Case2: 16-year-old male patient

DiseaseAssertion: monomorphic VT

FamilyInfo:NR

ParentalTesting:NR

CasePresentingHPOs:HP:0031676, HP:0033118, HP:0032643

CaseHPOFreeText: Moderately decreased right ventricular (RV) function and moderate RV dilation. moderate myocyte hypertrophy with mild to moderate interstitial fibrosis and rare adipose tissue. Cervical, mediastinal, abdominal, and pelvic FDG-avid lymphadenopathy. myocyte hypertrophy with patchy interstitial fibrosis.

CaseNotHPOs: NR

CaseNotHPOFreeText:NR

CasePreviousTesting:NR

Genotyping Method:NR

FunctionalAnalysis:NR

Variant: NM_001005242.3:c.148_151del

ClinVar: 45028

CAID: CA011079

gnomAD:NR

AdditionalInfo:NR

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

Case#: A 36-year-old Italian female

DiseaseAssertion: Restrictive cardiomyopathy (RCM), associated with a homozygous TPM1 p.Asn279His variant.

FamilyInfo: The patient’s parents are first cousins and confirmed heterozygotes for p.Asn279His (Fig 2).The patient’s 75-year-old father was diagnosed with HCM at 42 years of age. He reportedly has a history of heart failure but is currently asymptomatic. The patient’s 67-year-old mother had her first echocardiogram after the patient’s diagnosis.(Table I).

ParentalTesting: Father and mother

CasePresentingHPOs: HP:0100749, HP:0002875, HP:0002094, HP:0012764, HP:0003270, HP:0000131, HP:0001635

CaseHPOFreeText: She was diagnosed with RCM and is being evaluated for heart transplantation. was referred for chest pain, lightheadedness, shortness of breath, significant fatigue, dyspnea on exertion, three-pillow orthopnea and abdominal bloating. Eighteen months previously, she had been diagnosed with an unspecified form of cardiomyopathy after developing volume overload while hospitalized for a right oophorectomy and uterine fibroid removal. Her symptoms were consistent with NYHA III–IV heart failure. She has continued to have significant heart failure symptoms that have been difficult to control with medical therapy. Freedom from arrhythmias, however, has been notable. She is currently being considered for orthotopic heart transplantation but her evaluation has been complicated by psychiatric issues.

CaseNotHPOs: HP:0001279, HP:0010741

CaseNotHPOFreeText: She denied syncope and lower extremity edema

CasePreviousTesting: The patients father and mother were tested.

Genotyping Method: Sarcomere gene sequencing

FunctionalAnalysis: used computational analysis and evolutionary conservation to assess the variant of TPM1 p.Asn279His.

Variant: NM_001018005.2:c.835A>C

ClinVar: 43446

CAID: CA018397

gnomAD: NR

Case#: An El-Salvadoran 22-year-old female

DiseaseAssertion: Restrictive cardiomyopathy (RCM), associated with sarcomeric gene variants in MYL3 and MYL2

FamilyInfo: The patient’s mother was the only family member available for evaluation (Fig 2). On genetic testing she was found to be a double heterozygote for the p.Glu143Lys mutation in MYL3 and the p.Gly57Glu mutation in MYL2. She had a normal transthoracic echocardiogram, electrocardiogram, and physical exam at 45 years of age

ParentalTesting: Patients mother

CasePresentingHPOs: HP:0002099, HP:0012378, HP:0012764, HP:0001962, HP:0034807, HP:0001541, HP:0001410, HP:0031667, HP:0004749,

CaseHPOFreeText: diagnosed with RCM and advanced heart failure requiring heart transplantation. A prior diagnosis of childhood asthma presented with worsening fatigue and dyspnea on exertion over the course of 12 months. She reported having frequent episodes of shortness of breath as a child, also reported orthopnea, paroxysmal nocturnal dyspnea, and palpitations; her heart failure symptoms were classified as NYHA Class III–IV. did have ascites suggestive of congestive hepatopathy. Her cardiovascular examination revealed a nondisplaced, nonsustained point of maximal impulse, with a mild parasternal lift without a pulmonary artery tap.She had a normal S1, but P2>A2. She had an S3, but no S4. She had a soft I/IV holosystolic murmur over the apex; no knock or rub. Her electrocardiogram demonstrated atrial flutter with an atrial rate of 250–300 and a ventricular rate of 85.

CaseNotHPOs: HP:0002321, HP:0001279, HP:0010741

CaseNotHPOFreeText: She denied dizziness, syncope, and lower extremity edema.

CasePreviousTesting: The patient's mother was also tested to assess inheritance.

Genotyping Method: Sarcomere gene sequencing

FunctionalAnalysis: MYL2 p.Gly57Glu variant using sequence conservation and computational splice-site prediction

Variant: NM_000432.4:c.170G>A

ClinVar:43458

CAID: CA009910

gnomAD: gnomAD v2 12:111352094 C / T https://gnomad.broadinstitute.org/variant/12-111352094-C-T?dataset=gnomad_r2_1 gnomAD v3 12:110914290 C / T https://gnomad.broadinstitute.org/variant/12-110914290-C-T?dataset=gnomad_r3 , gnomAD v4 chr12-110914290-C-T https://gnomad.broadinstitute.org/variant/chr12-110914290-C-T?dataset=gnomad_r4