Case#:7 ¾ year old girl

DiseaseAssertion: Hypertrophic cardiomyopathy (HCM), with ventricular tachycardia and Stokes–Adams syndrome.

FamilyInfo: Parents not consanguineous, no family history of cardiovascular disease or sudden cardiac death.

ParentalTesting: Parents not consanguineous, no symptoms

CasePresentingHPOs: HP:0001639, HP:0001695, HP:0001663, HP:0001250, HP:0001678, HP:0001712 “Hypertrophic cardiomyopathy, cardiac arrest, ventricular tachycardia, seizures, atrioventricular block, left ventricular hypertrophy:”

CaseHPOFreeText: Diagnosed with cardiomyopathy in utero. Frequent cardiac arrests from 3-7, multiple seizures a year, cardiac mri showed heart enlargement, hypertrophy, after icd implant no cardiac arrests after 1 year.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: diagnosed with cardiomyopathy in utero, no other testing stated.

Genotyping Method: Whole exon sequencing

FunctionalAnalysis: protein modeling only, revealed to be “probably damaging” score 1.0

Variant: MYH7 NM_000257.3:c.2723T>C (p.Leu908Pro; p.L908P)

ClinVar: no id but is listed under https://www.ncbi.nlm.nih.gov/clinvar/RCV000158849.1/?cmd=HTOn&utm_source=chatgpt.com

CAID: N/A

gnomAD:N/A

AdditionalInfo: patient underwent ICD implantation and had no further arrests after a years time.

** PMID** : 35004917

** Gene** :MYH7

** HGNC ID** : HGNC:7577

Case 7: 47 year old male

DiseaseAssertion: novel MYH7 R1832C in the index case

FamilyInfo:His father died at the age of 47 years due to IDC, whereas a sibling of the index case died suddenly within her first year. It was not possible to obtain DNA from the deceased relatives.

ParentalTesting:NR

CasePresentingHPOs:HP:0012828,HP:0012835, HP:0034307, HP:0012666

CaseHPOFreeText: He had an early onset of symptoms, in his third decade as being the age of 33, with severe dilatation of his left ventricle and depressed LVEF, and required HTX 3 years after the onset of symptoms. A left ventricular end diastolic diameter (in mm and indexed by body surface area (cm/m2)); value of 86mm and 3.2cm/m2. Has a left ventricular ejection fraction of 20%. His clinical status is heart transplantation.

CaseNotHPOs:NR

CaseNotHPOFreeText:NR

CasePreviousTesting:NR

Genotyping Method:NR

FunctionalAnalysis:NR

Variant:NM_000257.4:c.5494C>T

ClinVar:161322

CAID:CA016134

gnomAD: gnomAD v2: 14:23884269 G / A gnomAD v3: 14:23415060 G / A gnomAD v4: chr14-23415060-G-A

AdditionalInfo: This mutation is located in the rod portion of MYH7 and replaces a basic arginine residue with a reactive neutral cysteine residue in the g-position of the heptad repeat in the α-helical myosin rod, and thus may destabilize the salt bridges required for myosin–myosin dimerization.

Case1: A 68-year-old female

DiseaseAssertion: dilated cardiomyopathy (DCM), with the MYH7 p.Lys637Glu (K637E) variant identified in the affected patient. The study investigated sarcomeric gene variants associated with DCM

FamilyInfo: The proband's father (M1, II:3) died suddenly at 36 years of age, 2 years after being diagnosed with DCM.

ParentalTesting: Yes from father

CasePresentingHPOs: HP:0011664, HP:0011713, HP:0003677, HP:0001635,

CaseHPOFreeText: was diagnosed as having left ventricular non-compaction (LVNC) based on echocardiography. A left bundle branch block on her ECG. Echocardiography revealed LVNC and she has had a slow progression towards heart failure and an increasing dilatation of her left ventricle. Age 48 at onset, left ventricular end diastolic diameter 59 mm, left ventricular ejection fraction 25%, ventricular extrasystoles for arrhythmia.

