Meta-analysis of cardiomyopathy-associated variants in troponin genes identifies loci and intragenic hot spots that are associated with worse clinical outcomes
Graphical abstract
Introduction
Cardiomyopathies are a heterogeneous group of primary diseases of the heart muscle, that can predispose to heart failure and cardiovascular death, with risk of sudden cardiac death (SCD) at first presentation [1]. Although many classifications exist, the American Heart Association classifies primary cardiomyopathies by genetic, mixed genetic, and non-genetic variants. Structural genetic primary cardiomyopathies include hypertrophic cardiomyopathy (HCM), left ventricular non-compaction cardiomyopathy (LVNC), and arrhythmogenic right ventricular cardiomyopathy (ARVC). Mixed structural cardiomyopathies, or those with both genetic and non-genetic etiologies, include dilated cardiomyopathy (DCM) and restrictive cardiomyopathy (RCM) [2].
The etiology of the majority of cardiomyopathies, independent of the clinical presentation, is believed to be genetic. Genetic variants resulting in molecular defects in the components of the contractile myofilaments represent a major cause of cardiomyopathies [3,4]. The cardiac troponin molecular complex (Tn) is essential for the regulation of striated muscle contraction and is located along the sarcomere thin filament [5,6]. Disruption of any of these processes likely leads to cardiac dysfunction and cardiomyopathy.
While variants in TNN-encoding genes are clear causes of cardiomyopathy, there is marked clinical heterogeneity. Genotype-phenotype correlations to explain this heterogeneity have been limited by small numbers of probands and a lack of comprehensive knowledge of population variants. Recent genetic studies have identified previously reported pathologic variants in large population studies as well as rare variants of unknown disease risk [7,8]. It is unclear how certain TNN variants are associated with disease while others are physiologically tolerated. To address this, we set out to 1) create a compendium of cardiomyopathy (CM)-associated variants and population-associated variants, and 2) identify prognostic characteristics associated with genotype.
Section snippets
Nomenclature
Nomenclature in this study is detailed in Supplemental Materials.
Compendium of cardiomyopathy-associated TNN variants
To compile pathologic TNN variants, PubMed and the Human Gene Mutation database were queried through June 2018 for studies identifying patients with cardiomyopathy and confirmed TNN variants [9]. Inclusion criteria for the studies included 1) study of individuals with primary cardiomyopathic disease, 2) comprehensive genetic analysis of the coding exons of TNNT2, TNNI3, or TNNC1, 3) availability of individual variants and their
Creation of troponin variant database and meta-analysis
To identify all pathologic variants and rare population variants, we created a compendium of cardiomyopathy-associated variants and gnomAD-based population variants (Fig. 1A). A comprehensive review of the literature identified 224 probands hosting variants in TNN from 70 studies. A total of 55 distinct variants were identified in TNNT2, 53 in TNNI3, and 16 in TNNC1 (Supplemental Table 1). Individual proband data for TNNT2, TNNI3, and TNNC1 are detailed in Supplemental Tables 2, 3, and 4,
Variant investigation in cardiomyopathy
In light of the rapid progression of precision or personalized medicine, efforts to utilize an individual's specific genetic abnormality to predict outcomes and guide therapy are underway. Thus, understanding both the functional and prognostic implications of rare variation is critical to the development of personalized medicine [20]. Recent studies have highlighted that specific genetic variation that is associated with the development of cardiomyopathy, in particular HCM, may guide rational
Limitations
Studies compiled were variable in data collection and were performed retrospectively. Comprehensive clinical data were not always available for probands and patients may have been lost to follow-up. Given that TNN variants are rare, we were likely underpowered to detect the prognostic impact of TNNC1 variants. Further, when calculating variant frequencies based on cardiomyopathy subtype, it is possible that minor cardiomyopathy variant frequencies are inflated due to limited patients screened
Clinical perspectives
In light of population-based data showing variants, it has become unclear how certain variants are well tolerated and others pathogenic. S:N analysis is a viable tool to better analyze variant hot spots, while integrating rare population variants. S:N analysis can be used to identify pathologic hot spots in other genes that demonstrate rare variants found in ostensibly healthy individuals.
Grant support
JRP is supported by the NIH Grant R01-HL128683. MSP is supported by AHA SDG #16SDG29120002. UF CTSI is supported by the NIH UL1TR001427. APL is supported by the Pediatric and Congenital Electrophysiology Society Paul C. Gillette Award, pilot grant funding from the Baylor College of Medicine Department of Pediatrics and Duke University School of Medicine.
Declaration of Competing Interest
No conflicts of interest to declare.
References (61)
- et al.
Mutations in troponin that cause HCM, DCM AND RCM: what can we learn about thin filament function?
J. Mol. Cell. Cardiol.
(2010) - et al.
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology
Genet. Med.
(2015) - et al.
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples
Genet. Med.
(2017) - et al.
Amino acid-level signal-to-noise analysis of incidentally identified variants in genes associated with long QT syndrome during pediatric whole exome sequencing reflects background genetic noise
Heart Rhythm.
(2018) - et al.
Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy
Mayo Clin. Proc.
(2008) - et al.
Cardiovascular precision medicine in the genomics era. JACC
Basic Transl. Sci.
(2018) - et al.
The intrinsically disordered C terminus of troponin T binds to troponin C to modulate myocardial force generation
J. Biol. Chem.
(2019) - et al.
Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy
J. Am. Coll. Cardiol.
(2004) - et al.
Multiple mutations in desmosomal proteins encoding genes in arrhythmogenic right ventricular cardiomyopathy/dysplasia
Heart Rhythm.
(2010) - et al.
Molecular effects of familial hypertrophic cardiomyopathy-related mutations in the TNT1 domain of cTnT
J. Mol. Biol.
(2012)