Case#: 29 year old female; diagnosed with DCM 8 years before death; died suddenly at home on 22 February 2017; forensic autopsy case

DiseaseAssertion: Dilated cardiomyopathy (DCM) with sudden cardiac death; MYBPC3-related

FamilyInfo: Family from Central-South China with a history of SCD. Father (I:1) reportedly died of a heart attack at 37, not genetically tested. Mother (I:2) and sister (II:2) are unaffected and do not carry the variant. No other affected relatives reported.

ParentalTesting: Not performed, both parents were not genotyped for the variant; the father was deceased before the study. Maternal non-carriage confirmed by Sanger, so the variant is either paternal or de novo; phase not established.

CasePresentingHPOs: HP:0001644; HP:0001645

CaseHPOFreeText: Diagnosed with DCM 8 years before death, with no other abnormalities. Found unresponsive at home at noon and expired; no prodromal symptoms documented. Autopsy: enlarged heart with valve thickening, myocardial fibrosis, and multi-organ congestion; no other fatal injury or disease. HE staining of left ventricle showed no hypertrophy or other anomalies. Toxicological screening for ethanol, benzodiazepines, barbiturates, amphetamine, methamphetamine, ketamine, morphine, MDMA, and THC-acid was negative; serum IgE normal (27 IU/ml); eosinophils 4.7% with no mast-cell degranulation.

CaseNotHPOs: HP:0001639; HP:0001634; HP:0003124

CaseNotHPOFreeText: No cardiomyocyte hypertrophy on histology, distinguishing this from HCM. No coronary, valvular, or congenital structural disease identified. No toxicological cause of death.

CasePreviousTesting: Whole-exome sequencing on postmortem blood, retaining synonymous variants; filtering against gnomAD and CMDB; in silico prediction with MutationTaster, PolyPhen-2, and SIFT; NetGene2-2.42 used to predict splice effects. Five variants in cardiomyopathy-related genes were found; only the MYBPC3 variant was classified likely pathogenic.

Genotyping Method: WES with Sanger confirmation on ABI 3100; family members genotyped by Sanger.

FunctionalAnalysis: Minigene assay pcDNA3.1-MYBPC3 construct spanning exon 1-intron 1-exon 2, transfected into HEK293 cells: wild-type and the c.10G>A negative control both produced a ~1,500 bp full-length band and a ~300 bp spliceosome band; the c.24A>C construct produced no spliceosome band, indicating abnormal splicing with intron 1 retention and frameshift. Immunohistochemistry showed decreased MYBPC3 protein in the proband's left ventricle versus a control heart.

Variant: MYBPC3 NM_000256.3:c.24A>C (p.Pro8Pro); heterozygous synonymous variant at the penultimate base of exon 1; disrupts the splice donor site; novel

ClinVar: 164098

CAID: CA11138

gnomAD: 0.00001541

AdditionalInfo: Classified likely pathogenic with PS3, PM2, PP1, PP3; note the paper's Discussion relabels the prediction code as PP4, an internal inconsistency. The authors describe it as the first reported deleterious synonymous MYBPC3 variant, acting by intron retention and reduced protein. The same splice site is affected by the known HCM variants c.24+1G>A and c.24+3A>C. Four other variants were found and classified likely benign or VUS: LDB3 c.2131T>C (VUS), BBS2 c.422A>G, EVC2 c.2643G>C, and BBS4 c.1548_1549del.

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)

Case#: Patient 1, individual II.1 (Fig. 2A); 22-year-old Salvadoran female

DiseaseAssertion: Restrictive cardiomyopathy (RCM) with advanced heart failure

FamilyInfo: Patient denied a family history of cardiomyopathy, although supporting records were unavailable. Her mother (I.2) was clinically unaffected at age 45 and heterozygous for both MYL3 p.Glu143Lys and MYL2 p.Gly57Glu. Other family members were unavailable for evaluation (Fig. 2A; Table I).

ParentalTesting: Mother (I.2) was confirmed heterozygous for MYL3 c.427G>A (p.Glu143Lys) and MYL2 c.170G>A (p.Gly57Glu). Paternal testing was not reported.

