Genomics-First Evaluation of Heart Disease Associated With Titin-Truncating Variants

Haggerty, Christopher M.; Damrauer, Scott M.; Levin, Michael G.; Birtwell, David; Carey, David J.; Golden, Alicia; Hartzel, Dustin N.; Hu, Yirui; Judy, Renae; Kelly, Melissa; Kember, Rachel; Kirchner, H. Lester; Leader, Joseph B.; Liang, Lusha W.; McDermott-Roe, Chris; Babu, Apoorva; Morley, Michael; Nealy, Zachariah; Person, Thomas N.; Pulenthiran, Arichanah; Small, Aeron; Smelser, Diane T.; Stahl, Richard C.; Sturm, Amy C.; Williams, Heather; Baras, Aris; Margulies, Kenneth B.; Cappola, Thomas P.; Dewey, Frederick E.; Verma, Anurag; Zhang, Xinyuang; Correa, Adolfo; Hall, Michael E.; Wilson, James G.; Ritchie, Marylyn D.; Rader, Daniel J.; Murray, Michael F.; Fornwalt, Brandon K.; Arany, Zoltàn

doi:10.1161/circulationaha.119.039573

Cited by 104 publications

(110 citation statements)

References 37 publications

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“…In the present study, higher frequency of atrial fibrillation was a predictor for HF recurrence, supporting previous findings of HF risk factors . Sustained atrial fibrillation has also been strongly associated with atrial fibrosis, and a recent study indicated that genetic variants of TTN could cause atrial fibrillation . These findings suggest that cardiomyocyte degeneration can lead to myocardial fibrosis, although the effect is different between atrial and ventricular muscles.…”

Section: Discussionsupporting

confidence: 90%

Long‐term prognostic value of ultrastructural features in dilated cardiomyopathy: comparison with cardiac magnetic resonance

et al. 2020

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Aims This study aims to determine the implications associated with long-term prognosis of heart failure (HF) in patients with dilated cardiomyopathy (DCM) presenting initially as decompensated HF. We stratified the phase of DCM patients without late gadolinium enhancement (LGE) based on ultrastructural changes in cardiomyocytes. Methods and results Left ventricular (LV) endomyocardial biopsy was performed in 55 consecutive DCM patients with initial decompensated HF. Ultrastructural changes in cardiomyocytes detected by electron microscopy were compared with data including LGE with cardiac magnetic resonance and HF recurrence. Of the 55 DCM patients, 24 (44%) showed LGE, and 26 (47%) showed recurrence decompensated HF, while 23 patients (42%) showed autophagic vacuoles in cardiomyocytes by electron microscopy. Multivariate analysis identified atrial fibrillation [hazard ratio (HR), 3.40; 95% confidence interval (CI), 1.45-7.98], haemoglobin level (HR, 0.82; 95% CI, 0.68-0.99), beta-blocker use (HR, 0.18; 95% CI, 0.05-0.74), and autophagic vacuoles (HR, 0.25; 95% CI, 0.09-0.65) as predictors of HF recurrence in the total patient population. In patients without LGE, only autophagic vacuoles were independent predictors of readmission because of HF (HR, 0.29; 95% CI, 0.09-0.90). In patients with LGE, atrial fibrillation (HR, 19.10; 95% CI, 2.97-123.09), and mid-linear LGE (HR, 12.96; 95% CI, 2.02-82.94) were independent predictors of readmission because of HF. Conclusions In DCM patients with LGE, characterised by progression of LV remodelling, the LGE pattern was a predictor of HF recurrence, whereas in patients without LGE, absence of autophagic vacuoles was a predictor of HF recurrence.

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Section: Discussionsupporting

confidence: 90%

Long‐term prognostic value of ultrastructural features in dilated cardiomyopathy: comparison with cardiac magnetic resonance

et al. 2020

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“…In the context of manifest disease, family-based studies demonstrate the incomplete and variable penetrance of ICC variants [ 7 – 9 ]. While genotype-first approaches overcome the ascertainment bias inherent to case series and family-based studies, phenotypic features described are often derived from retrospective electronic medical records, lack specific ICC-targeted investigations, and hence may underestimate the magnitude of any effect [ 10 – 14 ]. The few reports of ICC SF disclosure highlight challenges with interpreting variants and correlating them with clinical findings and family history, and with patient management [ 15 – 17 ].…”

Section: Introductionmentioning

confidence: 99%

Secondary findings in inherited heart conditions: a genotype-first feasibility study to assess phenotype, behavioural and psychosocial outcomes

et al. 2020

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Disclosing secondary findings (SF) from genome sequencing (GS) can alert carriers to disease risk. However, evidence around variant-disease association and consequences of disclosure for individuals and healthcare services is limited. We report on the feasibility of an approach to identification of SF in inherited cardiac conditions (ICC) genes in participants in a rare disease GS study, followed by targeted clinical evaluation. Qualitative methods were used to explore behavioural and psychosocial consequences of disclosure. ICC genes were analysed in genome sequence data from 7203 research participants; a two-stage approach was used to recruit genotype-blind variant carriers and matched controls. Cardiac-focused medical and family history collection and genetic counselling were followed by standard clinical tests, blinded to genotype. Pathogenic ICC variants were identified in 0.61% of individuals; 20 were eligible for the present study. Four variant carriers and seven non-carrier controls participated. One variant carrier had a family history of ICC and was clinically affected; a second was clinically unaffected and had no relevant family history. One variant, in two unrelated participants, was subsequently reclassified as being of uncertain significance. Analysis of qualitative data highlights participant satisfaction with approach, willingness to follow clinical recommendations, but variable outcomes of relatives’ engagement with healthcare services. In conclusion, when offered access to SF, many people choose not to pursue them. For others, disclosure of ICC SF in a specialist setting is valued and of likely clinical utility, and can be expected to identify individuals with, and without a phenotype.

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“…However, the association of Titin variants and dilated cardiomyopathy in individual of African ancestry has been reported as weak. 12 Liver disease was only documented in 24.5% of patients with ACM in our study group, with minimal hyperbilirubinemia noted in this group, possibly a reflection of some decrease in the hepatic excretory function. In this regard, the relationship between liver cirrhosis from alcohol in patients with ACM has been controversial; 1 however, a prospective study documented that cirrhosis was present in 43% of patients with ACM.…”

Section: Discussionmentioning

confidence: 51%

Alcoholic cardiomyopathy and liver disease in a community hospital in east Harlem in New York City

Bergasa¹,

Tuoyo²,

Shady³

et al. 2020

GHOA

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Genomics-First Evaluation of Heart Disease Associated With Titin-Truncating Variants

Cited by 104 publications

References 37 publications

Long‐term prognostic value of ultrastructural features in dilated cardiomyopathy: comparison with cardiac magnetic resonance

Long‐term prognostic value of ultrastructural features in dilated cardiomyopathy: comparison with cardiac magnetic resonance

Secondary findings in inherited heart conditions: a genotype-first feasibility study to assess phenotype, behavioural and psychosocial outcomes

Alcoholic cardiomyopathy and liver disease in a community hospital in east Harlem in New York City

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