Case3: 73 year old man

DiseaseAssertion: He carried the MYL2 p.Ala13Thr variant

FamilyInfo: Yes, his wife, son, and daughter

ParentalTesting: Yes with screening by ECG and Echocardiography; underwent 12-lead electrocardiography (ECG), echocardiography (M-mode, 2D, and Doppler), and cardiac magnetic resonance imaging (CMR).

CasePresentingHPOs: HP:0002094, HP:0003388, HP:0012828, HP:0001650, HP:0034313, HP:0030882

CaseHPOFreeText: presented with dyspnea on exertion and easy fatigability. He was found to have severe aortic stenosis with an aortic valve area of 1 cm2 and a peak gradient of 68 mmHg. He had mild LVH with a wall thickness of 13 mm on an echocardiogram and a left ventricular ejection fraction (LVEF) of > 70%. A 12-lead ECG was unremarkable without evidence of LVH. He also had an 80% luminal diameter stenosis of left anterior descending coronary artery on coronary angiography. He underwent aortic valve replacement and a single vessel coronary artery bypass surgery. He has been asymptomatic since surgery

CaseNotHPOs:NR

CaseNotHPOFreeText:NR

CasePreviousTesting: Whole exome sequencing (WES)

Genotyping Method: Sanger sequencing

FunctionalAnalysis:NR

Variant:NM_000432.4:c.37G>A

ClinVar:14064

CAID:CA010242

gnomAD: gnomAD v2 12:111356964 C / T , gnomAD v3 12:110919160 C / T ,gmonAD v4 chr12-110919160-C-T

AdditionalInfo:NR

Case4: 43 year old woman.

DiseaseAssertion: diagnosed with HCM and carried variants in TTN, ALPK3, and MYL2 (p.Ala13Thr).

FamilyInfo:Other family members, II-1 is a 72-year old woman with history of intermittent atrial flutter with a normal interventricular septal thickness (8 mm) and a normal LVEF (58%). Likewise, individual II-4 is an asymptomatic 70-year old male, who had normal ECG, echocardiogram, and myocardial stress perfusion tomography. Proband’s children (IV-1 and IV-2) were asymptomatic and had normal ECGs and echocardiograms on the last evaluation. Likewise, individual IV-3 was a 7-year old asymptomatic boy who had a normal ECG and echocardiogram.

ParentalTesting: Yes, mother, brother, and father were tested

CasePresentingHPOs:HP:0031664, HP:0012835, HP:0004972, HP:0001670, HP:0034313, HP:0031656, HP:0012825

CaseHPOFreeText: Her physical exam was notable for the presence of a II/VI mid-systolic ejection murmur at left sternal border that radiated toward base of the heart. She also had a mildly elevated arterial blood pressure. A 12-lead ECG showed evidence of LVH, interventricular conduction delay, and repolarization abnormalities. An echocardiogram showed severe asymmetric septal hypertrophy with a hyperdynamic LV systolic function, systolic anterior motion of the mitral leaflet, and a LVOT gradient of 60 to 70 mmHg at rest (Figure 3B). CMR findings were also notable for asymmetric septal hypertrophy and mild patchy hyperenhancement.

CaseNotHPOs:NR

CaseNotHPOFreeText:NR

CasePreviousTesting: Whole exome sequencing (WES)

Genotyping Method: Sanger sequencing

FunctionalAnalysis:NR

Variant:NM_000432.4:c.37G>A

ClinVar:14064

CAID:CA010242

gnomAD: gnomAD v2 12:111356964 C / T , gnomAD v3 12:110919160 C / T ,gmonAD v4 chr12-110919160-C-T

AdditionalInfo:NR

Case2: 63 year old woman, diagnosed with HCM

DiseaseAssertion: Individual carried the MYL2 p.Ala13Thr, TTN, and ALPK3 variants.

FamilyInfo: Yes, son and daughter and husband was all diagnosed.

ParentalTesting: Yes with screening by ECG and Echocardiography; underwent 12-lead electrocardiography (ECG), echocardiography (M-mode, 2D, and Doppler), and cardiac magnetic resonance imaging (CMR).

