A Single-Center Genotype-Phenotype Correlation Cohort Study of Hyperphenylalaninemia Patients: Genetic Analysis as a...

Hyperphenylalaninemia (HPA, increased blood phenylalanine levels) refers to a disorder spectrum, with phenylketonuria (PKU) being the most common, caused by PAH gene variants in an autosomal recessive inheritance form. Genetic differences significantly influence phenotypical outcomes in HPA patients. This study investigates the genotype-phenotype correlation of HPA patients, aiming to evaluate treatment consistency based on specific genotypes and demonstrate that genotyping can provide guidance for optimal treatment.

Genomic DNA was obtained from 50 PKU, 2 tetrahydrobiopterin (BH4) deficiency, and 1 dihydropteridin reductase deficiency patients for next-generation sequencing of HPA-associated genes. Variants were analyzed using the Sophia DDM program, dbSNP, ClinVar, Ensembl information services, and ACMG 2015 criteria. Allelic phenotypical values consistent with enzyme functionality based on literature data were assessed using anamnesis information.

Carriers of two null variants (homozygous/compound heterozygous) were unresponsive to BH4 therapy, reflecting the existing literature. Notably, BH4 therapy was also inadequate for two PKU patients who were compound heterozygous carriers with one null variant (P3, P10), even with other variants assumed protein function (PAH [NM_000277.3] c.1289T>C, c.143T>C). However, PAH variants c.1169A>G (P21) and c.898G>T (P25) demonstrated positive BH4 responses when compounding a null variant, along with a c.782G>A homozygous patient benefiting from BH4. Two novel variants were observed in PTS and QDPR genes, respectively.

This study implies that genetic testing is plausible in predicting pretreatment BH4 testing outcomes, aiding in decision-making before patient evaluation, and providing valuable guidance to metabolism specialists during HPA treatment. With more HPA genotypes analyzed and clinical data published, genotyping will hold a better deterministic position toward patient prognosis and therapeutic management.