PMID:30565988

Gene:TNNT2

HGNC ID:11949

Case#:A 65-year-old woman with severe hypertrophic cardiomyopathy

DiseaseAssertion:Severe hypertrophic cardiomyopathy

FamilyInfo:no information reported

ParentalTesting:no parental testing reported

CasePresentingHPOs:HP:0001639

CaseHPOFreeText: gene panel testing that identified a single variant

CaseNotHPOs: not found

CaseNotHPOFreeText: not found

CasePreviousTesting: gene panel testing that identified a single variant

Genotyping Method:clinical gene panel testing

FunctionalAnalysis: rapid insertion of TNNT2 gene variants into induced pluripotent stem cell-differentiated cardiomyocytes (iPSC-CMs) for functional annotation of the variants for (E251D)(Figure B)

Variant:c.753G>T (p.Glu251Asp)

ClinVar:not found

CAID:CA090003

gnomAD:not found

AdditionalInfo:not reported

PMID:41969674

Gene:TNNT2

HGNC ID:11949

Case#:male, 41, DCM

DiseaseAssertion:dilated cardiomyopathy

FamilyInfo:The proband reported that his mother died suddenly at approximately 35 years of age (specific cause unknown). Other family members were healthy with no history of cardiac disease. Written informed consent was obtained from all participants.

ParentalTesting:no parental testing reported. Sanger sequencing of available family members (daughter, half-brother, maternal uncle and maternal aunt) confirmed that none carried the variant, supporting its de novo origin

CasePresentingHPOs:HP:0002875, HP:0001644, HP:4000141, HP:6000313

CaseHPOFreeText: ECG showed sinus bradycardia, occasional atrial premature beats, delayed atrioventricular conduction, left atrial enlargement, left ventricular high voltage, incomplete right bundle branch block, and ST-T changes (Figure 1C). CMR revealed late gadolinium enhancement (LGE) in the basal to mid-septal and anterolateral segments of the left ventricle (Figure 1D).

CaseNotHPOs:HP:0000822, HP:0003077

CaseNotHPOFreeText:He denied a history of hyperlipidemia, hypertension, or substance abuse.

CasePreviousTesting:No reports of previous testing

Genotyping Method:whole-exome sequencing and Sanger sequencing

FunctionalAnalysis:not reported

Variant:c.547C>T p.Arg183Trp

ClinVar:43628

CAID:CA004294

gnomAD:Overall allele frequency: 0.000001239

AdditionalInfo:not reported

Case#:a 40-year-old woman with a history of hypokinetic-dilative cardiomyopathy and heterozygous for TNNT2 gene mutation

DiseaseAssertion:hypokinetic-dilative cardiomyopathy

FamilyInfo: her family appreciated the clear communication, and as her condition improved without further complications, she expressed gratitude for the care provided.

ParentalTesting:n/r

CasePresentingHPOs:HP:0001644, HP:0002094, HP:0002094, HP:0001695,

CaseHPOFreeText:Progressive dyspnea and fatigue began in January 2017. In February 2018, the patient had cardiac arrest due to ventricular fibrillation at 26 weeks’ gestation, followed by emergency caesarean section. She carried a heterozygous TNNT2 variant (c.547C>T, p.Arg183Trp)

CaseNotHPOs: HP:0031972, HP:0031972

CaseNotHPOFreeText:Coronary angiography showed no significant stenosis.

CasePreviousTesting:Testing method and scope

GenotypingMethod:n/a

FunctionalAnalysis:not reported

Variant: c.547C>T p.Arg183Trp)

Clinvar:not known

CAID:CA391630526

gnomAD:n/r

AdditionalInfo:n/r

PMID : 40008267

Gene: TNNT2

HGNC ID: 11949

PMID: 29367541

Gene: TNNT2

HGNC ID: 11949

PMID:39905734

Gene:TNNT2

HGNC ID:11949

Case#: a 50‐year‐old male who was clinically diagnosed with isolated CS and prescribed with prednisolone without much effect, and subsequent genetic analysis revealed pathogenic variants in LMNA and TNNT2, representative genes for cardiomyopathy.