CaseNotHPOs:NR

CaseNotHPOFreeText:NR

CasePreviousTesting:NR

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

FunctionalAnalysis:NR

Variant: NM_000257.4:c.1909A>G

ClinVar: 1329402

CAID:CA389049558

gnomAD: NR

AdditionalInfo: NR

Case 3: A 64 year old female

DiseaseAssertion: The case carried the novel MYH7 K637E mutation

FamilyInfo: Her mother died of a suspected but unconfirmed cardiac cause; thus, this was regarded as a non-FDC case. Two healthy sisters declined participation in the study.

ParentalTesting:NR

CasePresentingHPOs: HP:0003674, HP:0034307, HP:0002372, HP:0011675, HP:0005110

CaseHPOFreeText: Slowly from onset of symptoms at the age of 42 years, and received HTX in her sixth decade. Has left ventricular end diastolic diameter (in mm and indexed by body surface area (cm/m2)), 81mm and then 4.2m2. LVEF as 15%, ECG as normal. Arrhythmia as atrial fibrillation. NYHA as 4. Clinical status as heart transplantation. CAG has a normal level.

CaseNotHPOs:NR

CaseNotHPOFreeText:NR

CasePreviousTesting:NR

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

FunctionalAnalysis: NR

Variant:NM_000257.4:c.1909A>G

ClinVar:1329402

CAID:CA389049558

gnomAD:NR

AdditionalInfo:NR

PMID: 19293840

Gene: MYH7

HGNC ID: 7577

PMID: 24502034

Gene: MYH7

HGNC: 7577

General overview of Ebstein's Anomaly

PMID: 32369506

Gene: MYH7

HGNC: 7577

PMID: 24134628

Gene: MYH7

HGNC: 7577

PMID: 25189259

Gene MYH7

HGNC: 7577

https://www.ias.ac.in/article/fulltext/jgen/093/02/0557-0560

PMID: 24298987

Gene: MYH7

HGNC: 7577

PMID: 23676496

Gene: MYH7

HGNC: 7577

PMID: 27082122

Gene: MYH7

HGNC ID: 7577

Gene: PRKAG2

HGNC ID: 9386

PMID: 24085031

Gene: MYH7

HGNC: 7577

"Defective energy intake and not the reduced uptake of fat-soluble vitamins or cholesterol is responsible for cardiac dysfunction in hLPL0 mice. In addition, our studies suggest that adaptations in cardiac metabolism contribute to the beneficial effects of exercise on the myocardium of patients with heart failure"

PMID: 23656529

Gene: MYH7

HGNC: 7577

PMID: 23991079

Gene: MYH7

HGNC: 7577

"we here applied un-biased transcriptome-wide interrogation to identify molecular changes associated with novel SLP."

PMID: 28790153

Gene: MYH7

HGNC:7577

CaseAJV: 17 years diagnosis, Australia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: Father (index case) died awaiting cardiac transplant (carried both variants). Two possibly affected relatives.

CasePresentingHPOs: HP:0001639, HP:0006536

(Hypertrophic cardiomyopathy, Obstructive lung disease)

HPOsFreeText: Maximum left ventricular hypertrophy at 17 mm, Sudden cardiac death event at 17 years, Maximal wall thickness at 22mm,

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CasePreviousTesting: See Table 1

CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.

Variant:NM_000257.3:c.1954A>G (p.Arg652Gly)

ClinVarID:177626 https://www.ncbi.nlm.nih.gov/clinvar/variation/177626/

gnomAD: Not in gnomAD

Multiple Gene Variants:

MYBPC3 Variant

Variant: NM_000256.3:c.2980C>T (p.Leu994Phe)

ClinVarID:180992 https://www.ncbi.nlm.nih.gov/clinvar/variation/180992/

gnomAD: European (Non-Finnish) 1.624e-4, Overall 8.461e-5 https://gnomad.broadinstitute.org/variant/11-47355487-G-A

PMID: 24047955

Gene: MYH7

HGNC: 7577

"It is unclear why mutations in the filament-forming tail of myosin heavy chain (MHC) cause hypertrophic or dilated cardiomyopathy as these mutations should not directly affect contraction. To investigate this, we first investigated the impact of five hypertrophic cardiomyopathy-causing (N1327K, E1356K, R1382W, E1555K, and R1768K) and one dilated cardiomyopathy-causing (R1500W) tail mutations on their ability to incorporate into muscle sarcomeres in vivo."

