Heterogeneity of comprehensive clinical phenotype and longitudinal adaptive function and correlation with computational predictions of severity of missense genotypes in KIF1A-associated neurological disorder

Abstract

AbstractPurposePathogenic variants in Kinesin Family Member 1A (KIF1A) are associated withKIF1A-associated neurological disorder (KAND). We report the clinical phenotypes and correlate genotypes of individuals with KAND.MethodsMedical history and adaptive function were assessed longitudinally. In-person evaluations included neurological, motor, ophthalmologic and cognitive assessments.ResultsWe collected online data on 177 individuals. Fifty-seven individuals were also assessed in-person. Most individuals hadde novoheterozygous missense likely pathogenic/pathogenicKIF1Avariants. The most common characteristics were hypotonia, spasticity, ataxia, seizures, optic nerve atrophy, cerebellar atrophy, and cognitive impairment. Mean Vineland Adaptive Behavior Composite score (VABS-ABC) was low (M=62.9,SD=19.1). The mean change in VABS-ABC over time was -3.1 (SD=7.3). The decline in VABS-ABC was associated with the age at first assessment and abnormal electroencephalogram/seizure. There was a positive correlation between Evolutionary Scale Model (ESM) score for the variants and final VABS-ABC (p=0.003). Abnormal electroencephalogram/seizure, neuroimaging result, and ESM explain 34% of the variance in final VABS-ABC (p<0.001).ConclusionIn-person assessment confirmed caregiver report and identified additional visual deficits. Adaptive function declined over time consistent with both the neurodevelopmental and neurodegenerative nature of the condition. Using ESM score assists in predicting phenotype across a wide range of unique variants.