DiseaseAssertion:Dilated cardiomyopathy

FamilyInfo: not reported

ParentalTesting: He had no family history of heart disease or sudden death

CasePresentingHPOs:HP:0002094,HP:0005110,HP:0025169, HP:0005110

CaseHPOFreeText:Progressive cardiac conduction disease: first-degree AV block with left axis deviation on an earlier ECG progressed to high-grade and then complete AV block. At age 50, the patient also had mild dyspnoea on exertion (New York Class ll) and atrial fibrillation. The authors later stated that it was dilated cardiomyopathy.

CaseNotHPOs:HP:0033608,HP:0002716

CaseNotHPOFreeText:CT showed no enlarged lymph nodes, pulmonary nodules, or other organ abnormalities

CasePreviousTesting: whole‐exome sequencing analysis to evaluate the risk of inherited cardiomyopathies and identified two missense variants in TNNT2 (chr1:201364335(hg38), NM_001001430.3, c.422G>A, p.Arg141Gln) and LMNA (chr1:156136096(hg38), NM_170707.4, c.1132A>C, p.Lys378Gln) (Figure 3). Sanger sequencing analysis identified a heterozygous single‐base substitution (c.1132A>C) in the LMNA gene and c.422G>A in the TNNT2 gene (red arrows).

Genotyping Method:Whole-exome sequencing (WES) identified the variants; Sanger sequencing of the TNNT2 and LMNA variants is shown in Figure 3.

FunctionalAnalysis:Not reported

Variant:TNNT2: NM_001001430.3:c.422G>A (p.Arg141Gln),LMNA: NM_170707.4:c.1132A>C (p.Lys378Gln)

ClinVar:43637

CAID:CA004540

gnomAD:not reported

AdditionalInfo:not reported

PMID: 28815794

Gene: TNNT2

HGNC ID: 11949

PMID:20973921

Gene:TNNT2

HGNC ID:11949

Case#:A 70‐year‐old woman, previously healthy with a left ventricular ejection fraction presented with DCM

DiseaseAssertion:dilated cardiomyopathy and a 4-month history of progressive heart failure

FamilyInfo:"Family history was negative for IDC or heart failure (Figure 3), although an uncle (II‐3) reportedly had an enlarged heart, and three other relatives (II‐1, II‐2, and III‐4) had cardiac related deaths confirmed by death certificate. The proband’s father (II‐1) died of myocardial failure and pulmonary edema; her mother (II‐2) died of pulmonary embolism; and her sister (III‐4) died suddenly of coronary artery disease in her 60s. Her daughter, the proband’s niece (IV‐3), had a history of palpitations and lower extremity swelling, intermittent numbness, and blanching of the fingers at age 49. Her echocardiogram was normal. Her ECG showed nonspecific ST‐T wave changes and left anterior hemiblock."

ParentalTesting:no parental testing reported because both parents were deceased. The two offsprings that were reported were tested and carried both variants.

CasePresentingHPOs:HP:0001644, HP:0001635, HP:0002875, HP:0012378

CaseHPOFreeText:symptoms of progressive dyspnea on exertion and fatigue that began 2–3 months prior to her presentation. Also, she had an unrelenting progression of symptoms and was hospitalized with advanced NYHA Class IV heart failure 6 weeks later. Lastly, she received a heart transplant.

CaseNotHPOs:not reported

CaseNotHPOFreeText:no myocarditis or infiltrative process and no histological evidence of hemochromatosis,

CasePreviousTesting:Oligonucleotide hybridization‐based DNA sequencing was conducted in the proband for a panel of 19 DCM genes ( Table 1 )

Genotyping Method:Oligonucleotide hybridization‐based DNA sequencing and genomic DNA was extracted from whole blood and was sequenced in our laboratory in both directions to detect and/or confirm nucleotide variants in TNNT2 in the proband and the proband’s relatives using an Applied Biosystems 3130XL capillary sequencer

FunctionalAnalysis:R139H (Figure 4): Functional studies in porcine cardiac skinned fibers reconstituted with the mutant R139H troponin T protein showed decreased Ca2+ sensitivity at pH 7, characteristic of DCM.

Variant:416G>A (R139H) in exon 10 and 690–6G>A in intron 13.

ClinVar:not found

CAID:CA004513

gnomAD:not found

AdditionalInfo:not reported

Case5: 65 year-old male

DiseaseAssertion: carried a known TNNT2 K247R mutation as well as two novel intronic variants in MYH7 (IVS39+7C>A) and MYBPC3 (IVS25+13T>A)

FamilyInfo: None of his five siblings were affected, judged by their clinical presentation, nor was there any history of cardiac disease or sudden death in the family.

