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

Purpose: Pathogenic variants in kinesin family member 1A (KIF1A) are associated with KIF1A-associated neurological disorder. We report the clinical phenotypes and correlate genotypes of individuals with KIF1A-associated neurological disorder.

Methods: Medical history and adaptive function were assessed longitudinally. In-person evaluations included neurological, motor, ophthalmologic, and cognitive assessments.

Results: We collected online data on 177 individuals. Fifty-seven individuals were also assessed in-person. Most individuals had de novo heterozygous missense likely pathogenic/pathogenic KIF1A variants. 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 = .003). Abnormal electroencephalogram/seizure, neuroimaging result, and ESM explain 34% of the variance in final VABS-ABC (P < .001).

Conclusion: In-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.

Keywords: Adaptive function; Cognitive impairment; ESM; KIF1A; Neurological disorder.

Figure 1:

KIF1A likely pathogenic or pathogenic variants Each circle represents a single unrelated person with pathogenic/likely pathogenic KIF1A variants in this cohort that is color coded by inheritance. One individual with entire coding sequence deletion is not mapped in this figure. The top portion of the figure is the full-length protein, and the bottom portion of the figure is an enlargement of the motor domain. Missense variants are shown above the gene, other types of variants (splice variants, inframe indel, frameshift) are shown below the gene.

Figure 2:

(A) Violin plots illustrate Vineland Adaptive Behavior Scales 3rd Edition (VABS) standard score of individuals with pathogenic/likely pathogenic KIF1A variants at baseline (n=146). Each domain standard score has a mean of 100 and a standard deviation of 15. Socialization score was significantly higher than daily living skill, and motor skill score. (B) Violin plots illustrate differences between baseline and follow-up of growth scale value in each subdomain (n=80). There was no difference between growth scale value in each subdomain. (C) Violin plots illustrate differences between baseline and follow-up of VABS standard score in adaptive behavior composite and each subdomain (n=80). The change of socialization score was significantly different from motor skill subdomain.

Figure 3:

Overview of clinical phenotypes and VABS-ABC. (A) Correlation among baseline and clinical phenotypes. The order is determined by hierarchical clustering. There are 3 major blocks of phenotypes with moderate to high correlation within each block: (a) age and of 1st medical visit and diagnosis, (b) VABS-ABC, and (c) EEG, seizure, and structural disorders. (B) VABS-ABC over age of assessment. Each point represents an assessment, the points representing baseline and follow-up assessments of the same individuals are connected by an arrow. Some individuals only have one assessment. Individuals are colored by EEG or seizure status. In general, individuals with abnormal EEG or seizure have lower VABS-ABC. (C) Change of VABS-ABC between two assessment is associated with the age of 1st assessment. About half of individuals with baseline assessment at age younger than 6.9 years had substantial decrease of scores in the follow-up assessment. Most of the individuals with baseline assessment at age older than 6.9 do not have substantial decrease in the follow-up assessment. The dashed red line represents the median age (6.9 years).

Figure 4:

Association of clinical and genetics factors on Vineland ABC score. (A) Association of EEG or seizure status on final and change of VABS-ABC. Individuals with abnormal EEG or seizure have both lower final and change of VABS-ABC. (B) Association of neuroimaging results and optic nerve change on final VABS-ABC. Individuals with abnormal neuroimaging results or altered optic nerve showed lower final VABS-ABC than the reference group. (C) There is a significant positive correlation between ESM score and final VABS-ABC. (D) Strong positive correlations were found between predicted and observed final VABS-ABC, as well as predicted and observed change of VABS-ABC. Significance: * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001.