PMID: 39684770

Gene: TPM1

HGNC ID: 12010

PMID: 21823217

Gene: TPM1

HGNC ID: 12010

PMID: 20215591

Gene: TPM1

HGNC ID: 12010

PMID: 32176697

Gene: TNNI3

HGNC ID: 11947

Case2: Sex not stated, age 8 months at diagnosis, ethnicity not stated

DiseaseAssertion: Restrictive cardiomyopathy (RCM)

FamilyInfo: Patients 2 and 3, monozygotic twins, were diagnosed with RCM at the age of 8 and 13 months, respectively. No familial history of cardiac disorders was reported in the R170W case, parental testing confirmed that the R170W variant occurred de novo (however, no parental proof was performed)

ParentalTesting: Parental testing confirmed that the R170W variant occurred de novo (however, no parental proof was performed). Parents do not carry the variant

CasePresentingHPOs: HP:0001723, HP:0002875, HP:0005110

CaseHPOFreeText: Echocardiographic examination revealed a restrictive filling pattern and enlarged atria. Both children died at the age of 12 and 18 months, respectively, due to congestive heart failure and atrial fibrillation

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

Genotyping Method: Total genomic DNA was extracted from peripheral blood using FlexiGene DNA Kit (Qiagen) according to the manufacturer’s protocol. The TNNI3 gene was screened for mutations using dye terminator sequencing. In both cases additional target sequencing including a panel of 108 cardiomyopathy- and channelopathy-associated genes was performed using Illumina MiSeq as previously described

FunctionalAnalysis: Functional analysis performed on recombinant proteins. Both cTnI-R170G/W strongly enhanced the Ca2+-sensitivity of skinned fibres, as is typical for RCM-mutations. Both mutants strongly enhanced the affinity of troponin (cTn) to tropomyosin compared to wildtype cTn. The stability of reconstituted thin filaments was reduced as revealed by electron microscopy.

Variant: NM_000363.5:c.508C>T (p.Arg170Trp)

ClinVar: 179285

CAID: CA021778

gnomAD: chr19-55154071-G-A

AdditionalInfo: Monozygotic twin

Case1: Male, age 3 at diagnosis, ethnicity not stated

DiseaseAssertion: Restrictive cardiomyopathy (RCM)

FamilyInfo: Familial screening in the R170G proband documented a hypertrophic cardiomyopathy with restrictive filling pattern in patient’s father, but the family refused additional genetic testing. No other family history of cardiac disorders stated.

ParentalTesting: The family refused additional genetic testing

CasePresentingHPOs: HP:0001723, HP:0001650, HP:0001654

CaseHPOFreeText: Patient 1 showed an impaired left ventricular function and pulmonary hypertension at three years of age. Heart biopsy showed mild cardiomyocyte hypertrophy and interstitial fibrosis. He was diagnosed with RCM and died one year later of ventricular fibrillation.

CaseNotHPOs: NR

CaseNotHPOFreeText: Target sequencing including a panel of 108 cardiomyopathy- and channelopathy-associated genes revealed no additional pathogenic or likely pathogenic variants

CasePreviousTesting: Additional target sequencing including a panel of 108 cardiomyopathy- and channelopathy-associated genes was performed using Illumina MiSeq as previously described.

Genotyping Method: Total genomic DNA was extracted from peripheral blood using FlexiGene DNA Kit (Qiagen) according to the manufacturer’s protocol. The TNNI3 gene was screened for mutations using dye terminator sequencing. In both cases additional target sequencing including a panel of 108 cardiomyopathy- and channelopathy-associated genes was performed using Illumina MiSeq as previously described

FunctionalAnalysis: Functional analysis performed on recombinant proteins. Both cTnI-R170G/W strongly enhanced the Ca2+-sensitivity of skinned fibres, as is typical for RCM-mutations. Both mutants strongly enhanced the affinity of troponin (cTn) to tropomyosin compared to wildtype cTn. The stability of reconstituted thin filaments was reduced as revealed by electron microscopy.