Results suggest that small effects of mutations on helicity translate into a reduced ability to incorporate into sarcomeres, which may elicit compensatory hypertrophy.

PMID: 32607476

Gene: MYH7

HGNC: 7577

PMID: 32370479

Gene: MYH7

HGNC: 7577

PMID: 23707328

Gene: MYH7

HGNC: 7577

PMID: 32461996

Gene: MYH7

HGNC: 7577

PMID: 23674365

Gene: MYH7

HGNC: 7577

PMID: 32380038

Gene: MYH7

HGNC: 7577

Case2: female, 16 years old

DiseaseAssertion: Myopathy

FamilyInfo:

CasePresentingHPOs: HP:0040083, HP:0002650, HP:0003722, HP:0001371, HP:0009027, HP:0012515

"Toe walking, Scoliosis, Neck flexor weakness, Flexion contractures, Foot dorsiflexor weakness, Hip flexor weakness"

CaseHPOFreeText: Presented with toe-walking at age 5 years and required bilateral tendo-Achilles releases at ages 7 and 13 years. A progressive scoliosis required surgical stabilization at age 12 years. At age 13 years neck movements were markedly restricted in all directions except extension, and there were mild flexion contractures at the hips, knees and ankles. There was marked neck flexion weakness, moderate weakness of hip extension and ankle dorsiflexion, and mild weakness of shoulder abduction, hip flexion and knee flexion/extension. While walking her upper body was angled forward, there was external rotation of the feet and mild foot-drop. The axial involvement in this case largely spares the lumbar musculature and is restricted to the upper thoracic and neck regions.

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: Serum creatine kinase was 308 iu/l (24–215). There was moderate restrictive lung disease (as determined by formal pulmonary function testing) at age 12 years (FVC 55% of predicted). Electromyography, sural nerve biopsy and cardiac investigations (EKG and echocardiogram) were normal. A quadriceps muscle biopsy taken at age 13 years demonstrated congenital fiber type disproportion. There was type 1 fiber predominance (82%), marked type 1 hypotrophy and type 2 fiber hypertrophy. Muscle MRI scan at age 12 years showed selective fatty infiltration of spinalis muscles in the upper thoracic and cervical regions. Unreported heterozygous variants in RYR1 (p.Asn4200Ser), COL6A3 (p.Ser2829Pro) and TTN (p.Gly4604Glu) were detected, but were all present in a healthy parent. In addition, Sanger sequencing was normal for ACTA1, SEPN1, LMNA, TPM3, TPM2, TNNT1 and MYOZ2.

GenotypingMethod: A heterozygous MYH7 p.Leu1597Arg (c.4790T>G) missense change was found by whole exome sequencing studies, and confirmed by Sanger sequencing. This change was absent in parental DNA samples.

Variant: NM_000257.4:c.4790T>G (MYH7)

ClinVar: not found

CAID: CA389037627

gnomAD: not found

Case1: female, 32 years old

DiseaseAssertion: Myopathy

FamilyInfo: Neither parent presents with MYH7 mutation

CasePresentingHPOs: HP:0002828, HP:0040083, HP:0003722, HP:0012515, HP:0009027, HP:0001371

"Multiple joint contractures, Toe walking, Neck flexor weakness, Hip flexor weakness, Foot dorsiflexor weakness, flexion contractures"

CaseHPOFreeText: Generalized weakness that is most notable in the distal musculature, presented with toe walking age 2 years, required multiple Achilles tendon lengthening surgeries between ages 11–14 years. From age 19 years patient developed progressive weakness and contractures. At age 32 years, patient could walk only short distances and had prominent contractures of the finger flexors, neck flexors, and tendo-Achilles. There was marked weakness of neck flexion, shoulder abduction, hip flexion and ankle dorsiflexion and moderate weakness of wrist/hand flexors and mild weakness of knee flexion/extension. Facial and ocular muscle function was normal.

