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

Genetics in Medicine : Official Journal of the American College of Medical Genetics
S F GarbadeNenad Blau

Abstract

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. A total of 9336 PKU patients with 2589 different genotypes, carrying 588 variants, were investigated using an allelic phenotype value (APV) algorithm. 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 si...Continue Reading

References

May 2, 1991·The New England Journal of Medicine·Y OkanoH Lou
May 11, 1999·European Journal of Human Genetics : EJHG·L R DesviatM Ugarte
Dec 27, 2002·The New England Journal of Medicine·Ania C MuntauAdelbert A Roscher
Feb 27, 2008·Journal of Human Genetics·Dani BercovichYair Anikster
Jun 10, 2008·American Journal of Human Genetics·Søren W GerstingAnia C Muntau
Jan 19, 2010·Genetics and Molecular Research : GMR·L L SantosM R S Carvalho
Oct 26, 2010·Lancet·Nenad BlauHarvey L Levy
Mar 19, 2011·BMC Bioinformatics·Xavier RobinMarkus Müller
Aug 27, 2011·The Biochemical Journal·Ernst R WernerBeat Thöny
Jan 5, 2014·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Jerry VockleySusan A Berry
Jun 3, 2014·Expert Review of Molecular Diagnostics·Nenad BlauCarla Carducci
Jun 19, 2014·European Journal of Human Genetics : EJHG·Sarah WettsteinNenad Blau
Jan 15, 2015·Nature Reviews. Genetics·Marylyn D RitchieDokyoon Kim
Feb 11, 2015·Expert Opinion on Pharmacotherapy·Nenad Blau, Nicola Longo
Feb 27, 2016·Human Mutation·Nenad Blau
Apr 29, 2016·Journal of Human Genetics·Luis Aldámiz-EchevarríaMaría L Couce
Nov 28, 2017·Molecular Genetics and Metabolism·Nenad BlauBeat Thöny
Feb 3, 2018·Scandinavian Journal of Clinical and Laboratory Investigation·Zhan ZhangPing Wang
Mar 16, 2018·Journal of Inherited Metabolic Disease·Ron A Wevers, Nenad Blau

❮ Previous
Next ❯

Citations

Dec 7, 2018·Journal of Human Genetics·Shigeo Kure, Haruo Shintaku
Sep 11, 2019·Journal of Inherited Metabolic Disease·Roeland A F EversFrancjan J van Spronsen
Jul 19, 2020·International Journal of Molecular Sciences·Neha SarodayaSuresh Ramakrishna
Dec 18, 2019·International Journal of Neonatal Screening·Julia C van CampenAnn Dalton
Jul 16, 2020·American Journal of Human Genetics·Alicia HillertNenad Blau
Feb 1, 2020·American Journal of Human Genetics·Saskia B WortmannShamima Rahman
May 22, 2021·Nature Reviews. Disease Primers·Francjan J van SpronsenAnnet M Bosch
Aug 28, 2021·Journal of Clinical Medicine·Fernando AndradeJavier de Las Heras

❮ Previous
Next ❯

Software Mentioned

R
R package pROC
BIOPKU

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.