Whole exome sequencing study of families with single atrium and/or single ventricle identifies de novo mutations in CORIN and TTLL10 as potential pathogenic genes.

BACKGROUND

Single atrium and/or single ventricle (SA and/or SV) are severe congenital heart malformations linked to gene mutations, though the underlying genetic mechanisms remain unclear. This study seeks to elucidate these mechanisms.

METHODS

Trio-whole exome sequencing (trio-WES) was performed to identify de novo mutations in 36 familial SA/SV cases. Identified genes were analyzed using Gene Ontology (GO), KEGG pathways, and protein-protein interaction (PPI) analyses. Pathogenicity predictions were performed using established databases, and key de novo mutations were validated via Sanger sequencing. Zebrafish morpholino (MO) knockdown experiments were utilized to assess the functional impact of candidate genes.

RESULTS

Trio-WES analysis identified 183 candidate genes harboring de novo single nucleotide variants (SNVs), with 24 genes linked to congenital heart disease (CHD) and enriched in the heart morphogenesis signaling pathway. Screening through a deleterious variants database revealed ten de novo SNVs, eight of which were confirmed by Sanger sequencing. Subsequent screening using mouse, zebrafish, and cardiac single-cell databases highlighted two genes: CORIN and TTLL10. Zebrafish knockdown experiments showed cardiac defects and altered heart rate, supporting their involvement in SA/SV development.

CONCLUSIONS

Our findings suggest that mutations in de novo genes play a critical role in cardiac development, offering insights into SA/SV mechanisms and potential diagnostic targets.