Gene-disease assertions not curated here (add link or write note):
Disease | KIF1A-related syndromic intellectual disability |
|---|---|
Inheritance | Autosomal recessive / autosomal dominant / X-linked |
Prevalence |
Source: |
Rapid or full curation? |
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ClinGen Intellectual Disability and Autism GCEP classified 09/24/2020 | |
Clinical Validity Scoring Notes and points | 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). Gene Clinical Validity Standard Operating Procedures (SOP) - SOP7 Source: |
Clinical Validity Points Total | 14.5 Source: ClinGen Intellectual Disability and Autism GCEP |
Clinical Validity Classification | Definitive Source: ClinGen Intellectual Disability and Autism GCEP |
Molecular Mechanism | Loss of function / Gain of function / Dominant Negative c.1527C>G p.Y509* - PMID: 28191890 and 34312540 - two large autism / neurodevelopmental disorder papers, both list variant in supplement per HGMD comment, skipping for now. Gene is pLOF constrained, LOEUF =0.3 Pennings 2020 PMID:31488895 - Exome sequencing performed in heredtiary spastic paraplegia cohort from Netherlands.
c.798+1G>T - 33880452 c.1038-1G>A Vecchia 2022 PMID: 34487232 NM_004321.6(KIF1A):c.28delG p.(Val10Cysfs*11) - absent gnomAD, found in a patient with hereditary spastic paraplegia. Per supplement, the variant was in patient 4. Unclear if variant inherited or de novo, de novo codes were not applied using ACMG criteria. Ghafoor 2022 PMID: 36282036 - c.2658delC p.(Val887Serfs*89) - article requested. Absent gnomAD, NMD+. Per abstract, SNP analysis to find ROH followed by exome identified the variant in a family with severe manifestations of HSAN; hets only had scaly skin. PMID: 31512412 - c.275_276insAA p.(Cys92*) - de novo variant found in a girl with features of Rett syndrome. c.1187dupA p.(Asn396Lysfs*40) c.4096_4103dupCCCCGGAG p.(Asp1369Profs*17) c.4740dupG p.(Tyr1581Valfs*50) - NMD+ |
Penetrance (list source/PMID) | Source: |
Age of Onset (list source/PMID) | |
Severity | |
Clinical Features | Sources: |
HPO Terms | |
Gene SOPs & Notes | LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant |
Curation Summary | |
Case ID, Curator name, Date, Jira ticket link |