Submission Details

RBFOX2 was first reported in relation to autosomal dominant congenital heart disease in 2015 (Homsy et al., PMID: 26785492). At least 5 rare variants (1 missense, 4 loss-of-function) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. RBFOX2 has been noted to be associated with the following disease entities: aortic stenosis/atresia, atrial septal defects, double outlet right ventricle, hypoplastic aortic arch, and hypoplastic left ventricle (OMIM 619657). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism and inheritance pattern. Therefore, these disease entities have been lumped into one disease entity, Autosomal Dominant RBFOX2-related Congenital Heart Disorders. Variants in this gene have been reported in at least 5 probands in 2 publications from the same research consortium (PMIDs 26785492, 28991257), using an allele frequency threshold of 1x10-5. This gene-disease relationship is supported by animal models, expression studies, and functional assays. Expression studies confirmed that RBFOX2 is expressed during zebrafish embryogenesis (PMID 21925157), mouse embryogenesis (PMID 31241461) and in rat cardiac myoblasts (PMID 24151077). Depletion of Rbfox2 in rat cardiac myoblasts mouse cardiomyocytes led to aberrant splicing of target mRNAs (PMIDs 31241461, 31778749). Multiple zebrafish models demonstrated abnormal cardiac development after depletion of rbfox2 and rbfox1l, with rescue of the ventricular hypoplasia after introduction of rbfox2 mRNA (PMIDs 21925157, 36198703). Mouse embryos deficient for Rbfox2 resulted in thin ventricular walls (PMID 35137168). In summary, there is strong evidence to support this gene-disease relationship. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 3/5/24 (SOP Version 10).