Variant: NM_000363.5:c.508C>G (p.Arg170Gly)

ClinVar: 165517

CAID: CA021769

gnomAD: NR

AdditionalInfo: NR

PMID: 31524317

Gene: MYBPC3, MYPN

HGNC ID: 7551, 23246

PMID: 38616291

Gene: TNNT2

HGNC ID: 11949

PMID: 26163040

Gene: MYBPC3

HGNC ID: 7551

PMID: 35614389

Gene: TNNI3

HGNC ID: 11947

PMID: 20117444

Gene: TPM1

HGNC ID: 12010

PMID: 28815794

Gene: MYBPC3

HGNC ID: HGNC:7551

PMID: 28815794

Gene: TNNT2

HGNC ID: 11949

PMID: 25335496

Gene: MYBPC3

HGNC ID: 7551

Case1: Male, 24 years old at diagnosis, ethnicity not stated

DiseaseAssertion: Dilated cardiomyopathy (DCM)

FamilyInfo: Three affected family members carry the D94A mutation, mother (I.2, diagnosed age 21 with peripartum cardiomyopathy), sister (II.1, diagnosed age 29), and proband (II.2, diagnosed age 24). Sanger sequencing confirmed the MYL2 variant was present in all three affected family members (I.2, II.1, and II.2).

ParentalTesting: Mother confirmed as heterozygous carrier of D94A mutation with DCM phenotype. Father not a carrier, unaffected

CasePresentingHPOs: HP:0001644, HP:0006699

CaseHPOFreeText: The proband (II.2) and his sister (II.1) were diagnosed at ages 24 and 29 after preventive cardiovascular screening revealed mild global left ventricular systolic dysfunction. Medical therapy was initiated upon evidence of decreased ejection fraction. Patients II.1 and II.2 (proband) displayed abnormal ECG findings and systolic dysfunction as manifested by reduced EF. However, the LV and septal wall thickness were within the normal range.

CaseNotHPOs: NR

CaseNotHPOFreeText: Septal wall thickness measurements were within normal range in all affected family members. LV wall thickness within normal range.

CasePreviousTesting: No prior testing.

Genotyping Method: Twenty two variants, meeting our established criteria for exome sequencing analysis, were identified in the three affected family members of the pedigree. Exome sequencing performed; variant confirmed by Sanger sequencing. Sanger sequencing confirmed the MYL2 variant was present in all three affected family members (I.2, II.1, and II.2)

FunctionalAnalysis: Functional analysis performed on recombinant proteins, not directly on patient samples. Far-UV CD spectroscopy was used to analyze the effect of the D94A mutation on the secondary structure of the RLC. The mutation was observed to induce a reduction in the α-helical content of the RLC and imposed intra-molecular rearrangements. The mutation was seen to impair the binding of RLC to the MHC (myosin heavy chain), and its incorporation into the RLC-depleted porcine myosin. The actin-activated ATPase activity of mutant-reconstituted porcine cardiac myosin was significantly higher compared to ATPase of WT

Variant: NP_000423.2:p.Asp94Ala

ClinVar: 4710041

CAID: CA386698152

gnomAD: NR

AdditionalInfo: Three affected family members carry the variant (mother I.2, sister II.1, proband II.2)

PMID: 25825243

Gene: MYL2

HGNC ID: 7583

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.

PMID: 27483260

Gene: TNN13 MYBPC3 TNNT2

HGNC ID: 11947 7551 11949

PMID 38223010

Gene: TPM1

HGNC ID: 12010

PMID: 37569730

Gene: TPM1

HGNC ID: 12010

PMID: 29176140

Gene: TNNI3

HGNC ID: 11947

PMID: 30395933

Gene: TNNT1

HGNC ID: 11947

PMID: 40956134

Gene: MYL2

HGNC ID: 7583

Case1: Female, 85 at diagnosis, ethnicity not stated

DiseaseAssertion: Hypertrophic cardiomyopathy (HCM)

FamilyInfo: An index patient’s brother (II.6) was reported with moderate HCM and another brother (II.7) with sudden cardiac death at the age of 40 years. The clinical screening led to the diagnosis of HCM in two of the index patient’s descendants, a daughter and a son. Daughter (III.4, age 59) with septal hypertrophy of 16 mm confirmed by cardiac MRI, son (III.8, age 47) with septal hypertrophy of 15 mm. Daughter (III.6, age 50) is an unaffected carrier. Five other relatives (III.1, III.5, III.6, III.7, IV.1) were healthy with normal cardiac evaluation. Pedigree shown in Figure 1.

