Case#: 22-year-old man

DiseaseAssertion: NCCM and mildly reduced LV function

FamilyInfo: Mother and brothers have also been diagnosed with NCCM

ParentalTesting: Mother had cardio magnetic resonance imaging done

CasePresentingHPOs: not reported

CaseHPOFreeText:

CaseNotHPOs: HP:0001681, HP:0001279 Angina pectoris andSyncope

CaseNotHPOFreeText: no arrhythmic events

CasePreviousTesting: electrocardiogram, transthoracic echocardiography, cardiac-magnetic resonance imaging

Genotyping Method: next generation sequencing

FunctionalAnalysis: not reported

Variant: NM_001018005.1:c.20_22del; p.Lys7del

ClinVar:181682

CAID:CA018708

gnomAD:15-63042841-CAAG-C

AdditionalInfo:

PMID:37067544

Gene: TPM1

HGNC ID: 12010

Case1: Caucasian. Sex and exact age not specified for the proband

DiseaseAssertion: Dilated cardiomyopathy (DCM)

FamilyInfo: Family A was notable for severe HF and sudden death in young children. Individuals I-2, III-10 and IV-7 died suddenly at ages 3 years, 13 months, and 5 months respectively, without prior evidence of heart disease. Two siblings, IV-5 and IV-8, presented with DCM and advanced HF at 5 months of age (LVEF 27% and 29%). Individuals III-3 and IV-1 developed end-stage HF refractory to medical therapy as teenagers. III-3 presented at age 13 with refractory HF, underwent mitral and tricuspid valve replacement for functional regurgitation and died weeks later of multisystem organ failure. IV-1 was asymptomatic when diagnosed with DCM at 7 years during family screening, but developed severe HF at age 17 and underwent transplant at 18 years of age. Individuals III-4, III-7 and III-12 developed mild exercise intolerance in their 5th decade.

ParentalTesting: NR

CasePresentingHPOs: HP:0001635, HP:0001644

CaseHPOFreeText: No family members with TPM1 D230N had evidence of cardiac conduction disease, and with one exception, none had evidence of skeletal myopathy

CaseNotHPOs: NR

CaseNotHPOFreeText: No family members with TPM1 D230N had evidence of cardiac conduction disease, and with one exception, none had evidence of skeletal myopathy.

CasePreviousTesting: No prior testing.

Genotyping Method: Genomic DNA was isolated from blood using standard methods in probands with DCM. Direct DNA sequence analysis of all coding regions and intron/exon boundaries was performed in 6 sarcomere genes.

FunctionalAnalysis: Functional analysis performed on recombinant proteins but not patient tissue. In vitro studies demonstrated major inhibitory effects on sarcomere function with reduced Ca2+-sensitivity, maximum activation, and Ca2+ affinity compared to wildtype TPM1.

Variant: NM_000366.5:c.688G>A (p.Asp230Asn)

ClinVar: NR

CAID: UnregisteredVariant

gnomAD: NR

AdditionalInfo: The paper does not explicitly identify which pedigree member is the Family A proband

PMID: 20117444

Gene: TPM1

HGNC ID: 12010

Case2: Caucasian. Sex and exact age not specified for the proband

DiseaseAssertion: Dilated cardiomyopathy (DCM)

FamilyInfo: Young members of this family also presented with severe HF. Individual III-1 developed failure to thrive at 10 weeks of age and echocardiography revealed severe LV dilation (LVIDD Z-score 15.6) and systolic dysfunction (LVEF 15%). Transplantation was considered, but she had substantial recovery with basic medical therapy. By age 8 years, she was asymptomatic with only mild LV systolic dysfunction (LVIDD Z-score 1.3, LVEF 46%). At age 20, II-6 underwent cardiac transplantation shortly after presenting with refractory HF symptoms and severe LV systolic dysfunction (LVEF < 20%). Individual II-7 died of HF at 12 years, prior to genetic testing. In addition to DCM, he had congenital cataracts and skeletal muscle weakness. I-1 had unexplained syncope at age 56 years. Cardiac studies revealed ventricular tachycardia and DCM (LVEF 25%) which improved with medical management. Three other adults (II-2, II-3, II-4, ages 38, 36 and 33 years, respectively) had asymptomatic LV systolic dysfunction.

