KIF1A – Intellectual Disability, Autosomal Dominant 9

Kinesin family member 1A (KIF1A) encodes a neuron-specific ATP-dependent motor protein crucial for anterograde axonal transport of synaptic vesicle precursors. Heterozygous missense variants clustering in the conserved motor domain have been linked to a spectrum of early-onset neurodevelopmental disorders, including NESCAV syndrome, formally known as intellectual disability, autosomal dominant 9 (MONDO:0013656). A multicenter Polish cohort identified three novel de novo motor-domain variants, and functional assays confirm that pathogenic KIF1A mutations impair ATPase activity and microtubule binding.

In a series of nine unrelated Polish patients with NESCAV syndrome features, exome sequencing revealed three novel heterozygous motor-domain missense variants: c.442G>A (p.Glu148Lys), c.218T>G (p.Val73Gly), and c.609G>C (p.Arg203Ser) (9 probands PMID:37239332). All three variants were absent from population controls and prediction models indicated deleterious effects on the kinesin motor structure. No familial segregation was observed beyond each index case, consistent with a predominantly de novo autosomal dominant inheritance.

A separate case report described a de novo variant p.Arg169Thr associated with classical NESCAV syndrome in a single patient, supporting recurrent hotspot residues within the motor domain (1 proband PMID:34121983). The clinical phenotype across these probands includes severe global developmental delay, spastic paraparesis, peripheral neuropathy, optic nerve atrophy, progressive cerebellar atrophy, epilepsy, and hypotonia.

Collectively, ten unrelated probands with heterozygous KIF1A motor-domain missense variants, all absent in controls and predominantly de novo, provide robust genetic evidence for causality. No recurrent founder alleles have been reported, and variant spectrum is restricted to missense changes disrupting conserved regions of the motor domain. Penetrance appears complete for early-onset neurologic deficits in all affected individuals.

Functional studies of the p.Arg169Thr variant demonstrate a 70–80% reduction in microtubule-stimulated ATPase activity and impaired microtubule binding in vitro, consistent with loss-of-function via haploinsufficiency (ATPase assay and structural modeling PMID:34121983). Similar reductions in motor performance have been observed for other pathogenic motor-domain missense variants in KIF1A, correlating with severity of the neurodevelopmental phenotype.

Integration of the genetic and experimental data supports a Strong ClinGen gene–disease association (10 probands with de novo motor-domain missense variants, absent in controls, concordant functional defects) and Moderate genetic and functional evidence tiers. KIF1A testing is clinically indicated in early-onset intellectual disability with spasticity or neuropathy. Functional assays of novel KIF1A variants can aid variant classification and inform prognosis.

References

• Genes • 2023 • Expanding the Knowledge of KIF1A-Dependent Disorders to a Group of Polish Patients. PMID:37239332
• Frontiers in neuroscience • 2021 • The Novel KIF1A Missense Variant (R169T) Strongly Reduces Microtubule Stimulated ATPase Activity and Is Associated With NESCAV Syndrome. PMID:34121983

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