PMID: 30279906

Gene: TNNI3

HGNC ID: 11947

Case#: Female, 57, Korea

DiseaseAssertion:hypertrophic cardiomyopathy

FamilyInfo: Proband and 13 family members with diverse phenotypic expression of cardiomyopathies, elder sister had expired due to severe RCMP. large family, in which the p.Arg145Trp mutation of TNNI3 causes diverse phenotypes ranging from RCMP to HCMP to near-normal heart. Six relatives with RCMP or near-normal phenotypes also carried this mutation. Family pedigree (Figure 1) and Clinical data of affected individuals in a family with the c.433C>T mutation (table 1)

CasePresentingHPOs:HP:0002094, HP:0001640, HP:0001639, HP:6000313, HP:0031295, HP:0001670, HP:0004757, HP:0005135, HP:0004756, HP:0001962

CaseHPOFreeText:restrictive filling pattern, delayed hyper-enhancement, which reflects fibrotic change in the myocardium in the hypertrophied segments (Fig. 2D).

CaseNotHPOs:HP:0032092

CaseNotHPOFreeText:normal LV systolic function and normal cavity size

CasePreviousTesting:Chromatograms, Echocardiogram

Genotyping Method:Sanger Sequencing (Fig. 5)

FunctionalAnalysis:heterozygous nonsynonymous mutation

Variant:NM_000363.5(TNNI3):c.433C>T (p.Arg145Trp)

CAID:CA021667

gnomAD:chr19-55154146-G-A

PMID: 37646638

Gene: TNNI3

HGNC ID: 11947

Case#:24-year-old male

DiseaseAssertion:non-obstructive HCM and long QTc

FamilyInfo:family history of long QT (mother and maternal grandmother), (family pedigree in Fig. 2)

ParentalTesting:Sanger sequencing done in the father confirming the paternal origin of the variant.

CasePresentingHPOs:HP:0001712, HP:0001657, HP:0005135

CaseNotHPOs:HP:0001654, HP:0006673

CasePreviousTesting: Cardiac MRI, Electrocardiogram, echocardiogram

Genotyping Method:Next Generation Sequencing

FunctionalAnalysis:Pathogenic missense variant

Variant:NM_000363.5(TNNI3):c.592C>G (p.Leu198Val)

ClinVar:177694

CAID:CA022019

gnomAD:chr19-55151875-G-C

PMID:33777698

Gene:TNNI3

HGNC ID:11947

PMID:38548731

Gene:TNNI3

HGNC ID:11947

Case#:14 year old Female

DiseaseAssertion:nonobstructive hypertrophic cardiomyopathy

FamilyInfo:lacked any family history of cardiomyopathy, including sudden death or cardiac hypertrophy, Family Pedigree (Figure. 1a)

ParentalTesting:none, healthy parents

CasePresentingHPOs:HP:0001663

CaseHPOFreeText: cardiopulmonary arrest

CaseNotHPOs: HP:4000004

CaseNotHPOFreeText: myocardial edema, ventricular arrhythmias, obstructed outflow tract

CasePreviousTesting: echocardiogram, cardiac MRI

Genotyping Method:Whole genome sequencing

FunctionalAnalysis:heterozygous missense variant

Variant: NM_000363.5:c.583A>T (p.Ile195Phe)

CAID:CA407439576

PMID:28382084

Gene:TNNI3

HGNC ID:11947

PMID:30953456

Gene:TNNI3

HGNC ID:11947

Case#:52 year old female from a small mountainous village in Peloponnese, Greece

DiseaseAssertion:severely manifested phenotype of RCM leading to heart transplant at 41

FamilyInfo:Family Pedigree Figure 1.Parents were third-degree cousins from the same village and were heterozygous for the same variant but displayed no symptoms of the disease. The older sister who was also found heterozygous was asymptomatic. Twin sister and brother were homozygous for the same variant and displayed a restrictive and a hypertrophic phenotype, respectively. Their children are all carriers of the mutation and remain asymptomatic until the age of 21

ParentalTesting:Family of the proband had Electrocardiogram and Doppler Echocardiogram (shown in figure 2) as well as TNNI3 genetic testing by targeted Sanger sequencing for the detection of the variant. Her twin sister and her brother were found homozygous for the variant, while both parents and the older sister were found heterozygous.

CasePresentingHPOs:HP:0002875, HP:0004757

CaseNotHPOFreeText:normal left ventricular dimensions

CasePreviousTesting:electrocardiogram, Right heart catheterization

Genotyping Method:NGS (filtered using VariantStudio Data Analysis Software and the Sophia Genetics DDM platform)

FunctionalAnalysis: a novel homozygous TNNI3 variant

Variant:NM_000363.4:c.586G > C, p.(Asp196His)

ClinVar:2169619

CAID:CA407439559

PMID:40656892

Gene:TNNI3

HGNC ID:11947

Case#:53-year-old female

DiseaseAssertion:non-obstructive HCM with progressive deterioration of right heart function

FamilyInfo:mother has cardiac hypertrophy, the TNNI3 variant was also detected her sister and daughter

CasePresentingHPOs:HP:0005110, HP:0012398, HP:0001962, HP:0031352, HP:0033118, HP:0011675

CaseHPOFreeText:enlarged cardiac silhouette

CaseNotHPOs:HP:0030829, HP:0030148

CaseNotHPOFreeText: jugular venous distention

CasePreviousTesting:Electrocardiogram, Echocardiograms

Genotyping Method:next-generation sequencing (NGS)

FunctionalAnalysis: Hybridized pathogenic variant in exon 7 of TNNI3 (table 1)

Variant:NM_000363.4:c.470C>T(p.Ala157Val)

ClinVar:43388

CAID:CA021720

gnomAD:chr19-55154109-G-A