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Abstract

Rare monogenic diseases lack scalable prognostic frameworks, leaving patients and families without guidance after molecular diagnosis. Using KIF1A-associated neurological disorder (KAND) as a model system, we integrated single-molecule biophysical phenotyping of 91 pathogenic variants with longitudinal clinical characterization of 343 patients. Vineland Adaptive Behavior Scales (VABS) Adaptive Behavior Composite (ABC) and Growth Scales identified two divergent trajectories emerging after age 10: a stable group and a declining group characterized by seizures, abnormal EEGs, and optic nerve atrophy. A framework combining biophysical parameters, computational pathogenicity scores, and clinical variables classified patients as stable versus declining with AUC 0.834 and predicted VABS ABC scores with R{superscript 2} = 0.484 under leave-one-out cross-validation. For newly identified KIF1A variants, this approach offers a prognostic tool and a stratification strategy for clinical trials. Because kinesin motor function is mechanistically conserved, the framework may generalize to other kinesinopathies and to monogenic disorders amenable to quantitative functional assays.

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