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: Muscle MRI of the thigh reveals involvement of many muscles including sartorius, quadriceps, and adductors, with relative sparing of biceps femoris. Muscle MRI of the distal lower extremity shows fatty infiltration in the soleus and lateral gastrocnemius with relative sparing of the medial gastrocnemius. Electromyography (EMG) showed myopathic features and serum CK was mildly elevated. Cardiac evaluation (via EKG and echocardiogram) was unremarkable. At age 32 years, based on formal pulmonary function testing, patient exhibited moderate restrictive lung disease (forced vital capacity 63% of predicted). A quadriceps muscle biopsy performed at age 11 years showed non-specific myopathic changes while a gastocnemius biopsy performed at age 32 years showed prominent mini-cores, increased internalized nuclei (~40% of fibers), type I fiber predominance, mildly increased endomysial fibrosis and focal fatty replacement. Sanger sequencing was normal for RYR1 (full exonic sequencing), SEPN1, LMNA, and COL6A1/2/3.

GenotypingMethod: A heterozygous MYH7 p.Leu1597Arg (c.4790T>G) missense change was detected in the patient and not found in either parent.

Variant: NM_000257.4:c.4790T>G (MYH7)

ClinVar: not found

CAID: CA389037627

gnomAD: not found

PMID: 23478172

Gene: MYH7

HGNC: 7577

PMID: 23580644

Gene: MYH7

HGNC: 7577

PMID: 32424548

Gene: MYH7

HGNC: 7577

PMID: 24120154

Gene: MYH7

HGNC: 7577

This study investigated whether miR208a is a critical regulator in cardiomyocyte hypertrophy under mechanical stretch.

PMID: 32478919

Gene: MYH7

HGNC: 7577

Unable to access full text

PMID: 23674513

Gene: MYH7

HGNC: 7577

PMID: 32394868

Gene: MYH7

HGNC: 7577

PMID: 32380161

Gene: MYH7

HGNC: 7577

PMID: 32422568

Gene: MYH7

HGNC: 7577

Case1: male, 38, caucasian

DiseaseAssertion: hypertrophic cardiomyopathy

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting:

GenotypingMethod: the presence of p.M659I (c.1977G > A) mutation in the iPSC lines was confirmed by Sanger sequencing of exon 18 of MYH7 (Fig. 1F).

Variant: NM_000257.4:c.1977G>A

ClinVar: not found

CAID: CA389049400

gnomAD: not found

Case1: 7-year-old girl

DiseaseAssertion: HCM

FamilyInfo: clinical history was negative. Unable to obtain clinical information on first-degree relatives. Both parents carried MYH7 mutation.

CasePresentingHPOs: HP:0025490, HP:0100598

"Myocardial bridging, Pulmonary edema"

CaseHPOFreeText: In the last weeks, patient had frequently been visited by a pediatrician to treat seasonal allergies. Full-body CT-scan was performed to exclude abuse or trauma and did not show any anomaly. The heart (weight: 240 g, longitudinal diameter: 11 cm, transverse diameter: 10 cm, thickness of the anterior wall of the right ventricle: 0·3 cm, thickness of the left ventricle: 1·0 cm) did not reveal morphologic or structural anomalies of ventricular walls and valves. The coronary circulation was right-dominant and presented myocardial bridging (length: 1·1 cm, thickness: 0·5 cm) involving the middle segment of the left anterior descending coronary artery. No other significant elements were found upon macroscopic observation, with the exception of pulmonary edema. Histopathological examination showed patchy interstitial fibrosis, myocyte disarray and waving of the myofibers in the tissue surrounding the tunneled artery. Several areas of interstitial and subendocardic fibrosis in the other samples of the left ventricular myocardium were also observed.

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: The low value of serum tryptase (6·12 µg/L) excluded a fatal anaphylaxis. Toxicology tests were negative. NGS analysis used a custom resequencing panel which included 147 genes associated with cardiomyopathies and channelopathies. Authors identified five rare genetic variants in heterozygous state (Table 4).

