KLF13 – Congenital Heart Disease

Kruppel-like factor 13 (KLF13) has emerged as a key transcriptional regulator in cardiac development and has been implicated in familial forms of congenital heart disease (PMID:33215447). Loss-of-function variants in KLF13 disrupt the transcriptional program of cardiomyocyte differentiation and structural morphogenesis.

Two unrelated autosomal dominant kindreds harboring heterozygous nonsense variants in KLF13 have been described. In a consanguineous Chinese family, a novel truncating variant c.370G>T (p.Glu124Ter) co-segregated with double-outlet right ventricle and ventricular septal defect across three generations, with complete penetrance and absence in 312 controls (PMID:33215447). Independently, a second kindred exhibited c.430G>T (p.Glu144Ter) in a proband with patent ductus arteriosus, ventricular septal defect, and bicuspid aortic valve; this variant was absent in 400 controls and fully co-segregated in the small pedigree (PMID:35369534).

Variant spectrum is dominated by protein-truncating alleles; two recurrent LoF mutations (p.Glu124Ter, p.Glu144Ter) account for the familial cases to date. No missense or deep-intronic variants have been reported in multiple unrelated CHD cohorts.

Functional assays using dual-luciferase reporters demonstrate that Glu124Ter- and Glu144Ter-mutant KLF13 proteins fail to transactivate cardiac target genes (ACTC1, ANP, VEGFA), and abrogate synergistic activation with GATA4, GATA6, and TBX5, supporting a haploinsufficiency mechanism (PMID:33215447; PMID:35369534).

No conflicting reports have been published to date regarding the KLF13–CHD association. Integration of genetic segregation and concordant functional loss supports a strong causal link. KLF13 genetic testing should be considered in familial CHD cases, particularly those with outflow tract anomalies or septal defects.

Key Take-home: Heterozygous truncating variants in KLF13 cause autosomal dominant congenital heart defects via haploinsufficiency, informing genetic counseling and targeted diagnostics.

References

• European review for medical and pharmacological sciences • 2020 • KLF13 loss-of-function variation contributes to familial congenital heart defects. PMID:33215447
• Experimental and therapeutic medicine • 2022 • A novel KLF13 mutation underlying congenital patent ductus arteriosus and ventricular septal defect, as well as bicuspid aortic valve. PMID:35369534

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