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

• DOI: 10.1038/s41436-018-0081-x
• Publication Date: 2018-07-09T11:33:45Z
• Authors: Sven F. Garbade; Nan Shen; Nastassja Himmelr...; Dorothea Haas; Friedrich K. Trefz; Georg F. Hoffmann; Peter Burgard; Nenad Blau
• Keywords: Phenylalanine hydroxylase; Hyperphenylalaninemia; Phenylketonurias; Genotype-phenotype distinction

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