Genotype-phenotype correlations in 18 European patients with heterozygous KIF1A variants; Key Considerations for Assessing KIF1A Variant Causality

Anna Uhrova Meszarosova¹Elea Galiart²Petra Lassutova¹Konstantinos Kolokotronis³Benjamin Seidl³Alena Musilova¹Anna Peckova⁴Alena Takacsova⁵Emilie Vyhnalkova⁶Dagmar Grecmalova⁷Eva Vlckova⁸Vladana Skutilova⁹Katarina Steindl³Anita Rauch³Georg M. Stettner¹⁰Dana Safka Brozkova^1*

• ¹Neurogenetic laboratory, Department of Pediatric Neurology, Second Faculty of Medicine Charles University and University Hospital Motol, Prague, Czechia
• ²Neuromuscular Center Zurich and Department of Pediatric Neurology, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland
• ³Institute of medical genetics, University of Zurich, Schlieren, Switzerland
• ⁴Department of Medical Genetics, Masaryk Hospital, Usti nad Labem, Czechia
• ⁵Department of Medical Genetics and Genomics, Faculty Hospital, Brno, Czechia
• ⁶Department of Biology and Medical Genetics, Second Faculty of Medicine Charles University and University Hospital Motol, Prague, Czechia
• ⁷Institute of Molecular and Clinical Pathology and Medical Genetics, University Hospital Ostrava and Institute of Laboratory Medicine, Medical Faculty, Ostrava, Ostrava, Czechia
• ⁸Department of Neurology, Faculty Hospital, Brno, Brno, Czechia
• ⁹Department of Molecular Biology, Faculty Hospital Hradec Kralove, Hradec Kralove, Czechia
• ¹⁰Neuromuscular Center Zurich and Department of Pediatric Neurology, University Children's Hospital Zurich, Zurich, Switzerland

Background: Variants in the KIF1A have been described 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 diagnosed during the DNA diagnostics for neuromuscular or neurodevelopmental disorders. Clinical and genetic data were analysed retrospectively. Results: A total of 18 patients with heterozygous KIF1A variants are reported. The clinical spectrum ranges from a very severe congenital phenotype to mild spastic paraplegia or early onset slowly progressive neuropathy. In 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) also frameshift variant outside the motor domain was detected in one case. Conclusions: KAND phenotypes are not 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 the variant causality and the prediction of the associated phenotype.