Ataxia and cerebellar anomalies - narrow panel

Gene: KIF1A

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 5 Feb 2023, 5:18 p.m. | Last Modified: 5 Feb 2023, 5:18 p.m.

Panel Version: 3.30

Green List (high evidence)

Comment on list classification: There are sufficient cases (>3) with monoallelic KIF1A variants and cerebellar atrophy and/or ataxia to rate as Green on this panel.

Created: 5 Aug 2021, 4:12 p.m. | Last Modified: 5 Aug 2021, 4:12 p.m.

Panel Version: 2.226

Comment on mode of inheritance: Cerebellar anomalies associated with recessive KIF1A-related HSP are significantly milder than those observed in individuals with dominant HSP or NESCAV syndrome. There are also only 2 families with biallelic variants who presented with the relevant features, which does not reach the threshold for inclusion under this MOI at this time.

For this reason, the MOI has been set to 'monoallelic' only with the 'watchlist_MOI' tag to monitor future evidence linking biallelic variants with cerebellar ataxia.

Created: 5 Aug 2021, 4:12 p.m. | Last Modified: 5 Aug 2021, 4:12 p.m.

Panel Version: 2.225

KIF1A is associated HSP type 30 (MIM# 610357) which can be inherited recessively or dominantly, as well as NESCAV syndrome (MIM# 614255) caused by heterozygous variants in this gene.

Cerebellar signs including: ataxia; dysmetria; and saccadic ocular pursuit, associated with mild cerebellar atrophy, were reported in 2/4 families with recessive HSP (PMID: 21487076; 22258533; 28332297).

Variable ataxic features, cerebellar signs and cerebellar atrophy have been described in multiple cases with the complex forms of dominant KIF1A-related HSP (PMID: 31805580; 32737135), but these features are even more prominent in individuals with NESCAV syndrome (PMID: 25265257; 26125038; 26354034; 32096284; 34121983).

Of note, at least 11 heterozygous cases have been described in which congenital or early onset ataxia with cerebellar signs was the presenting clinical feature (PMID: 26354034; 32737135; 32746806; https://doi.org/10.1016/j.ejpn.2017.04.926)
Sources: Literature

Created: 5 Aug 2021, 4:10 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Spastic paraplegia 30, autosomal dominant, OMIM:610357; Spastic paraplegia 30, autosomal recessive, OMIM:610357; NESCAV syndrome, OMIM:614255

Publications

• 22258533
• 28332297
• 25265257
• 26125038
• 26354034
• 31805580
• 32096284
• 32737135
• 32746806
• 34121983
• https://doi.org/10.1016/j.ejpn.2017.04.926