ParentalTesting: Not preformed.

CasePresentingHPOs: HP:0001639, HP:0001279

CaseHPOFreeText: Admitted to the emergency unit with chest pain after a pre-syncopal episode at the age of 85. Electrocardiogram showed sinus rhythm, negative T waves in V1-V3 and signs of ventricular hypertrophy. Transthoracic echocardiography detected asymmetric septal hypertrophy of 25 mm with preserved ejection fraction, moderate diastolic dysfunction and mild left atrial enlargement. Twenty-four-hour Holter monitoring documented episodes of non-sustained ventricular tachycardia defined as ≥ 3 beats at a rate of ≥ 120 bpm

CaseNotHPOs: NR

CaseNotHPOFreeText: Coronary artery disease was ruled out

CasePreviousTesting: NR

Genotyping Method: The index patient’s genomic DNA was subjected to massively parallel sequencing to identify the genetic origin of the disease using a 251-gene cardiomyopathy diagnostic panel. Targeted massively parallel sequencing of the index patient’s genomic DNA was performed with an Agilent SureSelect custom library covering 251 genes. For the MYBPC3 gene: all exons including the complete sequence of introns. Sequencing performed on NovaSeq 6000 (Illumina), bioinformatics pipeline using BWA alignment and GATK variant calling, reference genome GRCh37/hg19. Sanger sequencing confirmed both variants

FunctionalAnalysis: Minigene and patient blood RNA splicing assays performed. Both the minigene and patients’ RNA splicing assays revealed that the MYBPC3 c.3331−26T>G variant promoted complete intron 30 retention in the mRNA, and also partial retention of the second half of intron 30. Normal MYBPC3 mRNA was not detected in the MUT lanes. The corresponding normal MYBPC3 fusion protein was not detected with either of the two antibodies in cells transfected with the MUT plasmid.

Variant: NM_000256.3:c.3331−26T>G

ClinVar: 1320039

CAID: CA2573146361

gnomAD: chr11-47332999-A-C

AdditionalInfo: This paper also identified two additional unrelated HCM probands carrying c.3331−26T>G in a large cohort of 9,611 HCM probands

