CMD1FF; CMD2A; CMH7; RCM1; TNNC1; cTnI
The TNNI3 gene is associated with autosomal dominant hypertrophic cardiomyopathy (HCM) (MedGen UID: 183649), dilated cardiomyopathy (DCM) (MedGen UID: 2880) and restrictive cardiomyopathy (RCM) (MedGen UID: 396236).
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Pathogenic TNNI3 variants are associated with 2% of clinical cases of HCM and <1% of DCM cases.
The TNNI3 gene enodes the cardiac muscle protein troponin I, cardiac muscle. Troponin I is a part of the sarcomere complex, which is present in both cardiac and skeletal muscle cells. The primary role of the sarcomere complex is muscle contraction. Mutations in genes that encode sarcomere proteins are a common cause of inherited cardiomyopathies.
The TNNI3 gene is associated with hypertrophic cardiomyopathy (HCM; MedGenUID: 183649), dilated cardiomyopathy (DCM; MedGenUID: 2880), and restrictive cardiomyopathy (RCM; MedGenUID: 396236).
These cardiomyopathies may lead to left ventricular outflow obstruction, cardiac dysfunction, heart failure, conduction disease, arrhythmia, blood clots, or stroke (PMID: 22068435, 29567486). Symptoms include palpitations, dizziness, syncope, chest pain, shortness of breath, fatigue, edema, and in some cases, sudden cardiac arrest or death (SCA/D; PMID: 22068435, 8995091, 29567486).
Cardiomyopathy may develop at any age, and affected individuals may be asymptomatic until late in the course of the disease (PMID: 29567486, 22068435).
The TNNI3 gene encodes the cardiac muscle protein troponin I. Troponin I, along with troponins T and C, forms the cardiac troponin complex that is involved in regulating myosin–actin binding and contraction (PMID: 19914256).
Pathogenic variants in TNNI3 exhibit autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing that variant on to each of their offspring. TNNI3pathogenic variants exhibit reduced penetrance and variable expression, meaning that not everyone who inherits the pathogenic variant and a predisposition for disease will develop cardiomyopathy (PMID: 29567486).
Most cases of TNNI3-related cardiomyopathy are inherited from a parent, but some cases occur spontaneously (i.e., an individual with a pathogenic variant has parents who do not have the variant; PMID: 29567486). Identification of a pathogenic variant allows for the recognition of at-risk relatives, who are recommended to pursue testing for the familial variant (PMID: 29097296). Up to 5% of individuals with HCM have more than one pathogenic variant, which has been associated with an earlier and more severe clinical presentation (PMID: 16199542, 12707239, 21839045).
Cardiomyopathy is recommended to be managed by a combination of lifestyle modification, medication, surgical and device therapy (pacemaker or implantable cardioverter defibrillator), and heart transplantation (PMID: 29097296, 29567486). Cardiac surveillance through imaging (by echocardiogram and MRI) and electrocardiographic monitoring (by standard and ambulatory methods) are recommended upon diagnosis, at set intervals depending on age and presentation, and whenever symptoms present or worsen (PMID: 22068435, 29567486).
Pregnant women with DCM may be at risk for adverse effects, whereas women with HCM usually tolerate pregnancy without greatly increased risks (PMID: 24451172). There is little known on the effects of pregnancy in women with RCM. Overall, women with cardiomyopathy who become pregnant are generally recommended to receive increased cardiac surveillance both for themselves and their fetus, genetic counseling, and an evaluation of treatment methods to weigh any risks to the pregnancy (PMID: 22068435, 24451172).
It is recommended that management decisions be made based on clinical presentation, symptoms, and family history, as well as appropriate SCA/D risk stratification (PMID: 29097296, 29567486).
Genetic testing is recommended for at-risk family members of an individual with a disease-causing pathogenic variant (PMID: 29097296, 29567486). Serial clinical screening by medical history, physical exam, echocardiogram, and ECG/EKG for at-risk family members is also recommended (PMID: 29097296, 29567486).
Review date: May 2018
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|