ID2 – Congenital Heart Disease

ID2 encodes an inhibitor of differentiation helix–loop–helix transcription factor that participates in cell fate decisions during cardiac morphogenesis. A chromosomal microarray analysis of 78 syndromic congenital heart disease patients lacking 22q11.2 deletion identified clinically significant copy number variations ≥300 kb in 10% (8/78) of cases (PMID:28336264), with implicated regions spanning multiple developmental loci including ID2 and other cardiac transcription factors. The CNVs included both deletions and duplications overlapping ID2, supporting a dosage-sensitive role in heart development. However, this cohort-level CMA lacked locus-specific breakpoint mapping and did not resolve which CNV type was most contributory. No families with segregating ID2-specific CNVs were reported, precluding segregation analysis. Therefore, while ID2 emerges as a candidate gene, variant-level causality remains unresolved.

To date, no sequence variants or targeted gene panels have identified ID2-specific pathogenic alleles in congenital heart disease, and no functional assays have been performed in a cardiac context. The absence of mechanistic in vitro or in vivo studies limits insights into the impact of ID2 haploinsufficiency or overexpression on cardiomyocyte differentiation and heart structure. Given its established role in regulating cardiogenic gene networks, such as repressing basic helix–loop–helix factors during ventricular specification, ID2 dosage perturbation is biologically plausible in CHD. Nevertheless, conclusive evidence requires breakpoint-defined variants, familial segregation, and functional validation in relevant cardiac models. Key take-home: ID2 resides within pathogenic CNVs in a subset of syndromic CHD cases and represents a candidate for diagnostic testing pending further functional and genetic confirmation.

References

• Jornal de pediatria • 2017 • Genomic imbalances in syndromic congenital heart disease. PMID:28336264

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