This study shows that tTTN-associated DCM is less severe at presentation and more amenable to standard therapy than LMNA mutation-induced DCM or iDCM.

Increasing numbers of patient relatives at risk of developing dilated or hypertrophic cardiomyopathy (DCM/HCM) are being identified and followed up by cardiologists according to the ACC/ESC guidelines. However, given limited healthcare resources, good-quality low-cost alternative approaches are needed. Therefore, we have compared conventional follow-up by a cardiologist with that provided at a cardiogenetic clinic (CGC) led by a genetic counsellor. Phenotype-negative first-degree relatives at risk for DCM/HCM were randomly assigned to see either a cardiologist or to attend a CGC. Uptake and resource use were recorded. For 189 participants, we evaluated quality of care experienced, patient satisfaction and perceived personal control (PPC) using validated questionnaires and estimated the average cost difference of these two modes of care. Maximum patient satisfaction scores were achieved more frequently at the CGC (86% vs 45%, Po0.01). In terms of follow-up care provided, the genetic counsellor did not perform worse than the cardiologist (95% vs 59%, Po0.01). The genetic counsellor more often enquired about the relative-at risk's health (100% vs 65%, Po0.01) and family health (97% vs 33%, Po0.01), measured blood pressure (98% vs 29%, Po0.01) and gave disease-specific information (77% vs 52%, Po0.01). Although PPC scores were equal in both groups, the average cost per patient of CGC follow-up was 25% lower. Follow-up of phenotype-negative relatives at risk for DCM/HCM at a CGC led to greater patient satisfaction and is well-appreciated at lower cost. CGC care is a good alternative to conventional cardiological follow-up for this growing group of patients.

Background In the past decade, we and others have reported three families with rare genetic variants in TNNI3K, encoding the cardiac-specific troponin-I interacting kinase (TNNI3K), co-segregating with a mixed, but highly penetrant, cardiac phenotype that features predominant atrial/junctional tachycardia occurring in combination with cardiac conduction disease and dilated cardiomyopathy. We demonstrated that while the p.Thr539Ala and p.Gly526Asp TNNI3K variants had decreased auto-phosphorylation activity the p.Glu768Lys variant, present in 3 independent families, leads to increased auto-phosphorylation levels, in line with the finding that increased levels of Tnni3k expression are associated with slower atrial-ventricular conduction in mice. Objective Identifying new genetic variants in the TNNI3K gene associated with cardiac disease and assessing their impact on TNNI3K auto-phosphorylation levels. Methods Through next generation sequencing of a panel of genes associated with cardiac disease we assessed TNNI3K in patients with cardiac arrhythmias and cardiomyopathies. All variants identified were assessed in vitro for effects on auto-phosphorylation. Briefly, wild-type and mutant TNNI3K constructs were transfected into HEK293 cells, protein was extracted after 48 hours and analyzed with anti-flag and anti-phospho-tyrosine antibodies on Western blot. Results We identified 7 novel and rare variants in TNNI3K in 11 additional probands, with predominantly cardiac conduction disease, with or without dilated cardiomyopathy, and atrial-ventricular-re-entry-tachycardia (AVNRT). Of these, multiple variants were found to have aberrant auto-phosphorylation including almost absent auto-phosphorylation capacity for one (TNNI3K-p.Val510Leu). All three-independent wild type TNNI3K transfected HEK293 cell lysates showed similar phosphorylated TNNI3K levels and the kinase-dead negative control demonstrated no phosphorylation activity. Conclusion We here present 7 novel genetic variants in TNNI3K in patients with a remarkable overlap in cardiac phenotype consisting mainly of AVNRT and cardiac conduction disease. We further show that some of these variants alter the auto-phosphorylation of TNNI3K. These results indicate a more prevalent role of variants in TNNI3K in human cardiac disease and a possible in vitro functional assay to assess the pathogenicity of such variants. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): The Dutch Research Council (NWO Talent Scheme VIDI-91718361)