Inheritance

Autosomal dominant

Prevalence

 Unknown

Source:ORPHA:178469

Rapid or full curation?

•  Rapid
•  Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

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

• Most variants are missense, predominantly located in the motor domain of the protein, De novo variants in this gene result in more severe phenotype. Het LOF variants appear to be causative for AD hereditary spastic paraplegia with normal cognition, MRIs, no history of visual problems or seizures (PMID: 33880452)

• GOF: KIF1A mutations associated with the hereditary SPG lead to hyperactivation of KIF1A motility. Introduction in C. elegans revealed abnormal accumulation of SVPs (synaptic vesicle precursors) at the tips of axons and increased anterograde axonal transport of SVPs. PMID: 31455732

• DN: KIF1A can be converted into a functional dimer. When co-expressed with WT in hipocamppal neurons, E253K resulted in a dramtically reduced level of expression of KIF1A-MD-E253K only (see fig 7) PMID: 28970574

• Boyle 2021 PMID: 33880452 - Increased severity is strongly associated with variants occuring in protein regions involved with ATP and MT binding (P loop, switch I, and switch II). Functional studies using recombinant proteins found that all variants result in defects in protein transport and they describe three classes - reduced MT binding, reduced velocity and processivity, and increased non-motile rigor MT binding. Rigor phenotype was associated with more severe clinical phenotype, reduced MT binding was associated with milder phenotypes.

  

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

https://hpo.jax.org/app/

Gene SOPs & Notes

• Determining which condition a variant is associated with is dependent on variant type and any prior clinical evidence reported for the variant.

• LOF variants are reported in AD hereditary spastic paraplegia; however the molecular mechanism for the remaining conditions (AD neurological / syndromic ID disorder, AR HSAN and AR HSP) is unknown.

• BEWARE OF LOF VARIANTS IN ALTERNATE ISOFORM: In addition, a single LOF variant in alternatively spliced exon 27 (NM:001244008.2) has been reported in individuals with AR HSAN. Limited evidence for this gene-disease relationship but it could potentially explain the difference in phenotype.

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 have been associated with autosomal dominant hereditary spastic paraplegia, typically without any additional clinical features (PMID: 31488895, 34487232). In addition, variants in KIF1A have been described in 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

Inheritance

Autosomal recessive

Prevalence

Source:

Rapid or full curation?

•  Rapid
•  Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

Mentioned in ClinGen Intellectual Disability curation. GenCC - Limited by Ambry

Clinical Validity Scoring Notes and points

Ghafoor 2022 PMID: 36282036 - c. 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

Clinical Validity Classification

Clinical Validity Points Total

• 2 POINTS (ALT EXON)

• NM_001244008.1:c.5271dupC p.(Ser1758Glnfs*7) (NMD- in exon 48, absent gnomAD, P in ClinVar by OMIM)- compound het in trans with c.2840delT Leu947Argfs*4 in family 4 per fig 4. 1 POINTS

PMID: 31734026

• NM_001244008.2:c.3871C>T p.R1291C - MAF seems too high 0.1%, 69/43308 East Asian chr in gnomAD v4, did not review papers further. Found in a patient with NM_001244008.2:c.3898G>A p.V1300M - 0.05% 33/42690 East Asian chr in gnomAD v4, REVEL 0.523 found in cohort of patients with SMA like symptoms. Walking disturbance, plantar sensory loss PER TABLE 2. Found via sanger per text. Not scoring either variant due to MAF.

Clinical Validity Points Total

5 POINTS

Clinical Validity Classification

LIMITED

Molecular Mechanism

Penetrance

(list source/PMID)

Age of Onset

(list source/PMID)

Severity

Clinical Features

Sources:

HPO Terms

https://hpo.jax.org/app/

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

Andrea Oza 11.28.2023 D-190115360-BH-4000-P-A