ETS1 – Congenital heart disease

Congenital heart disease (CHD) has a significant genetic component with de novo copy number variants (CNVs) contributing to pathogenesis. In a cohort of 538 CHD trios, 63 validated de novo CNVs were discovered in 51 probands, including a single de novo deletion encompassing ETS1 at 11q24.2-q25, implicating haploinsufficiency of ETS1 in CHD ([PMID:25205790]). No familial segregation has been observed for ETS1 variants in CHD, and recurrence data are absent, consistent with sporadic de novo events.

Functional network analysis demonstrates that ETS1 interacts with established cardiac transcription factors NKX2-5 and GATA4, placing ETS1 within the core regulatory circuitry of cardiac development. Integrative data from Jacobsen syndrome deletions support ETS1 as the likely pathogenic gene at 11q24.2-q25. However, direct in vitro or in vivo functional assays of ETS1 in cardiac morphogenesis remain limited, and additional models are required to confirm causality.

Key Take-home: De novo haploinsufficient loss of ETS1 is a plausible but as yet limited genetic contributor to sporadic CHD, warranting targeted functional studies and screening in larger cohorts.

References

• Circulation Research • 2014 • Increased frequency of de novo copy number variants in congenital heart disease by integrative analysis of single nucleotide polymorphism array and exome sequence data. PMID:25205790

Evidence Based Scoring (AI generated)