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

Functional annotation of PAH variants (VEP, SpliceAI) correlated with metabolic phenotype

Across 23,427 individuals carrying two PAH alleles with a metabolic phenotype, the authors enrich genotype-phenotype analysis with functional annotation (VEP, SpliceAI), classifying variants as loss-of-function, splice-uncertain, or missense/other. Genotype functional class is strongly linked to phenotype, with 0/0 genotypes predominantly classic PKU. Ordinal and multinomial models reach 0.79-0.84 accuracy for phenotype prediction, including on previously unseen genotypes. Functional-consequence annotation improves the portability of genotype-based prediction.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A large cohort confirming and refining genotype-phenotype predictability in PKU, with practical value for counseling and anticipating severity. The key contribution is functional anchoring (including splicing) rather than a simple allele-phenotype table. Lower performance for mPKU echoes the intrinsic limits of intermediate phenotypes.

Analysis by Dr Thibaut Benquey