Compound heterozygous loss-of-function mutations in KIF20A are associated with a novel lethal congenital cardiomyopathy in two siblings

• Published in: PLoS genetics Vol. 14; no. 1; p. e1007138
• Main Authors: Louw, Jacoba J, Nunes Bastos, Ricardo, Chen, Xiaowen, Verdood, Céline, Corveleyn, Anniek, Jia, Yaojuan, Breckpot, Jeroen, Gewillig, Marc, Peeters, Hilde, Santoro, Massimo M, Barr, Francis, Devriendt, Koenraad
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 22.01.2018; Public Library of Science (PLoS)
• Subjects: Adenosine triphosphatase; Aurora B protein; Biochemistry; Biology; Biology and Life Sciences; Birth defects; Cardiology; Cardiomyopathies - congenital; Cardiomyopathies - genetics; Cardiomyopathy; Cardiovascular disease; Cell division; Chromatin; Congenital diseases; Cytokinesis; Danio rerio; Female; Frameshift mutation; Funding; Gene mutation; Genes; Genes, Lethal; Genetic aspects; Genetics; Genomes; Grants; Health aspects; Heart; Heterozygote; Humans; Infant; Infant Death; Kinases; Kinesins - genetics; Linkage analysis; Male; Medical research; Medicine and Health Sciences; Mutation; Mutation, Missense; Myocardial diseases; Neonates; Pediatrics; Pedigree; Phenotypes; Physiological aspects; Pregnancy; Proteins; Recurrence; Research and Analysis Methods; Siblings; Single-nucleotide polymorphism; Studies; Supervision; Typing; Ventricle; United Kingdom > UK; Belgium
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1007138

Congenital or neonatal cardiomyopathies are commonly associated with a poor prognosis and have multiple etiologies. In two siblings, a male and female, we identified an undescribed type of lethal congenital restrictive cardiomyopathy affecting the right ventricle. We hypothesized a novel autosomal recessive condition. To identify the cause, we performed genetic, in vitro and in vivo studies. Genome-wide SNP typing and parametric linkage analysis was done in a recessive model to identify candidate regions. Exome sequencing analysis was done in unaffected and affected siblings. In the linkage regions, we selected candidate genes that harbor two rare variants with predicted functional effects in the patients and for which the unaffected sibling is either heterozygous or homozygous reference. We identified two compound heterozygous variants in KIF20A; a maternal missense variant (c.544C>T: p.R182W) and a paternal frameshift mutation (c.1905delT: p.S635Tfs*15). Functional studies confirmed that the R182W mutation creates an ATPase defective form of KIF20A which is not able to support efficient transport of Aurora B as part of the chromosomal passenger complex. Due to this, Aurora B remains trapped on chromatin in dividing cells and fails to translocate to the spindle midzone during cytokinesis. Translational blocking of KIF20A in a zebrafish model resulted in a cardiomyopathy phenotype. We identified a novel autosomal recessive congenital restrictive cardiomyopathy, caused by a near complete loss-of-function of KIF20A. This finding further illustrates the relationship of cytokinesis and congenital cardiomyopathy.