DNAJC12 p.Asp44Gly associated with mild hyperphenylalaninemia and migraine-like headaches: Structural and deep learning analyses

Abstract

Objective DNAJC12 encodes a J-domain co-chaperone involved in the function of aromatic amino acid hydroxylases, and its deficiency is associated with hyperphenylalaninemia (HPA) and monoamine neurotransmitter deficiency. We assessed a DNAJC12 c.131A > G (p.Asp44Gly, D44G) variant identified in a 19-year-old man who presented with mild HPA, recurrent migraine-like headaches, and phenylketonuria-like white matter changes, along with four reported clinically relevant missense variants (A62E, R72P, H102Q, and W103C), using an integrated deep learning (DL)-based approach. Methods DL-based and conventional prediction algorithms were integrated to evaluate the clinical and genetic findings, together with protein structural and pathogenic impact. Analyses incorporated AlphaFold2, AlphaMissense, REVEL, PolyPhen-2, and ThermoMPNN. Principal component analysis (PCA) was used to characterize overall, position-level, and substitution-level pathogenicity metrics. Pathogenicity classification followed American College of Medical Genetics and Genomics and ClinGen Sequence Variant Interpretation standards. Results The J-domain was confidently modeled, and Asp44 was located within the conserved His-Pro-Asp motif. DNAJC12 missense variants may affect predicted side-chain interactions and residue-contact patterns with thermodynamic changes. PCA of aggregated pathogenicity metrics indicated that the predicted deleteriousness of p.Asp44Gly was consistent with stronger position-specific constraint. D44G was classified as a variant of uncertain significance (PM1, PM2_Supporting, and PP3_Supporting). Conclusion Our findings provide additional clinical and genetic evidence relevant to DNAJC12-related disease and support a potential functional effect of D44G, but do not establish its pathogenicity yet. DNAJC12 should be included in the genetic evaluation of patients with unexplained HPA with neurological manifestations, and D44G warrants further functional validation.