Phenylalanine hydroxylase deficiency in Mexico: genotype-phenotype correlations, BH4 responsiveness and evidence of a...

Area of Science:

• Genetics
• Molecular Biology
• Medical Genetics

Background:

• The genetic landscape of phenylketonuria (PKU) in Mexico, specifically the phenylalanine hydroxylase (PAH) gene, remains largely uncharacterized.
• Geographical variations in PKU-causing variants and their impact on treatment response are poorly understood.

Purpose of the Study:

• To determine the mutational spectrum of the PAH gene in Mexican PKU patients.
• To establish genotype-phenotype correlations and predict tetrahydrobiopterin (BH4) responsiveness based on genotype.
• To investigate the geographic origin and haplotype associations of PAH alleles in Mexico.

Main Methods:

• Sequencing of the PAH gene in 48 Mexican patients.
• Determination of allele geographic origin and mini-haplotype association.
• Analysis of genotype-phenotype correlations.
• Genotype-based prediction of BH4 responsiveness.

Main Results:

• Identified 34 PAH variants, with c.60+5G>T being the most frequent (20.8%), potentially due to founder effect or genetic drift.
• Discovered two novel variants: c.1A>T and c.969+6T>C.
• Observed a 70.8% concordance in genotype-phenotype correlations.
• Predicted a 41.7% responsiveness to BH4 based on genotype.

Conclusions:

• The study elucidates the PAH mutational spectrum in Mexico, identifying key variants and their potential origins.
• Genotype-phenotype correlations were established, and genotype-based BH4 responsiveness prediction offers a tool for personalized treatment strategies.
• This data is crucial for guiding BH4 testing and therapy selection in Mexican PKU patients.