LEFTY2 — Visceral Heterotaxy

LEFTY2 encodes Left-Right Determination Factor 2, a secreted TGF-β ligand critical for embryonic left–right axis formation. In a cohort of 47 individuals with Visceral Heterotaxy and congenital cardiac anomalies, coding regions of LEFTY2 were sequenced but no pathogenic variants were identified, whereas variants in ZIC3 and ACVR2B accounted for approximately 8.5% of cases (PMID:21864452). No familial segregation of LEFTY2 alleles or functional deficits have been reported to date.

The absence of rare coding changes in LEFTY2 across a well-characterized heterotaxy cohort provides limited genetic support for its role in visceral heterotaxy. Furthermore, no expression studies, animal models, or rescue experiments have directly implicated LEFTY2 in human laterality defects. Additional deep-sequencing in larger, ethnically diverse populations and targeted in vivo functional analyses are required to establish any contributory role. Key Take-home: Current evidence is insufficient to justify clinical genetic testing of LEFTY2 for visceral heterotaxy.

References

• Cardiology in the Young • 2012 • Mutations in ZIC3 and ACVR2B are a common cause of heterotaxy and associated cardiovascular anomalies. PMID:21864452

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