Heterozygous KIF1A variants underlie a wide spectrum of neurodevelopmental and neurodegenerative disorders

Francesco Nicita, Monia Ginevrino, Lorena Travaglini, Stefano D'Arrigo, Giovanna Zorzi, Renato Borgatti, Gaetano Terrone, Michela Catteruccia, Gessica Vasco, Vesna Brankovic, Sabrina Siliquini, Silvia Romano, Chiara Veredice, Marina Pedemonte, Michelina Armando, Donatella Lettori, Fabrizia Stregapede, Luca Bosco, Antonella Sferra, Valeria TessarolloRomina Romaniello, Giovanni Ristori, Enrico Bertini, Enza Maria Valente, Ginevra Zanni

Research output: Contribution to journalArticlepeer-review


BACKGROUND: Dominant and recessive variants in the KIF1A gene on chromosome 2q37.3 are associated with several phenotypes, although only three syndromes are currently listed in the OMIM classification: hereditary sensory and autonomic neuropathy type 2 and spastic paraplegia type 30, both recessively inherited, and mental retardation type 9 with dominant inheritance.

METHODS: In this retrospective multicentre study, we describe the clinical, neuroradiological and genetic features of 19 Caucasian patients (aged 3-65 years) harbouring heterozygous KIF1A variants, and extensively review the available literature to improve current classification of KIF1A-related disorders.

RESULTS: Patients were divided into two groups. Group 1 comprised patients with a complex phenotype with prominent pyramidal signs, variably associated in all but one case with additional features (ie, epilepsy, ataxia, peripheral neuropathy, optic nerve atrophy); conversely, patients in group 2 presented an early onset or congenital ataxic phenotype. Fourteen different heterozygous missense variants were detected by next-generation sequencing screening, including three novel variants, most falling within the kinesin motor domain.

CONCLUSION: The present study further enlarges the clinical and mutational spectrum of KIF1A-related disorders by describing a large series of patients with dominantly inherited KIF1A pathogenic variants ranging from pure to complex forms of hereditary spastic paraparesis/paraplegias (HSP) and ataxic phenotypes in a lower proportion of cases. A comprehensive review of the literature indicates that KIF1A screening should be implemented in HSP regardless of its mode of inheritance or presentations as well as in other complex neurodegenerative or neurodevelopmental disorders showing congenital or early onset ataxia.

Original languageEnglish
JournalJournal of Medical Genetics
Publication statusE-pub ahead of print - Jul 31 2020


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