Genotype-Phenotype Relationships in Phenylalanine Hydroxylase Deficiency: Functional Annotation-Enhanced Analysis of 23,427 Individuals.

Authors

Nenad Blau, Nastassja Himmelreich

Published in

Genetics in medicine : official journal of the American College of Medical Genetics. Pages 102640. Jul 08, 2026. Epub Jul 08, 2026.

Abstract

Phenylalanine hydroxylase deficiency spans from mild hyperphenylalaninemia (MHP) to mild PKU (mPKU) and classic PKU (cPKU). Genotype-phenotype inference is complicated by allelic heterogeneity and incomplete functional annotation of cDNA-only variant strings.
We analyzed 23,427 individuals with two PAH alleles and metabolic phenotype (MHP 4,208 (18.0%), mPKU 5,295 (22.6%), cPKU 13,924 (59.4%); 10,108 (43.2%) had blood phenylalanine (Phe) values. Variants were functionally annotated with Ensembl Variant Effect Predictor (VEP) and SpliceAI and mapped to three functional classes: predicted loss-of-function (0), splice-uncertain, and missense/other. We quantified genotype-phenotype concordance and evaluated phenotype prediction using ordinal and multinomial models.
VEP provided functional consequences for 1,007 unique variants and annotated >99% of alleles. Genotype functional class showed a strong relationship with phenotype, with 0/0 genotypes predominantly classified as cPKU. Genotype-phenotype concordance increased with genotype frequency, and common genotypes displayed high phenotype consistency. An ordinal ridge model using allele identity plus functional class achieved accuracy 0.790 (quadratic weighted kappa 0.784) under genotype-held-out evaluation. A multinomial logistic model achieved accuracy 0.836 on a random patient split. Continuous Phe prediction using ridge regression on log(Phe) achieved Rˆ2 0.673 with mean absolute error 357 mmol/L. Benchmarking against the published allelic phenotype value/genotypic phenotype value (APV/GPV) system yielded 0.849 accuracy in 22,656 individuals with APVs for both alleles; performance was high for cPKU and MHP but lower for mPKU, consistent with prior reports.
In this large cohort, PAH genotype is strongly associated with metabolic phenotype. Functional consequence annotation enables mechanistic interpretation (loss-of-function and splice effects) and improves the portability of genotype-based prediction to previously unseen genotypes.

PMID:
42423070
Bibliographic data and abstract were imported from PubMed on 09 Jul 2026.

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