IRX4 – congenital heart disease

Limited case-level and functional data support a role for IRX4 in autosomal dominant congenital heart disease. Chromosomal microarray analysis in 78 CHD patients with extra-cardiac anomalies (excluding 22q11.2 deletion) identified clinically significant CNVs ≥300 kb in 8/78 individuals, one of which encompassed IRX4 among other cardiac genes (PMID:28336264). Although these CNVs implicate a potential dosage effect, they do not isolate IRX4 as the sole driver.

Sequencing of IRX4 in 698 CHD cases versus 250 controls revealed two unrelated probands harboring missense variants (c.253A>T (p.Asn85Tyr)) that significantly impair IRX4–RXRA interaction in mammalian two-hybrid assays (PMID:21544582). Irx4⁻/⁻ mice develop ventricular dysfunction, mirroring human cardiomyopathy and supporting haploinsufficiency. Overall, genetic evidence remains limited by small case counts and lack of segregation; however, concordant functional data provide moderate support. Key take-home: IRX4 variant screening may aid in diagnosis of ventricular septal defects but requires further validation.

References

• Jornal de pediatria • 2017 • Genomic imbalances in syndromic congenital heart disease. PMID:28336264
• Human genetics • 2011 • Two novel mutations of the IRX4 gene in patients with congenital heart disease. PMID:21544582

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