ParentalTesting:NR

CasePresentingHPOs:HP:0003677, HP:0012828, HP:0001635, HP:0005110, HP:0034307, HP:0012666,

CaseHPOFreeText: had late-onset at age 47 IDC, with a slow progression to severe heart failure and subsequently HTX. He also suffered from atrial fibrillation in the later stages of his disease. Had left ventricular end diastolic diameter (in mm and indexed by body surface area (cm/m2)) with a value of 68mm and 3.4cm/m2. As well with 30% of left ventricular ejection fraction. His ECG is normal, clinical status is heart transplantation from the age of 56. CAG is normal.

CaseNotHPOs:NR

CaseNotHPOFreeText:NR

CasePreviousTesting:NR

Genotyping Method:Genetically screened, also using GenBank with PCR by amplifying the coding region

FunctionalAnalysis: The variant could thus possibly result in the synthesis of a limited amount of the slightly modified β-myosin. The functional significance of this is not easily established, but it suggests that the variant may be a disease modifier.

Variant:NM_001276345.2:c.869A>G

ClinVar:4881578

CAID:CA344201883

gnomAD:NR

AdditionalInfo: MYH7 (IVS39+7C>A) increased the likelihood of a cryptic donor splice site to 70%, possibly resulting in the synthesis of mRNA coding for a β-myosin with a C terminus of –VGLE instead of –GLNEE. As the variant is located in the last exon, the faulty spliced mRNA is probably not degraded but results in the synthesis of a modified protein.

Case#: Female, Hispanic, 4

DiseaseAssertion:Dilated cardiomyopathy

FamilyInfo: Uncle who died at a young age of sudden cardiac death.

ParentalTesting:

CasePresentingHPOs: HP:0001638

"severe decompensated cardiomyopathy at age 4."

CaseHPOFreeText: NR

CaseNotHPOs: NR

CaseNotHPOFreeText:NR

CasePreviousTesting: NR

Genotyping Method: commercial genetic testing and Sanger sequencing

FunctionalAnalysis:

Variant: NM_001276345.2:c.*187C>T

ClinVar: NR

CAID:CA2649785730

gnomAD:NR

AdditionalInfo:

PMID: 26498512

Gene: TNNT2

HGNC ID: 11949

PMID: 28538763

Gene: TNNT2

HGNC ID: 11949

Case#: Male, 17

DiseaseAssertion: hypertrophic cardiomyopathy

FamilyInfo: All family members were asymptomatic, with normal TTE and ECG, with no evidence of VH.

ParentalTesting:

CasePresentingHPOs: HP:0001639, HP:0001279, HP:0001670, HP:0032092, HP:0031295

CaseHPOFreeText: diastolic type II dysfunction,

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: genetic analysis of the proband was performed through direct sequencing of the three sarcomere genes: MYH7, MYBPC3 and TNNT2

Genotyping Method: Sanger Sequencing

FunctionalAnalysis: NR

Variant: NR

ClinVar:NR

CAID: NR

gnomAD: NR

AdditionalInfo: underwent clinical and cardiovascular examination, including a 12-lead electrocardiogram (ECG), transthoracic echocardiography (TTE) and 24-hour Holter monitoring. TNNT2 sequenced, but not reported.

Case#: Female, 4 months, Swedish

DiseaseAssertion: dilated cardiomyopathy

FamilyInfo: Strong family history of DCM and faily history of SCD due to DCM. Maternal grandfather had enlarged left ventricle.

ParentalTesting:

CasePresentingHPOs: HP:0005162, HP:0031295, HP:0001653,

CaseHPOFreeText: enlarged left ventricle,

CaseNotHPOs:HP:0011947

CaseNotHPOFreeText: circulatory collapse

CasePreviousTesting: NR

Genotyping Method: Sanger sequencing

FunctionalAnalysis: NR

Variant: NM_001276345.2:c.548G>A

ClinVar:43649

CAID: CA004727

gnomAD:NR

AdditionalInfo: During cardiac catheterization, cardiac resuscitation due to circulatory collapse was needed.

