Abstract 18532: Cardiomyopathy Diagnoses in a General Population Study of TTN Pathogenic Variants: A Missed Opportunity to Diagnose Familial Cardiomyopathy?

Introduction: Intermountain Health’s HerediGene Population Study has been collecting samples from over 175,000 individuals since 2018 to identify those that could potentially benefit from early interventions. Variants in the TTN gene are the most common genetic causes of cardiomyopathy (CM). Here we examined all individuals with TTN pathogenic or likely pathogenic variants to determine differences in clinical characteristics among those with and without a clinical CM diagnosis (Dx).

Methods: Whole genome sequence was analyzed in 32,159 individuals. 411 (1.3%) had a pathogenic/likely pathogenic TTN variant . Of these 135 (32.8%) had a CM Dx and 276, (67.2%) did not. Differences in health histories, ECHO results, treatments, and major CV events were evaluated by presence or absence of CM Dx using the chi-square, Fisher exact, and Wilcoxon rank sum tests.

Results: Demographic and clinical characteristics were significantly different among those with and without a CM Dx (Table). In those without CM Dx, a total of 75 (27%) had some clinical indication of potential CM: 37 having a BNP ≥100, 7 had an LVIDd ≥ 5.5, 33 with an EF ≤55%, 3 experiencing cardiac arrest, and 45 with a heart failure Dx. Of these, 21 (28%) had 2 of these indications, 13 (17%) had 3 indications, and 1 (1%) had 4 indications. Among these with indication of CM without a Dx, 12 (16%) have died, and 22 (23%) have been hospitalized for heart failure. Only 8 individuals had a clinical genetic test for CM with a positive result for TTN variant.

Conclusion: About 1/3 of potential pathogenic TTN variant carriers had a CM Dx and 27% without a CM Dx had indication of possible CM. A small percentage of TTN variant carriers with a CM Dx and none of those with possible CM have undergone clinical genetic testing. This demonstrates a missed opportunity to diagnose potential TTN -related familial CM for earlier intervention and treatment of patients and family members.