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. 2021 Mar;9(3):e1559.
doi: 10.1002/mgg3.1559. Epub 2021 Jan 19.

Phenylketonuria in Portugal: Genotype-phenotype correlations using molecular, biochemical, and haplotypic analyses

Filipa Ferreira  1 , Luísa Azevedo  2   3   4 , Raquel Neiva  1 , Carmen Sousa  1 , Helena Fonseca  1 , Ana Marcão  1 , Hugo Rocha  1 , Célia Carmona  1 , Sónia Ramos  1 , Anabela Bandeira  5 , Esmeralda Martins  5 , Teresa Campos  6 , Esmeralda Rodrigues  6 , Paula Garcia  7 , Luísa Diogo  7 , Ana Cristina Ferreira  8 , Silvia Sequeira  8 , Francisco Silva  9 , Luísa Rodrigues  10 , Ana Gaspar  11 , Patrícia Janeiro  11 , António Amorim  2   3   4 , Laura Vilarinho  1   12
Affiliations

Phenylketonuria in Portugal: Genotype-phenotype correlations using molecular, biochemical, and haplotypic analyses

Filipa Ferreira et al. Mol Genet Genomic Med. 2021 Mar.

Abstract

Background: The impairment of the hepatic enzyme phenylalanine hydroxylase (PAH) causes elevation of phenylalanine levels in blood and other body fluids resulting in the most common inborn error of amino acid metabolism (phenylketonuria). Persistently high levels of phenylalanine lead to irreversible damage to the nervous system. Therefore, early diagnosis of the affected individuals is important, as it can prevent clinical manifestations of the disease.

Methods: In this report, the biochemical and genetic findings performed in 223 patients diagnosed through the Portuguese Neonatal Screening Program (PNSP) are presented.

Results: Overall, the results show that a high overlap exists between different types of variants and phenylalanine levels. Molecular analyses reveal a wide mutational spectrum in our population with a total of 56 previously reported variants, most of them found in compound heterozygosity (74% of the patients). Intragenic polymorphic markers were used to assess the haplotypic structure of mutated chromosomes for the most frequent variants found in homozygosity in our population (p.Ile65Thr, p.Arg158Gln, p.Leu249Phe, p.Arg261Gln, p.Val388Met, and c.1066-11G>A).

Conclusion: Our data reveal high heterogeneity at the biochemical and molecular levels and are expected to provide a better understanding of the molecular basis of this disease and to provide clues to elucidate genotype-phenotype correlations.

Keywords: Portuguese population; biochemical and genetic findings; haplotypic study; mutation spectrum; phenylketonuria.

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Conflict of interest statement

The authors declare that they have no competing interests and that no financial support was obtained for the publication of this manuscript.

Figures

FIGURE 1
FIGURE 1
Levels of phenylalanine mutations found in the most frequent homozygous individuals (at the neonatal screening)
FIGURE 2
FIGURE 2
Haplotypes observed in homozygous individuals carrying the most frequent variants in this study defined by six polymorphic single nucleotide polymorphisms (SNPs) [p.Gln232= (rs1126758), p.Val245= (rs1042503), p.Leu385= (rs772897), c.168+19T>C (IVS2+19T>C; rs17842947), c.441+47C>T (IVS4+47C>T; rs1718301) e c.510‐54G>A (IVS5‐54G>A; rs2251905)]. (Individuals carrying the ancestral alleles are shown in unfilled circles, homozygosity for the derivate alleles is shown in red circles and heterozygosity is shown in half filled circles) (GenBank: NM_000277.3; ENSG00000171759; ENST00000553106.6)
See this image and copyright information in PMC

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