PMID: 28669108

Gene: TNNT2

HGNC ID: 11949

PMID: 37122207

Gene: TNNT2

HGNC ID: 11949

Case#: 4 month old boy

DiseaseAssertion: Polymorphic ventricular tachycardia

FamilyInfo: His father carried the RYR2 variant and had ventricular premature beats. His mother carried the SCN10A variant and was asymptomatic.

ParentalTesting: Yes. Familial genetic testing showed the RYR2-A1855D variant was inherited from the father and the SCN10A-Q1362H variant was inherited from the mother.

CasePresentingHPOs: HP:0004756

CaseHPOFreeText: 4-month-old male presenting with polymorphic ventricular tachycardia.

CaseNotHPOs: not reported

CaseNotHPOFreeText: not reported

CasePreviousTesting: Clinical cardiac evaluation followed by genetic testing

Genotyping Method: Genetic testing identified novel heterozygous RYR2-A1855D and SCN10A-Q1362H variants.

FunctionalAnalysis: Functional studies showed abnormal calcium handling, prolonged action potentials, increased susceptibility to early afterdepolarizations, and disrupted Ca2+ homeostasis in cells carrying both variants.

Variant: RYR2 (heterozygous) SCN10A

ClinVar: not found

CAID: not found

gnomAD: not found

AdditionalInfo:

Case#: V-1; male; age 68

DiseaseAssertion: Familial hypertrophic cardiomyopathy

FamilyInfo: HCM was reported in the proband’s father and three daughters. The same heterozygous TNNT2 Δ160E variant was identified in all three daughters

CasePresentingHPOs: HP:0001712 HP:0012664 HP:4000141 HP:0004756

CaseHPOFreeText: Left ventricular hypertrophy; progressive left ventricular systolic dysfunction; left ventricular enlargement; cardiomyocyte hypertrophy; sustained ventricular tachycardia; advanced heart failure

CasePreviousTesting: Diagnosed with HCM at age 25; no previous genetic testing reported

Genotyping Method: Ion AmpliSeq cardiovascular research panel screening 404 genes, with direct Sanger sequencing confirmation

FunctionalAnalysis: Patient-derived and isogenic CRISPR/Cas9-edited iPSC-derived cardiomyocytes showed prolonged calcium decay, impaired relaxation, cardiomyocyte hypertrophy, and altered calcium-regulated signaling. EGCG partially improved the calcium and relaxation abnormalities.

Variant: c.478_480del, p.Δ160E; in-frame 3-bp deletion

ClinVar: 43648

CAID: CA004651

PMID: 35861968

Gene: TNNT2

HGNC ID: HGNC:11949

PMID: 27141495

Gene: TNNT2

HGNC ID: 11949

PMID: 27199119

Gene: TNNT2

HGNC ID: 11949

PMID: 31770195

Gene: TNNT2

HGNC ID: 11949

Case#: Female, 6 months

DiseaseAssertion: Dilated cardiomyopathy

FamilyInfo: Mother was age 40 at time of birth, which is a high-risk factor for birth defects

ParentalTesting:

CasePresentingHPOs: HP:0031664, HP:0010438, HP:0005162

CaseHPOFreeText: blood pressure of the four limbs was "92/44 mmHg at the right upper limb, 96/58 mmHg at the left upper limb, 101/60 mmHg at the right lower limb, and 103/54 mmHg at the left lower limb." Enlarged heart boundaries. Shifted apex.

CaseNotHPOs: HP:0000975

CaseNotHPOFreeText: decreased milk consumption

CasePreviousTesting: NR

Genotyping Method: genomic sequencing.

FunctionalAnalysis: NR

Variant: NM_001276345.2:c.548G>A

ClinVar:43649

CAID:CA004727

gnomAD: NR

AdditionalInfo:

Case#: Japanese female

DiseaseAssertion: Mild cardiac hypertrophy and asymmetric septal hypertrophy with myocardial hypertrophy increasing.

FamilyInfo: mother and grandmother showed phenotype. Probands mother has the Arg92Trp mutation of TNNT2.

ParentalTesting:not reported

CasePresentingHPOs: HP:0001670

CaseHPOFreeText: not reported

CaseNotHPOs:not reported

CaseNotHPOFreeText:not reported

CasePreviousTesting: DNA analysis

Genotyping Method: Patients with familial HCM

FunctionalAnalysis:not reported

Variant:NM_001276345.2:c.107A>T

ClinVar:not reported

CAID:CA344207376

gnomAD:not reported

AdditionalInfo: pedigree and phenotype associated with Family C.