CasePresentingHPOs: HP:0004383, HP:0005144, HP:0001962, HP:0001279, HP:0001278, HP:0031295, HP:0040284, HP:0011703, HP:0025275

CaseHPOFreeText: Echocardiographic findings of a hyperdynamic left ventricle and an interventricular septal thickness of 19 mm. She had a history of brief episodes of palpitations and one episode of syncope a few years earlier, which was thought to be due to orthostatic hypotension. A 12-lead ECG was notable for possible left atrial enlargement. A 30-day rhythm monitoring showed rare ventricular ectopic beats and episodes of sinus tachycardia. CMR showed a normal LV wall thickness and function and minimal patchy mid myocardial hyperenhancement in the basal inferior and infero-lateral wall.

CaseNotHPOs: HP:0000822, HP:0001639, HP:0032092

CaseNotHPOFreeText: No history of systemic arterial hypertension, valvular disease, or other conditions to explain cardiac hypertrophy. No LVOT obstruction.

CasePreviousTesting: Whole exome sequencing (WES)

Genotyping Method: Sanger sequencing

FunctionalAnalysis: NR

Variant:NM_000432.4:c.37G>A

ClinVar:14064

CAID:CA010242

gnomAD: gnomAD v2 12:111356964 C / T , gnomAD v3 12:110919160 C / T ,gmonAD v4 chr12-110919160-C-T

AdditionalInfo:NR

Case1: A 44-year old male of European (non-Finnish) ancestry.

DiseaseAssertion: Disease, with the MYL2 p.Ala13Thr variant.

FamilyInfo: Mother, father, and sister was diagnosed at different ages; they all had it.

ParentalTesting: Yes with screening by ECG and Echocardiography; underwent 12-lead electrocardiography (ECG), echocardiography (M-mode, 2D, and Doppler), and cardiac magnetic resonance imaging (CMR).

CasePresentingHPOs:HP:0100749, HP:0002094, HP:0031664, HP:0033678, HP:0011703, HP:0001712, HP:0031296,HP:0020034, HP:0031656

CaseHPOFreeText: Presented 3 years ago with persistent but mild chest pain and dyspnea. presence of II/VI mid-systolic murmur that increased with the Valsalva maneuver. Cardiac enzymes were negative for acute coronary syndromes. A 12-lead ECG was notable for sinus tachycardia at the rate of 104 bpm and evidence of left ventricular hypertrophy (LVH) with repolarization abnormalities. Myocardial stress perfusion tomography showed homogeneous distribution of the radiotracer in the myocardium. An echocardiogram showed a hyperdynamic left ventricle with moderate asymmetric septal hypertrophy, a maximum wall thickness of 1.8 cm. There was a resting left ventricular outflow tract (LVOT) gradient of 20 mmHg that increased to 40 mmHg upon Valsalva maneuver. CMR findings were notable for septal hypertrophy and diffuse patchy hyperenhancement, involving multiple myocardial walls. increasing dyspnea with a mild level of physical activity and chest pain. Evidence of LVH with repolarization abnormalities on a 12-lead ECG and a hyperdynamic left ventricle with a septal thickness of 2 cm, systolic anterior motion of mitral leaflets, mild to moderate mitral regurgitation, and an LVOT gradient of 100 mmHg on echocardiography (Figure 3A). Underwent surgical myectomy, which led to resolution of LVOT gradient and symptoms.

CaseNotHPOs: HP:0011675, HP:0011703

CaseNotHPOFreeText: Not show significant cardiac arrhythmias except for periods of sinus tachycardia at rest.

CasePreviousTesting: Whole exome sequencing (WES)

Genotyping Method: Sanger sequencing

FunctionalAnalysis: May affect cardiac contractile function and actin filament velocity, But NR about the MYL2 p.Ala13Thr variant.

Variant: NM_000432.4:c.37G>A

ClinVar:14064

CAID: CA010242

gnomAD: gnomAD v2 12:111356964 C / T , gnomAD v3 12:110919160 C / T gmonAD v4 chr12-110919160-C-T

AdditionalInfo: NR