CasePresentingHPOs: HP:0012764 (Orthopnea); HP:0004749 (Atrial flutter); HP:0031295 (Left atrial enlargement); HP:0030718 (right atrial enlargement)

CaseHPOFreeText: Worsening fatigue and exertional dyspnea over 12 months, paroxysmal nocturnal dyspnea, palpitations, NYHA Class III–IV heart failure, and ascites suggestive of congestive hepatopathy. Echocardiography showed severe biatrial enlargement and advanced left ventricular diastolic dysfunction with preserved systolic function. Additional findings included myocardial fibrosis and myofiber disarray on biopsy.

CaseNotHPOs: NR

CaseNotHPOFreeText: At initial presentation, patient denied dizziness, syncope, and lower-extremity edema. No S4 heart sound was detected. Recurrent syncope developed later.

CasePreviousTesting: Targeted sequencing of eight sarcomere genes (ACTC, MYBPC3, MYH7, MYL2, MYL3, TNNI3, TNNT2, TPM1). Genome-wide analysis was not reported. An additional heterozygous MYL2 variant, c.170G>A (p.Gly57Glu), was identified (ClinVar Variation ID: 43458; CAID: CA009910).

Genotyping Method: Sequencing of coding exons and intron–exon boundaries of MYL3 and seven additional sarcomere genes, performed by a commercial CLIA-certified laboratory (Correlagen Diagnostics, Inc.). The specific sequencing platform was not reported.

FunctionalAnalysis: NR

Variant: MYL3 NM_000258.2:c.427G>A (p.Glu143Lys); homozygous

ClinVar: 14063

CAID: CA013774

gnomAD: MYL3 c.427G>A (p.Glu143Lys). Highest reported ancestry-specific allele frequency: 0.0002333 (0.02333%) in the Admixed American population (AC = 14). Overall AF (exomes): 0.000008209; AF (genomes): 0.00001314; AF (total): 0.000008674. https://gnomad.broadinstitute.org/variant/3-46859529-C-T?dataset=gnomad_r4.

AdditionalInfo: Patient developed recurrent syncope and received an implantable cardioverter-defibrillator. She underwent orthotopic heart transplantation six months after RCM diagnosis. Authors considered the homozygous MYL3 and heterozygous MYL2 variants likely contributors to disease, although their individual contributions were not established. Clinical and family findings are reported in Patient 1, Figure 2A, and Table I.

Table III

Case 748: Italian, Female, 16yo

DiseaseAssertion: HCM

FamilyInfo: Family history of HCM and sudden cardiac death

CasePresentingHPOs: HP:0001712, HP:0004756, HP:0005110, HP:0001716 (left ventricular hypertrophy, ventricular tachycardia, atrial fibrillation, Wolff-Parkinson-White syndrome)

CaseHPOFreeText: maximum left ventricular wall thickness of ≥15 mm, LVWT = 17mm, automatic implantable cardioverter defibrillator, LV ejection fraction = 60%

CasePreviousTesting: echocardiography, Full testing (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1), additional testing: (GLA, LAMP2, PRKAG2), additional genes added with NGS: (TNNC1, MYH6, MYOM1, MYOZ2, ANKRD1, VCL, CALR3, CAV3)

CaseGenotypingMethod: Genomic DNA extracted from peripheral leukocytes, Sanger sequencing (73 samples), Next-gen sequencing (19 samples)

Variant: NM_000257.3(MYH7):c.5287G>A (p.Ala1763Thr)

ClinVar: 177846, https://www.ncbi.nlm.nih.gov/clinvar/variation/177846/

gnomAD: 0.00007423, https://gnomad.broadinstitute.org/variant/14-23884476-C-T

MultipleGeneVariants:

(1) LAMP2 Variant:

Variant: NM_002294.2(LAMP2):c.928G>A (p.Val310Ile)

ClinVar: 9982, https://www.ncbi.nlm.nih.gov/clinvar/variation/9982/

gnomAD: n/a

Case4: 47 year old male

DiseaseAssertion: Carried the MYBPC3 R326Q mutation

FamilyInfo:His father had onset of symptoms at 77 years of age and is stable on medication. Two asymptomatic young children (M21, III:1 and :2) had no signs of hypertrophy or dilatation on echocardiography and normal ECG.