PMID: 35513690

Gene: MYBPC3

HGNC ID: 7551

PMID: 27182706

Gene: LMNA

HGNC ID: 6636

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: 36739943

Gene: TPM1

HGNC ID: 12010

PMID: 35174310 Gene: TNNI3 HGNCID: HGNC:11947

PMID: 39682617

Gene: MYL2

HGNC ID: 7583

PMID: 34213952

Gene: TNNT2

HGNC ID: 11949

PMID:41703309

Gene: MYBPC3

HGNC ID: 7551

PMID: 29493010

Gene: MYBPC3

HGNC ID: 7551

PMID:37067544

Gene: TPM1

HGNC ID: 12010

PMID: 36143383

Gene: MYBPC3

HGNC ID: 7551

PMID: 33817105

Gene: TNNI3

HGNC ID: HGNC:11947

PMID: 39355877

Gene: MYBPC3

HGNC ID: 7551

PMID: 41134850

Gene: MYBPC3

HGNC ID: 7551

PMID: 41440877

Gene: TNNT2

HGNC ID: HGNC:11949

PMID:41728227

Gene: MYBPC3

HGNC ID: 7551

PMID: 37108997

Gene: TNNT2

HGNC ID: 11949

PMID: 34066613

GENE: TNNT2

HGNC ID: 11949

PMID: 21483645

Gene: TNNT2

HGNC ID: 11949

PMID: 19293840

Gene: TNNT2

HGNC ID: 11949

PMID: 32098556

Gene: TNNT2

HGNC ID: 11949

PMID: 20458009

Gene: TNNT2

HGNC ID: 11949

PMID: 37626566

Gene: TNNT2

HGNC ID: 11949

PMID: 32846832

Gene: TNNT2

HGNC ID: 11949

PMID: 35728000

Gene: TNNT2

HGNC ID: 11949

PMID: 21135372

Gene: TNNT2

HGNC ID: 11949

PMID:30565988

Gene:TNNT2

HGNC ID:11949

PMID:41969674

Gene:TNNT2

HGNC ID:11949

PMID: 41561115

Gene: MYBPC3

HGNC ID: 7551

PMID:17347475

Gene:MYOZ2

HGNC ID:1330

PMID:42233912

Gene:MYBPC3, FLNC, PKP2

HGNC ID:7551, 9024, 3756

PMID: 29367541

Gene: TNNT2

HGNC ID: 11949

PMID:39905734

Gene:TNNT2

HGNC ID:11949

PMID : 40008267

Gene: TNNT2

HGNC ID: 11949

PMID: 16679492

Gene: MYBPC3

HGNC ID:7551

Case#: Pedigree III:2; male; HCM diagnosed clinically at age 39 (1998); heart transplant after progression to end-stage heart failure

DiseaseAssertion: Hypertrophic cardiomyopathy (HCM), progressed to end-stage heart failure with systolic dysfunction

FamilyInfo: No family history of heart disease reported at diagnosis; no known consanguinity. Parents deceased and unavailable for testing. 12 relatives genotyped: one brother (III:3) homozygous, seven first- and second-degree relatives heterozygous. All heterozygotes have normal ECG, normal echo, and no cardiac symptoms. Three children of generation IV (IV:7, IV:8, IV:9) still awaiting results.⁠

ParentalTesting: Not performed; both parents deceased. Absence of consanguinity stated but not genetically confirmed; parental phase therefore inferred rather than tested.

CasePresentingHPOs: HP:0001639; HP:0002094 (Dyspnea); HP:0001658; HP:0001678

CaseHPOFreeText: Exertional dyspnea at age 39 with systolic murmur; IVS 26 mm, posterior wall >16 mm, LVOT peak velocity 2.8 m/s. Pacemaker 1999, extracted 2010 for infection. 2013 circumflex occlusion treated with stent (cholesterol 6.8 mmol/L, LDL 4.6 mmol/L; former smoker). Septum 27 mm, moderate systolic dysfunction, NSVT on Holter → ICD. 2014 AF with severe dyspnea; on beta-blocker, ACE inhibitor, and aldosterone antagonist. 2016 VO₂max 14 mL/kg/min; LVEDP 24 mmHg rising to 38 with exercise, pulmonary pressure 56/27 rising to 70/… systolic. Biopsy: moderate interstitial fibrosis, focal hypertrophy and atrophy, no infiltrative disease.

CaseNotHPOs: HP:0000822; HP:0000819

CaseNotHPOFreeText: BP normal throughout, no hypertension. No storage or infiltrative disease on biopsy. Spirometry normal. Narrow QRS, so CRT not indicated.

CasePreviousTesting: 84-gene cardiomyopathy NGS panel (MYBPC3 100% coverage); MLPA confirmed true homozygosity rather than hemizygous deletion; Sanger cascade in 12 relatives.

Genotyping Method: NGS panel followed by MLPA confirmation of homozygosity; Sanger for family cascade.

FunctionalAnalysis: None performed. Biopsy showed interstitial fibrosis with hypertrophy and atrophy, no infiltrative disease. Dominant-negative mechanism proposed, untested.

Variant: MYBPC3 NM_000256.3:c.2618C>A (p.Pro873His); homozygous missense; C7 domain. (Paper writes "c.2618 G>A" once, C>A is correct.)

