KIF1A Gene Curation
- Andrea Oza
KIF1A conditions seem to have overlap.
Lumping/Splitting: decided to split given there are different inheritance patterns, variant types, and variant 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 or pathogenic variants from HGMD 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).
Disease | KIF1A-related autosomal dominant neurological disorder (lumped NESCAV OR PEHO syndrome) |
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Inheritance | Autosomal dominant |
Prevalence | Unknown Source:ORPHA:178469
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Rapid or full curation? | Rapid Full |
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 (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed | 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 Complete (100%) High (≥80%) Moderate (<80% and >20%) Low (≤20%) (list source/PMID) | Unknown Source: |
Age of Onset Congenital Pediatric Adolescent Adulthood Late adulthood (list source/PMID) | Congenital PMID: 32096284, 21376300, |
Severity Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete. | 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 |
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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 |
Disease | KIF1A-related autosomal dominant hereditary spastic paraplegia |
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Inheritance | Autosomal dominant |
Prevalence |
Source: |
Rapid or full curation? | Rapid Full |
Mentioned in ClinGen Intellectual Disability curation. GenCC - Strong by Ambry. Not in BabySeq curation. Reviewed the LOF HGMD variants below: | |
Clinical Validity Scoring Notes and points | 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 LOF VARIANTS: Pennings 2020 PMID:31488895 - Exome sequencing performed in heredtiary spastic paraplegia cohort from Netherlands.
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. 2 points PMID: 31512412 - c.275_276insAA p.(Cys92*) - de novo variant found in a girl with features of Rett syndrome: Developmental delay, Did not achieve independent ambulation and absent speech at 13 months of age. Microcephaly. Hand clapping and mouthing, loss of hand skills, grinding teeth, breathing, and sleeping disturbance appeared around 8 months of age. Brain MRI was normal. No points:
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Clinical Validity Points Total | 14 points |
Clinical Validity Classification | Strong PMID: 31488895 |
Molecular Mechanism | Loss of function - see Scoring Notes and PoInts above for details. PMID: 31488895, 34487232
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Penetrance (list source/PMID) | Unknown Source: |
Age of Onset (list source/PMID) | Childhood - adulthood PMID: 31488895 |
Severity | Moderate |
Clinical Features | Slowly progressive hereditary spastic paraplegia, typically without any additional clinical features such as cognitive deficits. Sources: 31488895 |
HPO Terms |
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Gene SOPs & Notes | SEE ABOVE |
Curation Summary | SEE ABOVE |
Case ID, Curator name, Date, Jira ticket link | Andrea Oza 11.28.2023 D-190115360-BH-4000-P-A |
Disease | KIF1A-related autosomal recessive hereditary sensory neuropathy |
|---|---|
Inheritance | Autosomal recessive |
Prevalence |
Source: |
Rapid or full curation? | Rapid Full |
Mentioned in ClinGen Intellectual Disability curation. GenCC - Limited by Ambry | |
Clinical Validity Scoring Notes and points | Ghafoor 2022 PMID: 36282036 - NM_004321.8:c.2658delC p.(Val887Serfs*89) (not in the alternatively spliced exon- article requested and saved in our publication library. Absent gnomAD, NMD+. Per abstract, SNP analysis to find ROH followed by exome identified the variant in a family with severe manifestations of HSAN. Severe phenotype included developmental delay, hypoalgesia, decreased temperature sensation, dryness of skin which observed in individuals of the family, ulceration of limbs at the age of eight years with subsequent amputation. Het carriers did not have neuropathy symptoms, but had scaly skin. 2 POINTS Riviere 2011 PMID: 21820098 - Homozygosity mapping followed by KIF1A sequencing in Afghan family, then testing in 112 additional unrelated HSAN cases.
PMID: 31734026
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Clinical Validity Points Total | 7 points |
Clinical Validity Classification | Moderate |
Molecular Mechanism | Unknown, LOF suspected, but due to alternately spliced exon, not certain 2 NMD+ variants and one NMD-
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Penetrance (list source/PMID) |
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Age of Onset (list source/PMID) |
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Severity |
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Clinical Features |
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HPO Terms |
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Gene SOPs & Notes | SEE ABOVE |
Curation Summary |
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Case ID, Curator name, Date, Jira ticket link | Andrea Oza 11.28.2023 D-190115360-BH-4000-P-A |
Disease | KIF1A-related autosomal recessive spastic paraplegia |
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Inheritance | Autosomal recessive |
Prevalence |
Source: |
Rapid or full curation? | Rapid Full |
Mentioned in ClinGen Intellectual Disability curation. GenCC - Strong by Ambry | |
Clinical Validity Scoring Notes and points |
Erlich 2011 PMID: 21487076 - c.764C>T Ala255Val (absent gAD, REVEL=0.814) A Palestinian family (parents from same village, but no known consanguinity), with HSP. Genotyping to find ROH performed, then candidate genes were reviewed and selected KIF1A for sequencing via Sanger. Three sibs homozygous, parents and four unaffected heterozygous. (0.25^2)*(0.75^4)= 0.019775 0 points seg, 0.5 VARIANT POINTS. Lee 2023 PMID: 37001573 - NM_001244008.1:c.2751_2753delGGA Glu917del absent gnomAd Korean family with mild HSP underwent WES. Variant has high freq in gnomAD did not review further. gnomAD YONEKAWA 1998 - PMID 9548721 - KO MOUSE, showed motor and sensory disturbances, died within a day of birth. In nervous system of mutant mice, the transport of synaptic vesicle precursors showed a specific and significant decrease. marked neuronal degeneration and death occurred both in KIF1A mutant mice and in cultures of mutant neurons. 2 points mouse model LEE 2015 PMID: 25265257 - FIG 4. Recessive variants A255V and R350M, both variants showed increased proximal distribution compared to WT. +0.5 experimental points for both variants - 1 POINT. Calculating segregation manually due to family FSP1079 - 0.015625*0.019775*0.003707885= 0.00000114 likelihood, 3 points seg per https://docs.google.com/spreadsheets/d/1ynxrqsKevXAUMOkEK22Fflse_Ql2u_W_PXhR-LX6ua4/edit#gid=1134334
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Clinical Validity Points Total | 7.5 |
Clinical Validity Classification | MODERATE |
Molecular Mechanism | UNKNOWN |
Penetrance (list source/PMID) |
Source: |
Age of Onset (list source/PMID) |
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Severity |
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Clinical Features |
Sources: |
HPO Terms |
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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 | SEE ABOVE |
Case ID, Curator name, Date, Jira ticket link | Andrea Oza 11.28.2023 D-190115360-BH-4000-P-A |