ParentalTesting: NR

CasePresentingHPOs: HP:0011713, HP:0034307, HP:0012665, HP:0001635

CaseHPOFreeText: Had onset of symptoms at 42 years, LBBB on ECG and required cardiac resynchronization therapy. Has left ventricular end diastolic diameter (in mm and indexed by body surface area (cm/m2) of 81 mm and 3.6 cm/m2. A left ventricular ejection fraction as 20%. ECG as left bundle branch block. Clinical status as DCM/ congestive heart failure. CAG as normal. As well with cardiac resynchronization therapy.

CaseNotHPOs: HP:0011675

CaseNotHPOFreeText: No arrhythmia

CasePreviousTesting:NR

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

FunctionalAnalysis: It results in the replacement of a conserved charged arginine with neutral glutamine at residue 326 in the phosphorylatable MyBPC motif of cMyBPC. This charge change is likely to cause functional impairment.

Variant:NM_000256.3:c.977G>A

ClinVar:42813

CAID:CA016212

gnomAD: gnomAD v2: 11:47367871 C / T gnomAD v3: 11:47346320 C / T gnomAD v4: chr11-47346320-C-T

AdditionalInfo:NR

Case5: 65 year-old male

DiseaseAssertion: carried a known TNNT2 K247R mutation as well as two novel intronic variants in MYH7 (IVS39+7C>A) and MYBPC3 (IVS25+13T>A)

FamilyInfo: None of his five siblings were affected, judged by their clinical presentation, nor was there any history of cardiac disease or sudden death in the family.

ParentalTesting:NR

CasePresentingHPOs:HP:0003677, HP:0012828, HP:0001635, HP:0005110, HP:0034307, HP:0012666,

CaseHPOFreeText: had late-onset at age 47 IDC, with a slow progression to severe heart failure and subsequently HTX. He also suffered from atrial fibrillation in the later stages of his disease. Had left ventricular end diastolic diameter (in mm and indexed by body surface area (cm/m2)) with a value of 68mm and 3.4cm/m2. As well with 30% of left ventricular ejection fraction. His ECG is normal, clinical status is heart transplantation from the age of 56. CAG is normal.

CaseNotHPOs:NR

CaseNotHPOFreeText:NR

CasePreviousTesting:NR

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

FunctionalAnalysis: The variant could thus possibly result in the synthesis of a limited amount of the slightly modified β-myosin. The functional significance of this is not easily established, but it suggests that the variant may be a disease modifier.

Variant:NM_001276345.2:c.869A>G

ClinVar:4881578

CAID:CA344201883

gnomAD:NR

AdditionalInfo: MYH7 (IVS39+7C>A) increased the likelihood of a cryptic donor splice site to 70%, possibly resulting in the synthesis of mRNA coding for a β-myosin with a C terminus of –VGLE instead of –GLNEE. As the variant is located in the last exon, the faulty spliced mRNA is probably not degraded but results in the synthesis of a modified protein.

Case8: 56 year old male

DiseaseAssertion: A double heterozygous for the known MYBPC3 R326Q mutation.

FamilyInfo: His father died due to IDC in his fourth decade, whereas his brother developed IDC. DNA was not available from either of these individuals.

ParentalTesting:NR

CasePresentingHPOs:HP:0005110, HP:0034307,HP:0012666, HP:0011675, HP:0005110, HP:0100651

CaseHPOFreeText: He also developed atrial fibrillation, well regulated on medication. Had onset conditions at age 36. He had left ventricular end diastolic diameter (in mm and indexed by body surface area (cm/m2)); as a value of 65mm and 3.2 cm/m2. A LVEF, left ventricular ejection fraction as 15%. Arrhythmia level as atrial fibrillation. Clinical status as heart transplantation. He also has type 1 diabetes mellitus

