Submission Details

CTNNA3: Arrythmogenic Right Ventricular Cardiomyopathy Mode of Inheritance: Autosomal dominant inheritance (HP:0000006) HGNC: 2511 MONDO:0016587 Expert Panel: Arrythmogenic Right Ventricular Cardiomyopathy

Three papers were reviewed related to CTNNA3 and ARVD (23136403, 21254927, 224213630). In one paper the CTNNA3 gene was analyzed in 76 ARVD probands that were negative for PKP2, DSP, DSG2, DSC2, and JUP. In one of the probands the heterozygous NM_013266.3(CTNNA3):c.281T>A p.(Val94Asp) variant was found. This variant was not observed in 245296 reference alleles from gnomAD and was not present in both healthy parents and brother suggesting that the variant occurred de novo. Unfortunately no information was given about paternity testing or family history for ARVD. Another proband showed the heterozygous variant NM_013266.3(CTNNA3):c.2296_2298del p.(Leu766del). This variant was not found in 30971 reference alleles from gnomAD but was inherited from her father that only showed a mild right ventricular dilation. Her ant inherited the variant as well but she was asymptomatic. Yeast two-hybrid studies with both variants showed some aberrations (23136403). In another paper a missense variant was found in one of 55 Danish ARVD patients. The variant was found 37 times in 276338 (1 times homozygous) reference alleles in gnomAD making it less likely as a causal variant. In addition the proband did carry a missense variant of unknown significance in DSP (21254927). Germline knockout of alphaT-catenin encoded by ctnna3 in the mouse alters PKP2 distribution without affecting other junctional components of the areae Compositae. These mutant mice exhibit progressive dilated cardiomyopathy, gap junction remodelling, and increased sensitivity to ventricular arrhythmia following acute ischaemia, but not spontaneous ARVC (224213630). Total genetic evidence points calculated = 1.5; Total experimental evidence points calculated = 2; Total awarded points = 3.5; Final classification = Limited.