A single-center genotype-phenotype correlation cohort study of Hyperphenylalaninemia patients: Genetic analysis as a deterministic tool for treatment consistency

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Peker A., Yakut Uzuner S., Altıok Clark Ö., Toylu A., Dal Demirelli G., Akcan Paksoy B., ...More

The European Human Genetics Conference - ESHG 2024, Berlin, Germany, 1 - 04 June 2024, pp.1, (Summary Text)

  • Publication Type: Conference Paper / Summary Text
  • City: Berlin
  • Country: Germany
  • Page Numbers: pp.1
  • Akdeniz University Affiliated: Yes

Abstract

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.