CaseNotHPOs:NR

CaseNotHPOFreeText:NR

CasePreviousTesting:NR

Genotyping Method:NR

FunctionalAnalysis:NR

Variant:NM_000256.3:c.977G>A

ClinVar:42813

CAID:CA016212

gnomAD:gnomAD v2: 11:47367871 C / T gnomAD v3: 11:47346320 C / T gnomAD v4: chr11-47346320-C-T

AdditionalInfo:NR

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

Case6: 48 year old male

DiseaseAssertion: Carried the MYBPC3 E619K mutation

FamilyInfo:Three unaffected children were examined (IV:1, IV:2 and IV:3), all with normal echocardiography without signs of hypertrophy or dilatation. Both affected individuals as well as a 26-year-old unaffected daughter (M29, IV:3) carried the MYBPC3 E619K mutation

ParentalTesting:NR

CasePresentingHPOs: HP:0034307, HP:0012666, HP:0011713, HP:0001635

CaseHPOFreeText: Onset of symptoms in their third decade; the index case required heart transplantation 3 years after the onset of symptoms. Has onset at the age of 37. Has left ventricular end diastolic diameter (in mm and indexed by body surface area (cm/m2)) with the value of 79 mm and 3.2 cm/m2. They have a 20% of left ventricular ejection fraction. ECG as left bundle branch block. Clinical status as DCM/ congestive heart failure. CAG as normal.

CaseNotHPOs:NR

CaseNotHPOFreeText:NR

CasePreviousTesting:NR

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

FunctionalAnalysis:NR

Variant: NM_000256.3:c.1855G>A

ClinVar:161303

CAID:CA011336

gnomAD: gnomAD v2: 11:47362731 C / T gnomAD v3: 11:47341180 C / T gnomAD v4: chr11-47341180-C-T

AdditionalInfo:NR

Case IV-5: Male, Iranian, 30yo at diagnosis, 31yo at study, proband

DiseaseAssertion: DCM (initially); paper notes that phenotype is more consisted with hypokinetic non-dilated cardiomyopathy based on guideline from ESC working group on myocardial and pericardial diseases (PMID: 26792875)

FamilyInfo: consanguineous family, pedigree in fig. 1

CasePresentingHPOs: HP:0001712, HP:0002375, HP:000516 (left ventricular hypertrophy, hypokinesia, left ventricular dysfunction)

CaseHPOFreeText: New York Heart Association Class = II, left ventricular ejection fraction = 20-25%, left ventricular internal end-diastolic diameter = 5.7cm, left ventricular internal end-systolic diameter = 5.2cm, interventricular septum = 0.8cm, posterior wall = 0.9cm, normal ECG and normal sinus rhythm, Normal heart valve function

CaseNotHPOFreeText: Ischemic heart disease

CasePreviousTesting: ECG, Full testing (https://hyp.is/2c24ajtuEemXQ-fRmGkjTA/www.sciencedirect.com/science/article/pii/S1769721217300484)

CaseGenotypingMethod: WES, targeted exome sequence capture using SureSelectXT Human All Excon v5 kig (Agilent), co-segregation analysis via Sanger sequencing

Variant: NM_000257.3(MYH7):c.2863G>A (p.Asp955Asn)

ClinVar: 264608, https://www.ncbi.nlm.nih.gov/clinvar/variation/264608/

gnomAD: 0.000003976, https://gnomad.broadinstitute.org/variant/14-23893175-C-T

MultipleGeneVariants:

(1) TNNT2 Variant:

Variant: NM_000364.3(TNNT2):c.247A>C (p.Asn83His)

ClinVar: 427814, https://www.ncbi.nlm.nih.gov/clinvar/variation/427814/

gnomAD: n/a

Case III-10: Female, Iranian, 60yo

DiseaseAssertion: DCM

FamilyInfo: consanguineous family, pedigree in fig. 1

CasePresentingHPOs: HP:0001653, HP:0011713, HP:0005162, HP:0005185, HP:0002375 (mitral regurgitation, left bundle branch block, left ventricular dysfunction, systolic dysfunction, hypokinesia)

CaseHPOFreeText: New York Heart Association Class = II, left ventricular ejection fraction = 15-20%, left ventricular internal end-diastolic diameter = 5.6cm, left ventricular internal end-systolic diameter = 4.3cm, interventricular septum = 0.7cm, posterior wall = 0.6cm, Normal heart valve function, grade II diastolic dysfunction

