) were set equal to the higher-APV allele, which was assumed to be dominant over the lower-APV allele and to determine the metabolic phenotype. GPVs for 8872 patients resulted in cut-off ranges of 0.0-2.7 for classic PKU, 2.8-6.6 for mild PKU and 6.7-10.0 for mild hyperphenylalaninaemia. Genotype-based phenotype prediction was 99.2% for classic PKU, 46.2% for mild PKU and 89.5% for mild hyperphenylalaninaemia. The relationships between known pretreatment blood phenylalanine levels and GPVs (n = 4217), as well as tetrahydrobiopterin responsiveness and GPVs (n = 3488), were significant (both P < 0.001). CONCLUSIONS APV and GPV are powerful tools to investigate genotype-phenotype associations, and can be used for genetic counselling of PKU families.

Abstract

PURPOSE The nature of phenylalanine hydroxylase (PAH) variants determines residual enzyme activity, which modifies the clinical phenotype in phenylketonuria (PKU). We exploited the statistical power of a large genotype database to determine the relationship between genotype and phenotype in PKU. METHODS A total of 9336 PKU patients with 2589 different genotypes, carrying 588 variants, were investigated using an allelic phenotype value (APV) algorithm. RESULTS We identified 251 0-variants encoding inactive PAH, and assigned APVs (0 = classic PKU; 5 = mild PKU; 10 = mild hyperphenylalaninaemia) to 88 variants in PAH-functional hemizygous patients. The genotypic phenotype values (GPVs) were set equal to the higher-APV allele, which was assumed to be dominant over the lower-APV allele and to determine the metabolic phenotype. GPVs for 8872 patients resulted in cut-off ranges of 0.0-2.7 for classic PKU, 2.8-6.6 for mild PKU and 6.7-10.0 for mild hyperphenylalaninaemia. Genotype-based phenotype prediction was 99.2% for classic PKU, 46.2% for mild PKU and 89.5% for mild hyperphenylalaninaemia. The relationships between known pretreatment blood phenylalanine levels and GPVs (n = 4217), as well as tetrahydrobiopterin responsiveness and GPVs (n = 3488), were significant (both P < 0.001). CONCLUSIONS APV and GPV are powerful tools to investigate genotype-phenotype associations, and can be used for genetic counselling of PKU families.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > Genetics (clinical)
Language:English
Date:1 March 2019
Deposited On:29 Jan 2019 13:42
Last Modified:29 Jul 2020 09:41
Publisher:Nature Publishing Group
ISSN:1098-3600
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1038/s41436-018-0081-x
PubMed ID:29997390

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