KLF13 loss-of-function variation contributes to familial congenital heart defects

Congenital heart defect (CHD) represents the most common form of human developmental abnormality and contributes to substantial morbidity, mortality, and socioeconomic burden worldwide. Accumulating evidence underscores the strong genetic basis of CHD. Nevertheless, CHD is of pronounced genetic heterogeneity, and the genetic determinants underlying CHD in most patients are still unclear. This study was mainly sought to identify the causative gene for CHD in a consanguineous Chinese family.

Whole-exosome sequencing and bioinformatics analyses were performed in a Chinese family with CHD (double-outlet right ventricle and ventricular septal defect), which was transmitted in an autosomal dominant pattern. A total of 312 unrelated healthy individuals were then genotyped for the identified genetic variation. The functional effect of the identified variation was characterized by utilizing a Dual-Luciferase reporter assay system.

A novel heterozygous variation, NM_015995.3: c.370G>T; p.(Glu124*), was identified in the KLF13 gene, which encodes Kruppel-like factor 13 key to proper heart development. Genetic analysis of the pedigree unveiled that the variation co-segregated with CHD, with complete penetrance. The variation was absent from 624 control chromosomes. The biological analysis revealed that the Glu124*-mutant KLF13 protein failed to transactivate its cardiac target genes ACTC1 and ANP. Furthermore, the variation disrupted the synergistic transactivation between KLF13 and GATA4, as well as GATA6, two other genes that have been recognized to cause CHD.

These findings firstly indicate that genetically defective KLF13 predisposes to familial CHD, implying potential implications for genetic counseling and an improved prophylactic strategy in a subset of CHD patients.