CaseNotHPOFreeText: Ischemic heart disease

CasePreviousTesting: ECG

CaseGenotypingMethod: co-segregation analysis via Sanger sequencing

Variant: NM_000257.3(MYH7):c.2863G>A (p.Asp955Asn)

ClinVar: 264608, https://www.ncbi.nlm.nih.gov/clinvar/variation/264608/

gnomAD: 0.000003976, https://gnomad.broadinstitute.org/variant/14-23893175-C-T

MultipleGeneVariants:

(1) TNNT2 Variant:

Variant: NM_000364.3(TNNT2):c.247A>C (p.Asn83His)

ClinVar: 427814, https://www.ncbi.nlm.nih.gov/clinvar/variation/427814/

gnomAD: n/a

Case IV-6: Female, Iranian, 34yo at diagnosis, 37yo at study

DiseaseAssertion: DCM (initially); paper notes that phenotype is more consisted with hypokinetic non-dilated cardiomyopathy based on guideline from ESC working group on myocardial and pericardial diseases (PMID: 26792875)

FamilyInfo: consanguineous family, pedigree in fig. 1

CasePresentingHPOs: HP:0001653, HP:0002375 (mitral regurgitation, hypokinesia)

CaseHPOFreeText: New York Heart Association Class = II, left ventricular ejection fraction = 35%, left ventricular internal end-diastolic diameter = 5.2cm, left ventricular internal end-systolic diameter = 4.2cm, interventricular septum = 0.9cm, posterior wall = 1.0cm, normal sinus rhythm, grade I diastolic function

CaseNotHPOFreeText:

CasePreviousTesting: ECG, Full testing (https://hyp.is/2c24ajtuEemXQ-fRmGkjTA/www.sciencedirect.com/science/article/pii/S1769721217300484)

CaseGenotypingMethod: https://hyp.is/IKjfsDtxEem3Sh8RHHdYSg/www.sciencedirect.com/science/article/pii/S1769721217300484) WES, targeted exome sequence capture using SureSelectXT Human All Excon v5 kig (Agilent), co-segregation analysis via Sanger sequencing

Variant: NM_000257.3(MYH7):c.2863G>A (p.Asp955Asn)

ClinVar: 264608, https://www.ncbi.nlm.nih.gov/clinvar/variation/264608/

gnomAD: 0.000003976, https://gnomad.broadinstitute.org/variant/14-23893175-C-T

MultipleGeneVariants:

(1) TNNT2 Variant:

Variant: NM_000364.3(TNNT2):c.247A>C (p.Asn83His)

ClinVar: 427814, https://www.ncbi.nlm.nih.gov/clinvar/variation/427814/

gnomAD: n/a

Case: Case report, female, 41yo

CasePresentingHPOs: HP:0001270, HP:0002094, HP:0007340, HP:0010535, HP:0002540, HP:0003323, HP:0002015, HP:0100749, HP:0001662, HP:0005952 (motor delay, dyspnea, lower limb weakness, sleep apnea, inability to walk, progressive muscle weakness, dysphagia, chest pain, bradychardia, decreased pulmonary function)

HPOsFreeText: non-smoker, onset of neuromuscular disorders in early childhood, written language delay, difficulty completing exercise, dyspnea and lower limb weakness presenting during patient's first pregnancy (33yo), required mechanical ventilation machine, symptoms of skeletal muscle disorder began after delivery of first child, unable to get up without assistance, unable to climb stairs, required use of cane, walker, then eventually a wheelchair, episodes of paralysis in lower limbs, normal tone/bulk of arm muscles but bilateral weakness in shoulders and upper limbs (MRC scale of 3/5), intact fine finger movements, down-going toes, reduced perception of vibration in lower limbs, needle EMG showed tendency of myotonic potentials, muscle biopsy of left quadricep showed features of end-stage process consistent with chronic myopathy (Fig. 2A-D), forced vital capacity = 27%, forced expiratory volume per second = 29%

CaseNotHPOs: HP:0001513, HP:0040129 (obese, abnormal nerve conduction velocity)

