Phenotypic heterogeneity associated with KIF21A: Two new cases and review of the literature

Author:

Bhola Priya T.1ORCID,Mishra Radha2,Posey Jennifer E.3ORCID,Hamilton Leslie E.4,Graham Gail E.1,Punetha Jaya3,Lupski James R.3567ORCID,Boycott Kym M.18ORCID,D'Amours Damien2,Kernohan Kristin D.89,

Affiliation:

1. Department of Genetics Children's Hospital of Eastern Ontario Ottawa Canada

2. Department of Cellular and Molecular Medicine, Ottawa Institute of Systems Biology University of Ottawa Ottawa Canada

3. Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas USA

4. Department of Pathology and Laboratory Medicine Children's Hospital of Eastern Ontario and University of Ottawa Ottawa Canada

5. Department of Pediatrics Baylor College of Medicine Houston Texas USA

6. Texas Children's Hospital Houston Texas USA

7. Human Genome Sequencing Center Baylor College of Medicine Houston Texas USA

8. Children's Hospital of Eastern Ontario Research Institute, University of Ottawa Ottawa Canada

9. Newborn Screening Ontario (NSO) Ottawa Canada

Abstract

AbstractOur understanding of genetic and phenotypic heterogeneity associated with the clinical spectrum of rare diseases continues to expand. Thorough phenotypic descriptions and model organism functional studies are valuable tools in dissecting the biology of the disease process. Kinesin genes are well known to be associated with specific disease phenotypes and a subset of kinesin genes, including KIF21A, have been associated with more than one disease. Here we report two patients with KIF21A variants identified by exome sequencing; one with biallelic variants, supporting a novel KIF21A related syndrome with recessive inheritance and the second report of this condition, and another with a heterozygous de novo variant allele representing a phenotypic expansion of the condition described to date. We provide detailed phenotypic information on both families, including a novel neuropathology finding of neuroaxonal dystrophy associated with biallelic variants in KIF21A. Additionally, we studied the dominant variant in Saccharomyces cerevisiae to assess variant pathogenicity and found that this variant appears to impair protein function. KIF21A associated disease has mounting evidence for phenotypic heterogeneity; further patients and study of an allelic series are required to define the phenotypic spectrum and further explore the molecular etiology for each of these conditions.

Funder

Canadian Institutes of Health Research

Children's Hospital of Eastern Ontario Foundation

Genome Alberta

Genome British Columbia

Genome Canada

Génome Québec

National Heart, Lung, and Blood Institute

National Human Genome Research Institute

Ontario Genomics Institute

Ontario Research Foundation

Publisher

Wiley

Subject

Genetics (clinical),Genetics

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