New variants and genotype-phenotype correlation in <i>KIF5A</i> mutation: the contribution of a large Italian cohort.

Abstract

Variants in the Kinesin-family member 5A (<i>KIF5A)</i> gene are associated with a range of motor diseases, and a strong correlation between the protein domains (motor, stalk and tail) and the clinical phenotype has been proposed. However, several studies have reported exceptions contributing to a complex genotype-phenotype correlation in recent years. Further studies are needed to improve our knowledge about the prevalence of <i>KIF5A</i> variants and their genotype-phenotype correlation. 390 patients (220 hereditary spastic paraplegia, 80 Charcot-Marie-Tooth disease type 2 and 90 amyotrophic lateral sclerosis) have been selected for next-generation sequencing Clinical Exome. Five patients have been found to carry causative variants in the <i>KIF5A</i> gene. Of these, three are familiar cases, and two are sporadic. Segregation analysis was performed on the familiar probands. The five patients with pathogenic variants represent 4% of the studied population, and the clinical and genetic analysis of these five families allowed us to examine different scenarios.Some of these data support the hypothesis of a complex correlation between domains and disease. These data confirm the complex genotype-phenotype correlation, both in terms of clinical heterogeneity associated with a specific domain and variability within the members of the same family, but also suggest a strong genotype-phenotype correlation, both intrafamiliar and interfamiliar, produced by a few variants.