ParentalTesting: NR

CasePresentingHPOs: HP:0001635, HP:0001644

CaseHPOFreeText: NR

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: No prior testing.

Genotyping Method: Genomic DNA was isolated from blood using standard methods in probands with DCM. Direct DNA sequence analysis of all coding regions and intron/exon boundaries was performed in 6 sarcomere genes.

FunctionalAnalysis: Functional analysis performed on recombinant proteins but not patient tissue. In vitro studies demonstrated major inhibitory effects on sarcomere function with reduced Ca2+-sensitivity, maximum activation, and Ca2+ affinity compared to wildtype TPM1.

Variant: NM_000366.5:c.688G>A (p.Asp230Asn)

ClinVar: NR

CAID: UnregisteredVariant

gnomAD: NR

AdditionalInfo: The paper does not explicitly identify which pedigree member is the Family B proband

PMID: 39684770

Gene: TPM1

HGNC ID: 12010

Case#: II.3, 30-year-old man from an Indian family.

DiseaseAssertion: Familial hypertrophic cardiomyopathy.

FamilyInfo: Figure 1A. His father (I.1), brother (II.1), and sister (II.2) had HCM and carried TPM1 p.Gln68Arg. His mother (I.2) had a normal echocardiogram and tested negative for the variant. The authors report autosomal dominant segregation.

ParentalTesting: Father positive for TPM1 p.Gln68Arg. Mother negative.

CasePresentingHPOs: HP:0001639, HP:0001712, HP:0005144, HP:0031656, HP:0001653, HP:0010872, HP:4000004

CaseHPOFreeText: Echo showed asymmetric septal hypertrophy and trivial mitral regurgitation. The interventricular septum measured 2.1 cm and the left ventricular posterior wall measured 1.2 cm. ECG showed a left ventricular hypertrophy strain pattern with T-wave inversions in leads II, III, aVF, and V2–V6. Cardiac MRI showed patchy STIR hyperintensity and late gadolinium enhancement in the thickened septum.

CaseNotHPOs: HP:0000822 (no history of hypertension), HP:0032092 (no left ventricular outflow tract obstruction at rest)

CaseNotHPOFreeText: Asymptomatic at presentation. Both atria and the right ventricle were normal in size and function. Left ventricular ejection fraction was 63%.

CasePreviousTesting: NR (prior genetic testing details not available in the article).

Genotyping Method: Custom targeted amplicon sequencing panel of nine sarcomeric genes on the Ion Torrent PGM. Sanger sequencing confirmed the TPM1 variant.

FunctionalAnalysis: NR (functional assay results not available in the article).

Variant: NM_001018005.2(TPM1).203A>G (p.Gln68Arg), heterozygous.

ClinVar: 1490086

CAID: NR (CAID not listed in the article).

gnomAD: No variant record found in gnomAD v4.1 for 15-63044115-A-G.

AdditionalInfo: PMID 38223010. Figure 1A identifies the proband and shows the pedigree. Figures 1B–D show cardiac imaging. Figure 1E shows Sanger sequencing. Figure 1F shows conservation of the affected residue. The authors also report computational predictions of a damaging effect.

PMID 38223010

Gene: TPM1

HGNC ID: 12010

PMID: 39554508

Gene: TPM1

HGNC ID: 12010

Additional Information: The authors looked at exome data from 200 patients with HCM. They found no TPM1 variants in the HYPERGEN cohort.

Case#: 31 year old man of European ancestry. Patient ID NR.

DiseaseAssertion: Nonischemic dilated cardiomyopathy.

FamilyInfo: No reported family history of dilated cardiomyopathy. Both parents had normal heart exams and echocardiograms.

ParentalTesting: Both biological parents tested negative for the TPM1 variant. Sequencing coverage was 500 to 600×. The authors thought the variant likely arose de novo. They could not rule out parental germline mosaicism.

