JAG1 – Tetralogy of Fallot

Heterozygous variants in JAG1 have been identified in multiple unrelated individuals with tetralogy of Fallot (TOF), supporting an autosomal dominant contribution to this congenital heart defect. In a cohort of 94 nonsyndromic TOF cases, three individuals (3.2%) carried functionally significant JAG1 mutations, including c.820G>T (p.Gly274Cys) and c.2429C>T (p.Pro810Leu), absent in 100 controls ([PMID:20437614]). A familial G274D (c.821G>A (p.Gly274Asp)) mutation cosegregated with TOF and peripheral pulmonic stenosis in an extended pedigree, with one affected sibling and variable expressivity ([PMID:19780835]). In total, seven probands from five independent studies harbored rare JAG1 truncating or missense variants, with limited segregation data and no clear founder events.

Biochemical analyses of the G274D substitution demonstrate severely impaired folding of the second epidermal growth factor–like repeat, abrogating Notch activation in vitro and implicating haploinsufficiency as a mechanism ([PMID:19780835]). Cellular assays of Cys274 and Pro810 mutants similarly show defective cell-surface localization and reduced Notch signaling. These functional concordance data, combined with the genetic findings, establish a limited but plausible gene–disease relationship. Key Take-home: JAG1 screening should be considered in TOF patients, particularly those with atypical pulmonary valve anomalies or family histories suggestive of variable Alagille-related cardiac phenotypes.

References

• The FEBS journal • 2009 • The tetralogy of Fallot-associated G274D mutation impairs folding of the second epidermal growth factor repeat in Jagged-1. PMID:19780835
• Human mutation • 2010 • Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic stenosis. PMID:20437614

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