Submission Details

TGFB: Arrythmogenic Right Ventricular Cardiomyopathy Mode of Inheritance: Autosomal dominant inheritance (HP:0000006) HGNC: 11769 MONDO:0016587 Expert Panel: Arrythmogenic Right Ventricular Cardiomyopathy

Eleven papers were reviewed related to TGFB and ARVD (7951245, 15639475, 20864495, 222232248, 20124997, 15639468, 11127465, 12529708, 22878021, 24238504, Rampazzo A. Cardiovasc Res. 2012; 96: 191-194). It all started in 1994 with linkage to markers on chromosome 14q42.3 in a large Italian family (7951245) and followed by linkage to this region in several other Italian families and sequence analysis of candidate genes by the same group in 2000, 2003, 2005 and reviewed in 2012 (11127465, 12529708, 15639475, Rampazzo A. Cardiovasc Res. 2012; 96: 191-194). In six of 28 families linkage to 14q23-q24 was found; in two families, significantly positive lod scores were obtained with markers closely linked to ARVD1 locus (11127465). One family 112 had a LOD score of 5.2 (affected only LOD score of 2.71) another family 119 had a LOD score of 1.51. The critical interval for ARVD1 contained 40 known genes; 6 of them (POMT2, KIAA0759, KIAA1036, C14orf4, TAIL1 and TGFb3) were unsuccessfully screened for pathogenic ARVC mutations in the coding exons (12529708). In family 112 a non-coding variant (Chr14(GRCh37):g.76447266C>T; NM_003239.4(TGFB3):c.-30G>A, in the paper indicated as c.-36G>A) was identified in TGFB. This variant is observed 10 times in 249028 reference alleles from gnomAD. In an unrelated ARVD proband a TGFB variant was found in the 3’UTR (Chr14(GRCh37):g.76425035G>A: NM_003239.4(TGFB3):c.*495C>T, in the paper indicated as c.1723C>T) . This variant was not observed in 30272 reference alleles from gnomAD. Both variants were tested in a Luciferase C2C12 expression assay and both showed a 2.5 times increased activity compared to wildtype (15639475). In the review paper Rampazzo describes that in two unrelated families with linkage to this region showed no mutations in TGFB3 coding sequences, UTRs and promoter region and that in one of these two families, a large deletion encompassing the entire PKP2 gene was identified (15639475). Two coding variants of unknown significance were observed in this gene in two ARVD probands in another study (24238504). Total genetic evidence points calculated = 1.2; Total experimental evidence points calculated = 1; Total awarded points = 2.2; Final classification = Limited.