ClinVar: Not stated; conflicting interpretations noted in the literature. Pepper please verifiy for me!

CAID: N/A

gnomAD: AF 0.00006781 (14/206,446; 13/97,288 European non-Finnish) per the authors.

AdditionalInfo: ACMG Class 2 (likely pathogenic) heterozygous. Authors argue homozygosity drove progression to end-stage failure; alternative triggers considered, prior myocarditis (1989) and the 2013 infarct; but judged insufficient to explain severity.

PMID: 29663722 Gene: MYBPC3 HGNC: HGNC:7551

PMID:20973921

Gene:TNNT2

HGNC ID:11949

Whole genome sequencing in paediatric channelopathy and cardiomyopathy

PMID: 38586174 Gene: MYBPC3 HGNC ID: 7551

PMID 37498360

Gene: TPM1

HGNC ID: 12010

Chronic Activation of Tubulin Tyrosination Improves Heart Function

PMID: 39279670 Gene: MYBPC3 HGNC ID: 7551

Hydroxychloroquine Cardiotoxicity and Sarcomeric Hypertrophic Cardiomyopathy.”

PMID: 40514126 Gene: MYBPC3 HGNC ID: 7551

Case#: 51-year-old Spanish man

DiseaseAssertion: Hypertrophic cardiomyopathy

FamilyInfo: Familial HCM

ParentalTesting:

CasePresentingHPOs: Hypertrophic cardiomyopathy

CaseHPOFreeText: not reported

CaseNotHPOs: not reported

CaseNotHPOFreeText: not reported

CasePreviousTesting: not reported

Genotyping Method: Genetic testing/sequencing

FunctionalAnalysis:

Variant: g.47363647G>A, p.Ala562Val

ClinVar: not found

CAID: CA078267

gnomAD: not found

AdditionalInfo: not reported

PMID: 32453731

Gene: MYL2

HGNC ID: 7583

Case1: Male, Infant, Tunisian

DiseaseAssertion: infantile-onset HCM and mitral valve dysplasia

FamilyInfo: Family with consanguinity in which four children had died before one year of age. The father (37 years old) and mother (27 years old) of the proband are consanguineously related. Two infants (VI:1 and VI:2) died at less than 30 days of age from cardiorespiratory arrest, and two (VI:3 and VI:4, proband) of them displayed abnormal cardiac findings on chest roentgenogram. While all four children displayed hepatomegaly and general hypotonia, VI:3 and VI:4 had a marked increase in heart size and died from refractory cardiogenic shock. The status of the MYL2 allele in siblings is unknown. The proband (fs/fs) was homozygous for the MYL2-fs allele while the parents were found to be heterozygous (fs/wt) carriers. The father (37 years old) and mother (27 years old) of the proband are consanguineously related, were asymptomatic from a cardiac standpoint and had normal cardiac anatomy and function as evaluated by an echocardiogram

ParentalTesting: Homozygous variant in the proband and that the parents are heterozygous carriers using Sanger DNA sequencing of the genomic region. Father (37 years old) and mother (27 years old) were asymptomatic from a cardiac standpoint and had normal cardiac anatomy and function as evaluated by an echocardiogram

CasePresentingHPOs: HP:0200128, HP:0001653, HP:0002092, HP:0001639, HP:0002240

CaseHPOFreeText: Showed a rapid decline in health and was treated for various periods in neonatal intensive care units. The patient also displayed severe mitral valve regurgitation with abnormal thickening of the mitral valve leaflets and pulmonary arterial hypertension. Post-mortem examination of the proband’s heart confirmed severe biatrial dilatation, significant biventricular hypertrophy with small ventricular cavities and severe mitral valve dysplasia

