Genotype-phenotype correlations in 18 European patients with heterozygous KIF1A variants: key considerations for assessing KIF1A variant causality.

Background: Variants in the KIF1A have been associated with a wide range of phenotypes. Most variants are found in the protein's motor domain. The clinical phenotype of KIF1A-associated disorders (KAND) correlates with the position and the type of variant. Missense variants in the motor domain are predominantly associated with severe phenotypes and often occur de novo. Methods: Patients from the Czech Republic and Switzerland were identified during DNA diagnostics for neuromuscular or neurodevelopmental disorders. Clinical and genetic data were analyzed retrospectively. Results: A total of 18 patients with heterozygous KIF1A variants were reported. The clinical spectrum ranges from a very severe congenital phenotype to mild spastic paraplegia or early-onset slowly progressive neuropathy. Among patients with early clinical manifestation (n = 13; congenital symptoms, gross motor delay, complicated/pure spastic paraplegia, neuropathy), all detected variants were missense and localized in the motor domain, eight times confirmed to be de novo. In individuals with adult onset (n = 5; all spastic paraplegia), a frameshift variant outside the motor domain was also detected in one case. Conclusion: KAND phenotypes are not only limited to severe and early-onset phenotypes but also include adult-onset less severe ones. The localization of a missense KIF1A variant in the motor domain corresponds with a more severe disease, but not exclusively. Given the broad phenotypic spectrum associated with KIF1A variants, each variant should be individually evaluated for pathogenicity. Based on our findings, we propose a supporting algorithm outlining key considerations to support variant causality and the prediction of the associated phenotype.