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KIF1A conditions seem to have overlap. I split them for now
Lumping/Splitting: decided to split given there are different inheritance patterns, variant types, and LOF variants appear to only be reported in spastic paraplegia w/o cognitive deficits. Each scored at least moderate. Some helpful papers to get at lumping splittingvariant locations.
Summary:
MAKE SURE TO REVIEW THE GENE SOP FOR INTERPRETATION
All conditions meet at least moderate
LOF in NM_004321.6 is a clear mechanism for disease for AD hereditary spastic paraplegia w/o cognitive deficits. HOWEVER, please note there is an alternately spliced exon present only in NM_001244008, no truncating variants in this exon have been described in AD HSP.
AR HSAN - LOF suspected, a truncating variant reported in several families by Riviere 2011 is located in an alternately spliced exon (exon 27 in NM_00244088.2).
Helpful papers with good reviews:
Montenegro-Garreaud 2020 PMID: 32935419 - A good review. Propose that KIF1A dysfunction is a single neuromuscular disorder w/ variable involvement of other organs rather than a set of discrete disorders converging at a single locus. However, later they acknowledge that there is a striking distinction between variants that tend to cause pure HSP vs those causing the vast majority of HSP cases with CNS involvement, indicative of variant-specific phenotypes in heterozygous KIF1A dysfunction, and that this may be due to underlying molecular mechanism (potentially differential impact of kinesin motor domain)
AD de novo missense variants reported to cause AD intellectual disability, characterized by a variable expression of lower limb spasticity, hyperreflexia, intellectual disability, hypotonia, ataxia, microcephaly, cerebellar atrophy, nystagmus, and optic atrophy
De novo Missense variants reported as a cause of PEHO syndrome with overlapping features similar to those in the AD ID syndrome.
Het variants reported to cause hereditary spastic paraplegia, which can be pure (ie just HSP) or complicated ( additional neurological symptoms are found, such as seizures, intellectual disability, and peripheral neuropathy among others)
Pathogenic, heterozygous LOF variants seem to typically appear only in conjunction with spastic paraplegia w/o cognitive defects (cites Pennings 2020)
Boyle 2021 PMID: 33880452 - reviewed the literature, propose a dominant negative mechanism for AD intellectual disability. increased severity observed w/ missense variants particularly those found experimentally to have a non-motile rigor MT binding phenotype. Note that the het LOF patients described in Pennings 2020 have AD HSP but normal cognition (some evaluated in their 60s).AR HSAN - a truncating variant reported in several families by Riviere 2011 is located in an alternately spliced exon (exon 27 in NM_00244088.2).
Disease | KIF1A-related autosomal dominant neurological disorder (lumped NESCAV OR PEHO syndrome) | |||||
|---|---|---|---|---|---|---|
Inheritance | Autosomal dominant | |||||
Prevalence
| Unknown Source:ORPHA:178469 | |||||
Rapid or full curation? |
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ClinGen Intellectual Disability and Autism GCEP classified 09/24/2020. Moderate by Ambry | ||||||
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 | Dominant negative or GOF suggested
Gabrych 2019 PMID: 31616253 - review… pulled some of the papers above from this article. Did not review in full. | |||||
Penetrance
(list source/PMID) | Unknown Source: | |||||
Age of Onset
(list source/PMID) | Congenital PMID: 32096284, 21376300, | |||||
Severity
| Severe | |||||
Clinical Features | Neuro: Hypotonia, hypertonia, microcephaly, peripheral neuropathy Seizures Cognitive/Behavioral: DD/ID, autism, ADHD, anxiety Gastrointestinal: GERD, constipation Ophth: optic nerve atrophy/hypoplasia, cortical visual impairment, strabismus Urogenital Neuroimaging - abnormal MRI, cerebellar atrophy, corpus callosum atrophy/hypoplasia Other: short stature, scoliosis Sources: PMID: 33880452 | |||||
HPO Terms | ||||||
Gene SOPs & Notes |
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Curation Summary
| The KIF1A gene is associated with several conditions with allelic and phenotypic heterogeneity. KIF1A-related neurological disorder is inherited in an autosomal dominant pattern and is typically caused by de novo missense variants. It is characterized by intellectual disability, developmental delay, hypotonia, hypertonia, microcephaly, peripheral neuropathy, optic nerve atrophy or hypoplasia, cortical visual impairment, abnormal brain MRI, and additional clinical features (PMID: 33880452, 21376300). Heterozygous loss-of-function variants in KIF1A (NM_004321.8) are associated with autosomal dominant hereditary spastic paraplegia, typically without any additional clinical features (PMID: 31488895, 34487232). In addition, variants in KIF1A are associated with autosomal recessive hereditary sensory neuropathy and autosomal recessive spastic paraplegia (PMID: 16434418, 22258533, 21820098). | |||||
Case ID, Curator name, Date, Jira ticket link | Andrea Oza 11.28.2023 D-190115360-BH-4000-P-A |
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