CaseNotHPOs: NR

CaseNotHPOFreeText: no gross developmental defects

CasePreviousTesting: No prior genetic testing reported before exome sequencing

Genotyping Method: Performed exome sequencing on the proband. Exome libraries were constructed using the Agilent SureSelectQXT Target Enrichment System for Illumina Multiplexed Sequencing Protocol (Agilent Technologies, CA). DNA libraries were captured with the Agilent Clinical Research Exome Kit. Paired-end 150 base pair reads were generated for exome-enriched libraries sequenced on the Illumina HiSeq 4000 to a targeted depth of 100× coverage

FunctionalAnalysis: Functional analysis performed. Immunohistochemical analysis of MYL2 expression in the proband’s ventricular myocardium shows a remarkable reduction in the expression of MYL2 as compared to control. Also, MYL2 mRNA was detected in the ventricle of the proband by RT-PCR. This suggests that the frameshift variant adversely affects the levels of MYL2 protein in the proband. Using immunoblot analysis, we observed that overexpression of the MYL2-fs variant was significantly reduced compared to stop-gain variants and the missense variant. When the H9c2 cells were treated with MG-132 after transfection with the MYL2-fs construct, the GFP signal corresponding to MYL2-fs was recovered. The in vitro experiments indicate that the MYL2-fs variant is not stable and that proteasome-mediated degradation of the translated product plays a key role in the instability of the protein. The overexpression of the fs variant identified in our proband or the MYL2-G162R missense variant failed to rescue the phenotype. Results reported in Figures 2, 3, and 4.

Variant: NM_000432.3:c.431_432delCT

ClinVar: NR

CAID: UnregisteredVariant

gnomAD: NR

AdditionalInfo: 4 siblings who died before 1 year of age but MYL2 genotyping was only confirmed in the proband (VI:4)

PMID: 28538763

Gene: TNNT2

HGNC ID: 11949

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: 27141495

Gene: TNNT2

HGNC ID: 11949

PMID: 27199119

Gene: TNNT2

HGNC ID: 11949

PMID: 29709087

Gene: MYL3

HGNC ID: 7584

PMID: 31770195

Gene: TNNT2

HGNC ID: 11949

PMID: 28669108

Gene: TNNT2

HGNC ID: 11949

Case1: Male, 37 years old, Colombian

DiseaseAssertion: asymmetric septal hypertrophic cardiomyopathy

FamilyInfo: During genetic assessment, a family history of hypertrophic cardiomyopathy (HCM) was detected. The patient’s mother had HCM and died at the age of 66; two living brothers have HCM (51 and 60 years of age). In addition, two of his brothers under the age of 35 died suddenly, two more brothers died from an unknown cause before the age of 5, and yet another brother is being examined for possible heart disease. Findings indicated a dominant inheritance pattern for HCM in this family. Pedigree shown in Figure 2.

ParentalTesting: NR

CasePresentingHPOs: HP:0001639, HP:0001663, HP:0001962, HP:000209, HP:0002315

CaseHPOFreeText: At the age of 25, his symptomatology started, including intense fatigue and mild thoracic pain due to physical activity. At the age of 32, an echocardiogram revealed asymmetric septal hypertrophic cardiomyopathy. The thickness of the interventricular septum was 19.5 mm in the basal third, 22 mm in the middle third, and 23 mm in the apical third, and ventricular tachycardia was also present. Alcohol septal ablation was performed. However, ventricular tachycardia and disabling symptoms persisted, so he required an implantable cardioverter-defibrillator at the age of 35. A routine echocardiogram at the age of 36 yielded the following findings: an LV of normal size, mild hypertrophy of the septum, normal systolic function, and diastolic dysfunction with slow LV relaxation. The patient still suffers dyspnea during physical effort and occasionally thoracic pain with palpitations

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

Genotyping Method: A molecular panel for HCM including 17 genes was performed using next-generation sequencing. Sanger sequencing chromatogram focusing on the targeted region including the variation

FunctionalAnalysis: NR

Variant: NM_000432.3:c.260G>C

ClinVar: 43461

CAID: CA009968

gnomAD: NR

AdditionalInfo: NR

PMID: 33139982

Gene: MYL2

HGNC ID: 7583

PMID: 21823217

Gene: MYL3

HGNC ID: 7584

PMID: 26498512

Gene: TNNT2

HGNC ID: 11949

Case#: Single proband ; 63-year-old female; palpitations at presentation July 2025; HCM diagnosis established at age 63

