The European Human Genetics Conference - ESHG 2024, Berlin, Almanya, 1 - 04 Haziran 2024, ss.1, (Özet Bildiri)
Background/Objectives:
Hyperphenylalaninemia (HPA, increased blood phenylalanine levels) refers to a disorder
spectrum, with Phenylketonuria (PKU) being a widespread autosomal recessive form caused
by PAH gene mutations. Phenotypical outcomes and symptom severity are significantly
influenced by genetic variations in HPA. This study investigates the genotypical-phenotypical
correlation in a cohort of HPA patients, aiming to evaluate treatment consistency concerning
specific genotypes and demonstrate that genotyping can provide guidance for optimal
treatment and prognosis.
Methods:
Genomic DNA was obtained from 31 PKU, 2 Tetrahydrobiopterin (BH4) deficiency, and 1
Dihydropteridin Reductase deficiency patients for Next-Generation Sequencing of HPAassociated
genes. Variants were analyzed using Sophia DDM program, dbSNP, ClinVar,
Ensembl services, and ACMG 2015 criteria. Allelic phenotypic values consistent with enzyme
functionality regarding literature data were assessed with patient anamnesis‘.
Results:
Carriers of two null variants (homozygous/compound heterozygous) were unresponsive to
BH4 therapy, reflecting the literature. Notably, BH4 therapy was also inadequate for two PKU
patients who were compound heterozygous carriers with one null variant, albeit other variants‘
assumed protein function (PAH [NM_000277.3] c.1289T>C, c.143T>C). However, PAH
variants c.1169A>G, c.533A>G, c.1114A>T, c.898G>T demonstrated positive BH4 responses
when compounding a null variant. Homozygous c.782G>A variant, linked to classical PKU,
responded to BH4 therapy along with diet.
Conclusion:
This study implies genetic testing is plausible in predicting pre-treatment BH4 testing
outcomes, aiding in decision-making before patient evaluation as it also provides valuable
guidance to metabolism specialists during treatment. With more HPA genotypes analyzed and
clinical data published, genotyping will hold better deterministic position towards patient
prognosis and therapeutic management.