Neuropediatrics 2021; 52(S 01): S1-S53
DOI: 10.1055/s-0041-1739693
Freier Vortrag

Novel Biallelic Variants in KIF21A Cause a Novel Phenotype of Fetal Akinesia with Neurodevelopmental Defects

Sebahattin Cirak
1   Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
2   Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine, University of Cologne, Germany
,
Özkan Özdemir
1   Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
2   Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine, University of Cologne, Germany
3   Department of Medical Genetics, Faculty of Medicine, Acıbadem Mehmet Ali Aydınlar University, Istanbul, Turkey
4   Department of Genome Studies, Acıbadem Mehmet Ali Aydınlar University, Institute of Health Sciences, Istanbul Turkey
,
Hülya-Sevcan Daimagüler
1   Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
2   Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine, University of Cologne, Germany
,
Ezgi Karaca
5   Izmir Biomedicine and Genome Center, Izmir, Turkey
6   Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Turkey
,
Rosanne Sprute
1   Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
2   Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine, University of Cologne, Germany
,
Matthias Pergande
1   Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
2   Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine, University of Cologne, Germany
,
Thomas Lücke
7   Universitätskinderklinik Bochum, Germany
,
Jaya Punetha
8   Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
,
Pascal Joset
9   Institute of Medical Genetics, University of Zurich, CH-8952, Schlieren, Switzerland
,
Priya T. Bhola
10   CHEO Research Institute, University of Ottawa, Ottawa, Ontario, Canada
,
Anna Kostera-Pruszczyk
11   Department of Neurology, Medical University of Warsaw, Warsaw, Poland
,
Peter Nürnberg
2   Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine, University of Cologne, Germany
12   Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany
,
Jennifer E. Posey
8   Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
,
Anita Rauch
9   Institute of Medical Genetics, University of Zurich, CH-8952, Schlieren, Switzerland
,
Kym D. Kernohan
10   CHEO Research Institute, University of Ottawa, Ottawa, Ontario, Canada
,
Anju Shukla
13   Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India
,
James R. Lupski
8   Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
14   Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States
15   Texas Children's Hospital, Houston, Texas, United States
16   Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States
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    Background: Fetal akinesia (FA) is a complex disease entity, sharing arthrogryposis as a common feature.

    Methods: Using whole-exome-sequencing, we identified eight mutations that are loss of function mutations predicted to cause premature stop codon or essential splice site mutations that would lead to aberrant KIF21A isoforms.

    Results: We report five unrelated individuals with bi-allelic variants in the kinesin family member 21A gene (KIF21A), a member of the kinesin-4 family that is functional in axon growth and guidance by transporting cargo anterograde to the synapses. We showed that the affected individuals with those variants had severe phenotypes with neurodevelopmental disorder, structural brain abnormalities, arthrogryposis of multiple joints, muscular hypotonia, and hypokinesia. Furthermore, all these phenotypes strongly correlate with the recently published porcine phenotype that also has bi-allelic truncating variants, with a few of patients showing features of a neuropathy.

    Discussion: In contrast with our findings, previous reports have indicated that the known phenotypic effect of KIF21A caused by the heterozygous variants that lead to missense mutations or deletions and are significantly clustered in the motor domain or coiled-coil region of KIF21A, which in turn causes an isolated ophthalmologic phenotype with congenital fibrosis of the extraocular muscles type 1 (CFEOM1). Conclusively, we describe a novel disease in the FA spectrum with a primary neurogenic defect due to biallelic variants in the KIF21A.


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    No conflict of interest has been declared by the author(s).

    Publication History

    Article published online:
    28 October 2021

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