DiseaseAssertion: Hypertrophic cardiomyopathy (HCM) complicated by apical left ventricular aneurysm and mid-ventricular obstruction⁠

FamilyInfo: No family history of cardiac disease or sudden cardiac death at a young age reported. Both parents deceased (one of cancer, one of natural causes at age 92), neither with reported cardiovascular disease; proband has no siblings. Only first-degree relative is her son, who carries the KCNJ5 c.464G>A variant but not the MYBPC3 c.278delA variant, and has a normal echocardiogram with no myocardial hypertrophy. No pedigree beyond the son (Fig. 3B).⁠

ParentalTesting: Not performed; both parents deceased, no DNA available; authors state a valid familial segregation analysis could not be performed. Only one family member (son) was available for cascade Sanger screening.⁠

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy); HP:0001649 (Tachycardia), palpitations; HP:0001712 (Left ventricular hypertrophy).

CaseNotHPOFreeText: No history of hypertension, diabetes, or hyperlipidemia. Phenocopies excluded: no extra-cardiac manifestations of Fabry disease and GLA testing negative; cardiac amyloidosis excluded (no apical sparing, normal serum free light chains, negative serum protein electrophoresis and immunofixation); no significant coronary stenosis on coronary CT angiography. No QT prolongation or features of Andersen–Tawil syndrome on ECG.

CasePreviousTesting: Whole exome sequencing identified both variants; all rare and known variants validated by Sanger sequencing, with cascade Sanger screening in available one family member. No prior genetic testing reported before this episode.

Genotyping Method: Targeted region capture with next-generation high-throughput sequencing (whole exome, exonic plus flanking regions); variants confirmed by bidirectional Sanger sequencing. Cascade screening by Sanger in the son. MYBPC3 variant absent from 1000 Genomes, ESP6500, ExAC, and the Besuper local database. KCNJ5 variant absent from 1000 Genomes and ESP6500, ExAC frequency, absent from local Basenhall controls.⁠

FunctionalAnalysis: None performed; authors list absence of functional studies and lack of mRNA-level validation as limitations. MYBPC3 frameshift predicted to trigger nonsense-mediated decay.⁠

Variant: MYBPC3 NM_000256.3:c.278delA (p.Lys93ArgfsTer3); heterozygous; exon 2; novel, not in ClinVar or HGMD; classified Likely Pathogenic by ACMG (PVS1, PM2). Second variant: KCNJ5 NM_000256.3:c.464G>A (p.Arg155Gln); heterozygous; exon 2; novel, not in ClinVar or HGMD; classified VUS (PM2, PP3). Note the paper's KCNJ5 accession is written as NM_000256.3, which is the MYBPC3 transcript, most likely a typo in the article Pepper please conform for me the correct KCNJ5 accession

ClinVar: No ClinVar record for either variant; nearby KCNJ5 missense variants c.451G>A, c.452G>A, c.470T>G, and c.473C>G are documented as pathogenic/likely pathogenic for long QT syndrome or aldosteronism, and downstream frameshift/nonsense variants at the MYBPC3 locus are classified pathogenic or likely pathogenic.

CAID:Not found.

gnomAD: No allele frequency available, so no MAF to report.