CasePresentingHPOs: HP:0001644, HP:0025169, HP:0001635, HP:0001640, HP:0002202, HP:0002875, HP:0002094, HP:0012764, HP:0034807

CaseHPOFreeText: He first felt short of breath during activity. Later he felt short of breath at rest. He also had a persistent cough and abdominal swelling. Chest CT showed an enlarged heart and fluid around both lungs. The echo showed that both ventricles were enlarged and pumped poorly. His left ventricular ejection fraction was 12%. His heart failure worsened and he needed a heart transplant.

CaseNotHPOs: HP:4000004 (no myocardial late gadolinium enhancement on cardiac MRI).

CaseNotHPOFreeText: The biopsy and exam of the removed heart did not show evidence of active myocarditis.

CasePreviousTesting: NR

Genotyping Method: The Invitae Dilated Cardiomyopathy Panel used next generation sequencing to test 41 genes.

FunctionalAnalysis: Thin filaments with T237S needed more calcium to reach the same level of activation. At low calcium the mutant filaments were less likely to be open and myosin ATPase activity was lower. Omecamtiv mecarbil restored calcium sensitivity in the lab assay. See Figures 3 through 5 and Tables 1 and 2.

Variant: NM_001018005.2(TPM1):c.710C>G (p.Thr237Ser). Heterozygous.

ClinVar: 1067773

CAID: CA392724554

gnomAD: No variant record found in gnomAD v4.1.

AdditionalInfo: PMID 36739943. Figure 1 shows the echo and biopsy results. The clinical report called the variant a VUS. The study authors considered it likely pathogenic after lab testing.

PMID: 36739943

Gene: TPM1

HGNC ID: 12010

PMID: 37569730

Gene: TPM1

HGNC ID: 12010

PMID: 38773858

Gene: TPM1

HGNC ID: 12010

Additional Information: This review included patients with HCM and TPM1 variants. The results are reported by group. Table S3 shows what information each study provided. It does not link a specific TPM1 variant to an individual patient.

PMID 37498360

Gene: TPM1

HGNC ID: 12010

PMID: 35029218

Gene: TPM1

HGNC ID: 12010

Case#: Proband(II-1)

DiseaseAssertion: DCM1Y

FamilyInfo: Chinese Han family with DCM phenotypes.

ParentalTesting: not reported

CasePresentingHPOs: HP:0001644

CaseHPOFreeText: Proband diagnosed with dilated cardiomyopathy and found to carry a TPM1 variant.

CaseNotHPOs: not reported

CaseNotHPOFreeText: not reported

CasePreviousTesting: not reported

Genotyping Method: Next-generation sequencing (NGS), confirmed by Sanger sequencing

FunctionalAnalysis: none reported

Variant: TPM1 c.340G>C (p.E114Q) missense variant

ClinVar: not found

CAID: CA392721071

gnomAD:

AdditionalInfo:

Case#: 11 year old girl

DiseaseAssertion: hypertrophic cardiomyopathy

FamilyInfo: unremarkable

ParentalTesting: Both parents were tested and neither carried the variant

CasePresentingHPOs: HP:0001639 HP:0011675

CaseHPOFreeText: Post-mortem examination revealed asymmetric non-obstructive hypertrophy of the interventricular septum.

CaseNotHPOs: Syncope absent

CaseNotHPOFreeText: No complaints, normal exercise tolerance, no syncope, no medications, and no significant family history.

CasePreviousTesting: Autopsy and sudden cardiac death investigation.

Genotyping Method: Genetic testing performed as part of post-mortem investigation; familial cascade screening.

FunctionalAnalysis:

Variant: TPM1 c.656A>T (p.Asp219Val, p.D219V)

ClinVar: absent

CAID: CA2998480361

gnomAD: absent

AdditionalInfo: Variant classified as likely pathogenic (Class IV) by the authors and determined to be de novo.

PMID: 36613463

Gene: TPM1

HGNC ID: 12010

PMID: 30923642

Gene: TPM1

HGNC ID: 12010

PMID: 35004917

Gene: TPM1

HGNC ID: 12010

PMID: 31179125

Gene: TPM1

HGNC ID: 12010