Enhancing Genotype-Phenotype Correlation in Pediatric PKU: A Comparative Analysis of Hotspot Mutations and Prediction Models Across 12 Chinese Regions.

OBJECTIVE:Phenylketonuria (PKU) is a genetic metabolic disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene, with an incidence rate in China of approximately 1 in 11,000. PKU exhibits high heterogeneity, making the study of genotype-phenotype correlations essential for effective diagnosis and treatment. METHODS:This study aimed to analyze the genotype-phenotype correlation in pediatric PKU patients in China, with a special focus on hotspot mutations across different regions.We compared the accuracy of two prediction models: the allele phenotype value/genotype-phenotype value system and the prediction system based on the sum of assigning value (AV) scores from PAH activity, evaluating both models based on available patient data from various regions. RESULTS:The majority of genotypes in PKU patients were found to be compound heterozygotes. Classical PKU patients (cPKU) accounted for the highest proportion (44%), while the percentage of patients with mild hyperphenylalaninemia was relatively low at 22%. Among the eight regions studied, the APV/GPV system demonstrated higher accuracy (72.02%) compared with the AV score prediction system (56.82%, p < 0.05); however, for the cPKU phenotype alone, the difference in accuracy was not significant (p > 0.05). DISCUSSION:This study provides insights into the relationship between genotypes and phenotypes in PKU patients across different regions of China, emphasizing the importance of analyzing hotspot mutations for understanding genotype-phenotype correlations. The findings highlight the need to enhance hotspot mutation spectra for PKU patients and advocate for the development of more accurate prediction models, which can offer better protection for PKU patients and alleviate the burden on patients and their families.