KIF5A variant in familial dystonia: A clinicogenetic study of a large Roma kindred

Mutations in the KIF5A gene were associated with several neurological diseases, including hereditary spastic paraplegia type 10, Charcot-Marie-Tooth type 2, amyotrophic lateral sclerosis, and neonatal intractable myoclonus. To date, none of the KIF5A variants was linked with dystonia. This study presents the first family with autosomal-dominant dystonia exhibiting incomplete penetrance, potentially linked to a KIF5A variant.

Seven family members were recruited between 2017 and 2024. Detailed medical history and neurological examination were conducted for all. Genetic screening, including Sanger sequencing, MLPA analysis of SGCE, and PCR RFLP/BseRI for the common dystonia TOR1A mutation (c.907-909del), followed by whole exome sequencing, was performed on the proband and one affected relative. The genetic status of the remaining five individuals was assessed with Sanger sequencing.

A missense variant in the KIF5A c.118G > A was found in four affected and one asymptomatic individual, while it was absent in two non-affected individuals. The variant is rare in the general population (0.00001 in gnomAD 4.0), affects a highly conserved amino acid, and in silico models (M-CAP) indicates it is pathogenic. It was classified as likely pathogenic per ACMG criteria (PM1, PM2, PP2, PP3).

Our study suggests that KIF5A could represent a potential dystonia gene and sheds light on the broader role of motor proteins in human health and disease. This further expands the phenotypes associated with KIF5A and highlights the importance for clinicians to include this variant in their screening panels, as it tends to be underrepresented in current databases.