SORBS2 – Congenital Heart Disease

SORBS2 has a Limited ClinGen validity for association with congenital heart disease based on a single clinically significant CNV encompassing SORBS2 identified in 1 of 78 patients with syndromic CHD and negative for 22q11.2 deletion (PMID:28336264). No multi-family segregation or recurrent independent probands have been reported, and only one proband harbors a relevant CNV region.

Genetic evidence is Limited: a heterozygous duplication including SORBS2 was found in one proband with CHD; no additional segregation data or point mutations have been described in CHD cohorts.

Functional studies provide Moderate support: Sorbs2 knockout mice demonstrate profound disruption of intercalated disc integrity and manifest right ventricular dilation, dysfunction, arrhythmias, and premature death, consistent with a critical role in cardiac structural integrity (PMID:32808564).

No conflicting evidence has been reported to date.

In summary, while functional data support a role for SORBS2 in cardiac tissue integrity, human genetic evidence for congenital heart disease remains limited. Further studies are required to establish causality definitively.

Key take-home: SORBS2 haploinsufficiency from rare CNVs may contribute to congenital heart disease, but additional cases and segregation analyses are needed for confirmation.

References

• Jornal de pediatria • 2017 • Genomic imbalances in syndromic congenital heart disease PMID:28336264
• Journal of the American Heart Association • 2020 • Knockout of SORBS2 Protein Disrupts the Structural Integrity of Intercalated Disc and Manifests Features of Arrhythmogenic Cardiomyopathy PMID:32808564

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