PMID: 27082122

Gene: TNNT2

HGNC ID: 11949

Case1: 35, Female, Caucasian

DiseaseAssertion: Patient was asymptomatic

FamilyInfo: “ significant family history of hypertrophic cardiomyopathy (HCM), including sudden cardiac death of unknown cause in one son and HCM in two other children”

CaseHPOFreeText: “extensive, diffuse, poorly demarcated LGE throughout the LV ventricle”

CaseNotHPOFreeText: “CMR showed normal left ventricular (LV) systolic function…and normal wall thickness ”

CasePreviousTesting:

Genotyping Method: Subsequent genotyping

Variant: c.305G>A (p.Arg102Gln)

ClinVar:CA004273

PMID: 19087273

Gene: TNNT2

HGNC ID: 11849

Case1: Female, 53

DiseaseAssertion: Restrictive Cardiomyopathy

FamilyInfo:Pedigree in Fig 1. shows “ The proband (II.11) has five siblings and three nieces with cardiomyopathy,” “the proband’s two oldest siblings were diagnosed with idiopathic DCM”

CasePresentingHPOs: HP:0002094, HP:0001962, HP:0031329, HP:0001688, HP:0001709

CaseHPOFreeText:”Echocardiography revealed massive biatrial enlargement (Fig. 2a) and markedly abnormal diastolic function” “she had mild hypertrophy localized to the mid-septum” “progressive atrial enlargement”

CaseNotHPOs:HP:0012436,

CaseNotHPOFreeText: “with no systolic anterior motion of the anterior mitral valve leaflet or left ventricular outflow tract obstruction” “The sample was negative for eosinophilic infiltrate, myocarditis, sarcoidosis, amyloidosis and hemochromatosis.”

CasePreviousTesting: Sequenced TNNT2, TTN, MYL3, MYBPC, MYL2, MYH7, ACTC1, TPM1, and TNNI3

Genotyping Method: PCR

Variant: c.266T>A (p.Ile89Asn)

ClinVar:CA004157

gnomAD: To be found

AdditionalInfo: Autosomal Dominant trait, heterozygous missense mutation in TNNT2

PMID: 18651846

Gene: TNNT2

HGNC ID: 11949

Case#: A 29 years old male DCM patient

DiseaseAssertion:Familial dilated cardiomyopathy (FDCM), associated with the TNNT2 gene missense variant p.Arg144Trp (R144W)

FamilyInfo: Family members had revealed its presence in three other individuals with DCM. A history of sudden cardiac deaths (SCD) in the family. Two individuals in the family, who were diagnosed with DCM, had died due to severe congestive heart failure at the age of 45 and 25 years. However, a 66-year-old individual in the same family with DCM having mild symptoms.

ParentalTesting:NR

CasePresentingHPOs: HP:0001644, HP:4000141, HP:0012664, HP:0004308, HP:0012828, HP:0001653

CaseHPOFreeText: Dilated cardiomyopathy with left ventricular dilation, Age of onset, 25, left ventricular internal diastolic dimension of 72mm, reduced ejection fraction of 26%, has Ventricular arrhythmia, severe mitral regurgitation.

CaseNotHPOs:NR

CaseNotHPOFreeText: NR

CasePreviousTesting:NR

Genotyping Method: Used PCR with GenBank No. NM_000364, then followed by mutation subsequent screening analysis

FunctionalAnalysis:The R144W mutation was found to be within the tropomyosin-binding domain of cTnT and alters the charge of the residue, so it is expected to have a significant impact on the structure and function of the protein. The novel unique/private R144W mutation identified in our present study is associated with FDCM

Variant:NM_001276345.2:c.445C>T

ClinVar:43640

CAID:CA004505

gnomAD: gnomAD v2: 1:201333470 G / A https://gnomad.broadinstitute.org/variant/1-201333470-G-A?dataset=gnomad_r2_1 gnomAD v4: chr1-201364342-G-A https://gnomad.broadinstitute.org/variant/chr1-201364342-G-A?dataset=gnomad_r4

AdditionalInfo:25 bp deletion was found to be associated with both HCM and DCM in India and south Asia

PMID: 24992688

Gene: TNNT2

HGNC ID: 11949

PMID: 23494605

Gene: TNNT2

HGNC ID: 11949