PMID: 42428486

Gene: MYBPC3

HGNC: HGNC:7551

AdditionalInfo:Single-case report, no case numbering system used. Treated with dapagliflozin, metoprolol, rivaroxaban, and recombinant human BNP for 13 days, discharged on the first three; mexiletine added at 1-week follow-up for persistent palpitations. ICD recommended but declined due to financial constraints; 3-month follow-up showed good adherence with occasional palpitations and no serious arrhythmic events. Authors conclude MYBPC3 c.278delA is likely pathogenic for HCM, while the KCNJ5 variant shows no clinical phenotype in the proband or her son and may be incidental or a modifier.⁠

PMID: 27082122

Gene: TNNT2

HGNC ID: 11949

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:

PMID: 33288880

Gene: MYL3

HGNC ID: 7584

PMID: 41999369

Gene: MYL2

HGNC ID: 7583

PMID: 31127036

Gene: MYL2

HGNC ID: 7583

Case1: Male, Infant, ethnicity not stated

DiseaseAssertion: congenital fiber-type disproportion (CFTD) and fatal infantile cardiomyopathy

FamilyInfo: The father was a healthy 20-yr old with no particular medical concerns, and there was no family history of neuromuscular or genetic disorders on either side. Both parents confirmed as heterozygous carriers of the MYL2 c.188del variant by Sanger sequencing

ParentalTesting: Both parents were confirmed as heterozygous carriers of MYL2 c.188del p.(Asn63Metfs7) by Sanger sequencing. Father confirmed as heterozygous carrier of NEB c.25435C>T p.(Gln8479)

CasePresentingHPOs: HP:0001290, HP:0001252, HP:0001640, HP:0001638, HP:0001639

CaseHPOFreeText: Newborn exam revealed normal first and second heart sound with gallop rhythm and palpable liver at the right costal margin, as well as generalized hypotonia and diminished reflexes. Echocardiogram was performed at 11 d of age and revealed patent foramen ovale with left to right shunt and right atrial enlargement. At age 5 mo, the proband was admitted to hospital in decompensated heart failure and intubated on inotropic support. Echocardiography revealed left ventricular dilatation, mild to moderate mitral valve regurgitation, and left atrial enlargement, with left ventricular function moderately to severely decreased with shortening fraction of 12% and ejection fraction of 23%. A vastus lateralis biopsy performed at 5 mo of age because of persistent muscle weakness and hypotonia revealed variability in fiber size with checkerboard pattern of 1:1 ratio of type 1 and type 2 fibers exhibiting hypotrophy of type 1 fiber size in comparison to the type 2 fibers. high lactate level (7.8 mmol/L)

CaseNotHPOs: NR

CaseNotHPOFreeText: Gomori trichrome–stained light micrographs and electron microscopy (EM) showed no evidence of ragged red fiber or nemaline rods, and oxidative stains revealed no evidence of cores, targetoid, or target fibers. Normal serum creatine kinase level. Normal birth weight, length, and head circumference. There was no histopathologic evidence of Pompe disease and GAA enzyme-level testing was normal. Genetic testing for POLG and Noonan syndrome genes normal

CasePreviousTesting: Genetic testing was performed for DNA polymerase γ, catalytic subunit (POLG) and Noonan syndrome genes (PTPN11, SOS1, KRAS, RAF1, BRAF, MAP2K1, MAP2K2, and HRAS), all of which were normal. There was no histopathologic evidence of Pompe disease and GAA enzyme-level testing was normal. Muscular dystrophy was considered unlikely given the histopathologic findings and normal serum creatine kinase level.

Genotyping Method: Next-generation sequencing was performed by the Laboratory for Molecular Medicine (LMM) of Partners Healthcare Personalized Medicine using the Agilent SureSelect Design process. The gene panel utilized an all exon approach for 43 genes of interest for neuromuscular and cardiac conditions by targeting coding exons with bait out to coding sequence (CDS) ±65 bases. The complete coding regions of all genes were sequenced to average depth of 316 reads

FunctionalAnalysis: No functional analysis of the variant was performed

Variant: NM_000432.3:c.188del

ClinVar: NR

CAID: UnregisteredVariant

gnomAD: NR

AdditionalInfo: This case also has a heterozygous pathogenic NEB variant c.25435C>T p.(Gln8479*) inherited from the father, classified as pathogenic but considered unlikely to be a significant contributor to disease as no second NEB allele was identified.

PMID: 37646638

Gene: TNNI3

HGNC ID: 11947

PMID:22957257

Gene:MYL3

HGNC ID:7582