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Should genetic analysis in newborn screening and a heterozygote test for hyperphenylalaninaemia be recommended? An
A Rottoli1, M L Gianní, E Verduci
1Department of Paediatrics, San Paolo Hospital, Milan, Italy. clinped@mailserver.unimi.it
Insights
Genetic analysis for phenylketonuria (PKU) in Italy is not cost-effective for screening. Current methods do not improve sensitivity or benefit-cost ratio for population-wide detection of phenylalanine hydroxylase (PAH) deficiency.
Area of Science:
- Medical Genetics
- Biochemistry
- Public Health
Background:
- Phenylalanine hydroxylase (PAH) deficiency, also known as phenylketonuria (PKU), is an inherited metabolic disorder.
- Early detection and management through newborn screening are crucial for preventing severe health consequences.
Purpose of the Study:
- To evaluate the economic viability and effectiveness of incorporating genetic analysis for PAH deficiency into Italian regional screening programs.
- To determine if genetic screening offers a significant benefit-cost advantage over existing methods.
Main Methods:
- Genomic DNA was extracted from leukocytes of 151 hyperphenylalaninemia patients across Italy.
- Polymerase chain reaction (PCR) amplified PAH exons, followed by restriction enzyme analysis and DNA sequencing to identify mutations.
Main Results:
- The eight most prevalent PAH mutations identified accounted for only 49% of mutant alleles.
- This detection rate falls significantly short of the 90% threshold required for effective population screening.
Conclusions:
- Genetic screening for PAH deficiency in Italy does not enhance diagnostic sensitivity or improve the benefit-cost ratio.
- The current lack of a strong genotype-phenotype correlation for optimizing dietary interventions limits the advantages of genetic screening.
Objective:
To determine whether the introduction of genetic analysis for phenylalanine hydroxylase (PAH) deficiency into regional screening programmes can be supported by the benefit-cost ratio.
Method:
Tests for the genetic PAH locus were carried out in 151 patients with hyperphenylalaninaemia originally from all of the Italian regions. PAH mutations were identified by extraction of genomic DNA from leucocytes (whole blood in EDTA), PAH exon amplification was determined by polymerase chain reaction, restriction enzyme analysis was carried out for some recognised mutations, and DNA sequence analysis for the other mutations.
Results:
It was found that the eight most common mutations in the population accounted for 49% of the mutant alleles, which is well below the required standard for effective population screening (90%).
Conclusions:
Genetic screening for PAH deficiency in Italy does not increase the sensitivity of the methodology and the benefit-cost ratio, and thus provides no advantage, particularly as the correlation between genotype and the metabolic phenotype needed to optimise dietary intervention is still being studied.