GenotypingMethod: Genomic DNA was extracted from postmortem whole blood of the proband. Whole blood samples of the proband mother, father and sister were obtained to extract genomic DNA and thus to perform Sanger sequencing to analyze the segregation of each genetic variant identified by NGS. Authors performed Sanger sequencing on the DNA extracted from the mother, the father and the sister of the proband. The father carried both variants identified in the DPP6 gene, whereas the mother carried the rare variants identified in MYH7, SCN2B and NOTCH1. The sister carried all the genetic variants.

Variant: NM_000257.4:c.2585C>T

ClinVar: 36636

CAID: CA012680

gnomAD: https://gnomad.broadinstitute.org/variant/14-23894072-G-A

0.00008014 African/African-American

PMID: 32361481

Gene: MYH7

HGNC: 7577

PMID: 32492895

Gene: MYH7

HGNC: 7577

"The objectives of this study were to assess the spectrum of genetic variants and genotype–phenotype relationships within a Korean HCM population. Methods: Eighty-nine consecutive unrelated HCM patients were included. All patients underwent genotypic analysis for 23 HCM-associated genes. Clinical parameters including echocardiographic and cardiac magnetic resonance (CMR) parameters were evaluated. A composite of major adverse cardiac and cerebrovascular events was assessed. Results: Genetic variants were detected in 55 of 89 subjects. Pathogenic variants or likely pathogenic variants were identified in 27 of HCM patients in MYBPC3, TNNI3, MYH7, and MYL7."

PMID: 23590259

Gene: MYH7

HGNC: 7577

PMID: 23444318

Gene: MYH7

HGNC: 7577

PMID: 24300783

Gene: MYH7

HGNC: 7577

PMID: 24093860

Gene: MYH7

HGNC: 7577

PMID: 23567182

Gene: MYH7

HGNC: 7577

TRIM72 expression

PMID: 24113344

Gene: MYH7

HGNC: 7577

This study sought to reassess single-nucleotide variant classification in hypertrophic cardiomyopathy probands. a total of 136 unrelated hypertrophic cardiomyopathy probands had genetic testing, of which 63 (46%) carried at least one pathogenic mutation. MYBPC3 (n = 34; 47%) and MYH7 (n = 23; 32%)

PMID: 32481709

Gene: MYH7

HGNC: 7577

PMID: 24119082

Gene: MYH7

HGNC: 7577

24 rare variants (3 in MYH6, 3 in MYH7, 3 in MYBPC3, 2 in TNNT2, and 13 in TTN) affecting 52 subjects in 25 families:

MYH7 (c.2945 T>C, p.M982T; c.4300 C>T, p.R1434C; c.4498 C>T, p.R1500W)

PMID: 23663701

Gene: MYH7

HGNC: 7577

PMID: 23508784

Gene: MYH7

HGNC: 7577

PMID: 24183960

Gene: MYH7

HGNC: 7577

PMID: 28790153

Gene: MYH7

HGNC:7577

CaseAJV: 17 years diagnosis, Australia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: Father (index case) died awaiting cardiac transplant (carried both variants). Two possibly affected relatives.

CasePresentingHPOs: HP:0001639, HP:0006536

(Hypertrophic cardiomyopathy, Obstructive lung disease)

HPOsFreeText: Maximum left ventricular hypertrophy at 17 mm, Sudden cardiac death event at 17 years, Maximal wall thickness at 22mm,

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CasePreviousTesting: See Table 1

CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.

Variant:NM_000257.3:c.1954A>G (p.Arg652Gly)

ClinVarID:177626 https://www.ncbi.nlm.nih.gov/clinvar/variation/177626/

gnomAD: Not in gnomAD

Multiple Gene Variants:

MYBPC3 Variant

Variant: NM_000256.3:c.2980C>T (p.Leu994Phe)

ClinVarID:180992 https://www.ncbi.nlm.nih.gov/clinvar/variation/180992/

gnomAD: European (Non-Finnish) 1.624e-4, Overall 8.461e-5 https://gnomad.broadinstitute.org/variant/11-47355487-G-A