Related Experiment Video
Updated: Jun 17, 2026
07:15
Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
Variations in genotype-phenotype correlations in phenylketonuria patients
L L Santos1, C G Fonseca, A L P Starling
1Departamento de Biologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil.
Genetics and Molecular Research : GMR
|January 19, 2010
Summary
Phenylalanine hydroxylase deficiency (PKU) genotype-phenotype correlations were studied in Brazilian patients. While genotype predicted clinical course, 51% of predicted phenotypes for PKU did not match observed phenotypes, indicating complex genetic influences.
Area of Science:
- Genetics
- Biochemistry
- Medical Science
Background:
- Phenylalanine hydroxylase deficiency (PKU) exhibits significant phenotypic variability.
- This variability is largely attributed to allelic heterogeneity at the phenylalanine hydroxylase (PAH) gene locus.
Purpose of the Study:
- To investigate the genotype-phenotype correlation in 54 phenylketonuria patients from Minas Gerais, Brazil.
- To evaluate the predictive accuracy of a phenotype prediction system based on arbitrary values (AV) assigned to PAH mutations.
Main Methods:
- Genotyping of 54 PKU patients.
- Phenotype prediction using arbitrary values (AV) for mutations: AV=1 (classical PKU), AV=2 (moderate PKU), AV=4 (mild PKU), AV=8 (non-PKU hyperphenylalaninemia).
- Correlation analysis between predicted and observed phenotypes, clinical diagnosis via phenylalanine loading tests, and phenylalanine levels.
Main Results:
- Among 51 PKU patients analyzed, 51% showed a mismatch between predicted and observed phenotypes.
- The highest concordance was observed in patients with null/null genotypes.
- Significant correlations were found between initial phenylalanine levels, predicted residual activity, genotype, and the sum of arbitrary values.
Conclusions:
- Genotype is a significant predictor of the clinical course in phenylketonuria patients.
- The current arbitrary value system has limitations in accurately predicting phenotypes for all PKU genotypes.
- Further research is needed to refine genotype-phenotype correlation models for PKU.
Related Concept Videos
01:20Inborn Errors of Metabolism
Phenylketonuria (PKU) is a protein metabolism disorder characterized by high blood levels of the amino acid phenylalanine. This results from a mutation in the gene responsible for phenylalanine hydroxylase, an enzyme that converts phenylalanine into tyrosine. When this enzyme is deficient, phenylalanine builds up in the blood, leading to symptoms such as vomiting, rashes, seizures, growth deficiency, and severe mental retardation. An early diagnosis and a diet restricting phenylalanine intake...
01:29Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu
Genetic variations significantly influence drug response through pharmacokinetics, receptor interactions, and biologic milieu modifications. Pharmacokinetic alterations impact drug metabolism and clearance, affecting efficacy and toxicity. Variants in drug-metabolizing enzymes, such as CYP2C9 and CYP2C19, alter drug activation and elimination. For example, CYP2C9 loss-of-function variants require lower warfarin doses to prevent excessive bleeding, while CYP2C19 variants reduce clopidogrel...
01:27Principles of Pharmacogenetics: Types of Genetic Variants
The human genome is over 99.9% identical between individuals, yet genetic differences exist at millions of bases. The human genome contains approximately 3 million variant positions per individual, many of which are heterozygous, contributing to genetic diversity and individual traits. Genetic variations include single-nucleotide polymorphisms (SNPs), insertions, deletions, and copy number variations (CNVs).SNPs, the most common variation, involve single-base changes in DNA. These can be...
01:35Pedigree Analysis
Overview
01:28Pharmacogenetics of Phase I Enzymes: Cytochrome P450 Isozymes
Cytochrome P450 (CYP450) enzymes are a superfamily of heme-containing monooxygenases that play a pivotal role in Phase I drug metabolism by catalyzing oxidation and reduction reactions.These enzymes transform lipophilic xenobiotics into more hydrophilic metabolites, facilitating subsequent Phase II conjugation and eventual excretion. The CYP450 family is classified into families (e.g., CYP1–CYP3) and subfamilies (e.g., CYP2A, CYP2C), based on amino acid sequence homology.CYP450 isoenzymes,...
01:39Epistasis
In addition to multiple alleles at the same locus influencing traits, numerous genes or alleles at different locations may interact and influence phenotypes in a phenomenon called epistasis. For example, rabbit fur can be black or brown depending on whether the animal is homozygous dominant or heterozygous at a TYRP1 locus. However, if the rabbit is also homozygous recessive at a locus on the tyrosinase gene (TYR), it will have an unshaded coat that appears white, regardless of its TYRP1...