Dominant cardioskeletal titinopathies reflect distinct mechanisms of disease

We identified novel dominant skeletal/cardioskeletal titinopathies segregating in families with single truncating, splice-site or deletion TTN variants. To investigate mechanism of disease. Tibialis anterior biopsies were studied via Western blot, RNASeq, EM, and muscle fiber mechanic studies in 12 cases, 10 controls, and one disease control. Western blot revealed normal full-length and truncated titin in the deletion case (exons 346-362), but only normal titin in the truncating and splice-site cases. TTN transcript levels were reduced in the truncating and deletion cases and in the HMERF control, but normal in the splice-site cases. Skipping of exons 347-361 was observed in the deletion case. Dominant truncating, splice-site or deletion variants appear to result in distinct disease mechanisms in skeletal titinopathies, including dominant negative modes of action. We identified novel dominant skeletal/cardioskeletal titinopathies segregating in families with single truncating, splice-site or deletion TTN variants. To investigate mechanism of disease. Tibialis anterior biopsies were studied via Western blot, RNASeq, EM, and muscle fiber mechanic studies in 12 cases, 10 controls, and one disease control. Western blot revealed normal full-length and truncated titin in the deletion case (exons 346-362), but only normal titin in the truncating and splice-site cases. TTN transcript levels were reduced in the truncating and deletion cases and in the HMERF control, but normal in the splice-site cases. Skipping of exons 347-361 was observed in the deletion case. Dominant truncating, splice-site or deletion variants appear to result in distinct disease mechanisms in skeletal titinopathies, including dominant negative modes of action.