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Further delineation of KIF21B-related neurodevelopmental disorders

Abstract

Kinesin Family Member 21B (KIF21B) encoded by KIF21B (MIM*608322), belongs to the Kinesin superfamily proteins, which play a key role in microtubule organisation in neuronal dendrites and axons. Recently, heterozygous variants in KIF21B were implicated as the cause of intellectual disability and brain malformations in four unrelated individuals. We report a 9-year-old male with delayed speech, hyperactivity, poor social interaction, and autistic features. A parent-offspring trio exome sequencing identified a novel de novo rare heterozygous variant, NM_001252102.2: c.1513A>C, p.(Ser505Arg) in exon 11 of KIF21B. In vivo functional analysis using in utero electroporation in mouse embryonic cortex revealed that the expression of Ser505Arg KIF21B protein in the cerebral cortex impaired the radial migration of projection neurons, thus confirming the pathogenicity of the variant. Our report further validates pathogenic variants in KIF21B as a cause of neurodevelopmental disorder.

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Acknowledgements

We thank the family for their co-operation. This work was funded by grants from INSERM (ATIP-Avenir programme, JDG), the French state funds through the Agence Nationale de la Recherche under the project JCJC CREDO ANR-14-CE13-0008-01 (JDG) and the programme Investissements d’Avenir labelled (ANR-10-IDEX-0002-02, ANR-10-LABX-0030-INRT, to JDG), INSERM/CNRS and University of Strasbourg. This work of the Interdisciplinary Thematic Institute IMCBio, as part of the ITI 2021-2028 programme of the University of Strasbourg, CNRS and Inserm, was supported by IdEx Unistra (ANR-10-IDEX-0002), and by SFRI-STRAT’US project (ANR 20-SFRI-0012) and EUR IMCBio (ANR-17-EURE-0023) under the framework of the French Investments for the Future Program. JRA was funded through the IGBMC PhD programme (ANR-10-IDEX-0002-02, ANR-10-LABX-0030-INRT). JRA is currently supported by the Fondation pour la recherche médicale. PT is a research assistant at the University of Strasbourg. JDG is INSERM investigator. We are grateful to the mouse facility of the Institut Clinique de la Souris (ICS) for taking care of the mice, to the Molecular Biology service of the IGBMC (in particular Thierry Lerouge) for their collaboration in making the plasmids used in this study and to Noémie Schwaller for her technical help. We acknowledge the National Institutes of Health, United States for funding the study titled, ‘Genetic Diagnosis of Neurodevelopmental Disorders in India’ (1R01HD093570-01A1). DLN is a DBT/Wellcome Trust India Alliance Early Career Clinical and Public Health Research Fellow.

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DLN collected clinical data, and drafted the manuscript. JRA performed the experiments on mice and analyzed the data. PT performed experiments on mice. MCdR did in-silico modeling. VB was involved in collecting clinical information. JDG and AS supervised the work and design of research.

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Correspondence to Juliette D. Godin or Anju Shukla.

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Narayanan, D.L., Rivera Alvarez, J., Tilly, P. et al. Further delineation of KIF21B-related neurodevelopmental disorders. J Hum Genet 67, 729–733 (2022). https://doi.org/10.1038/s10038-022-01087-0

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