Submission Details

KIF1A was first reported in relation to autosomal dominant syndromic intellectual disability in 2011 (Hamdan, et al., PMID: 21376300). Affected individuals present with global developmental delay, spasticity, and variable intellectual disability. Additional features may include optic atrophy, peripheral neuropathy, seizures, ataxia, cerebellar atrophy, and cerebral atrophy. More than 70 pathogenic or likely pathogenic variants in KIF1A have been reported in ClinVar; the majority of the variants are missense and are enriched in the motor domain of KIF1A protein. Evidence supporting this gene-disease relationship includes case-level data and experimental data. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The gene-disease relationship is also supported by an animal model. Of note, recent findings suggested that KIF1A-related disorders constitute a wide phenotypic spectrum (Nemani, et al., PMID: 32096284). Defects in the KIF1A gene may result in 1) NESCAV (neurodegeneration and spasticity with or without cerebellar atrophy or cortical visual impairment) syndrome, 2) Neuropathy, hereditary sensory, type IIC, 3) Spastic paraplegia 30, autosomal dominant, and 4) Spastic paraplegia 30, autosomal recessive (see OMIM). In summary, KIF1A is definitively associated with autosomal dominant syndromic intellectual disability. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 8/02/20 (SOP Version 7).