NotHPOsFreeText: pronator drift, sensory deficit, ocular muscle involvement

FamilyInfo: mother died at 66yo due to heart attack associated with non-compaction cardiomyopathy, daughter (11yo) has signs of muscle disorders, congenital muscular torticollis, excessive growing pains, and underdeveloped muscles in half of body

CaseGenotypingMethod: WES, variants confirmed via Sanger Sequencing

Variant: NM_000257.4(MYH7):c.1370T>G (p.Ile457Arg)

ClinVar: 560881, https://www.ncbi.nlm.nih.gov/clinvar/variation/560881/

gnomAD: absent

MultipleGeneVariants:

(1) SNCB Variant

Variant: NM_003085.5(SNCB):c.368C>A (p.Pro123His)

ClinVar: 7026, https://www.ncbi.nlm.nih.gov/clinvar/variation/7026/

gnomAD: 0.0001929, https://gnomad.broadinstitute.org/variant/5-176048219-G-T

(2) GDF6 Variant:

Variant: NM_001001557.4(GDF6):c.746C>A (p.Ala249Glu)

ClinVar: 8371, https://www.ncbi.nlm.nih.gov/clinvar/variation/8371/

gnomAD: 0.001948, https://gnomad.broadinstitute.org/variant/8-97157413-G-T

Supplementary Data: Table 2

Case D: proband, female

DiseaseAssertion: Hypertrophic cardiomyopathy

CasePresentingHPOs: HP:0001639 (hypertrophic cardiomyopathy)

CasePreviousTesting: 12-lead electrocardiogram (ECG), echocardiography, exercise test and 24-hour (or 48-hour) Holter monitoring, cardiac MRI, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplemental table 2

CaseGenotypingMethod: genomic DNA isolated from peripheral blood, initially analyzed via Sanger Sequencing then by next-generation sequencing using targeted gene panels, variant pathogenicity assed using in silico prediction tools, Haplotype analysis was performed using 16 microsatellite markers around MYH7 (DNA from the 14 probands was analysed, and DNA samples of 6 family members carrying the mutation were used to verify the phase and reconstruct the haplotype Supplementary Data: Table 1)

Variant: NM_000257.2(MYH7):c.5754C>R (p.Asn1918Lys)

ClinVar: 66082, https://www.ncbi.nlm.nih.gov/clinvar/variation/66082/

gnomAD: n/a

MultipleGeneVariants:

(1) DSC2 Variant:

Variant: NM_004949.4(DSC2):c.2194T>G (p.Leu732Val)

ClinVar: 36005, https://www.ncbi.nlm.nih.gov/clinvar/variation/36005/

gnomAD: 0.001181, https://gnomad.broadinstitute.org/variant/18-28650748-A-C

(2) DSG2 Variant:

Variant: NM_001943.4(DSG2):c.1174G>A (p.Val392Ile)

ClinVar: 36009, https://www.ncbi.nlm.nih.gov/clinvar/variation/36009/

gnomAD: 0.002137, https://gnomad.broadinstitute.org/variant/18-29111109-G-A

(3) DSP Variant:

Variant: NM_001008844.2(DSP):c.1778A>G (p.Asn593Ser)

ClinVar: 44867, https://www.ncbi.nlm.nih.gov/clinvar/variation/44867/

gnomAD: 0.0005695, https://gnomad.broadinstitute.org/variant/6-7571692-A-G

Supplementary Data: Table 2

Case E: proband, male

DiseaseAssertion: Dilated Cardiomyopathy

CasePresentingHPOs: HP:0001644 (dilated cardiomyopathy)

CasePreviousTesting: 12-lead electrocardiogram (ECG), echocardiography, exercise test and 24-hour (or 48-hour) Holter monitoring, cardiac MRI, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplemental table 2

CaseGenotypingMethod: genomic DNA isolated from peripheral blood, initially analyzed via Sanger Sequencing then by next-generation sequencing using targeted gene panels, variant pathogenicity assed using in silico prediction tools, Haplotype analysis was performed using 16 microsatellite markers around MYH7 (DNA from the 14 probands was analysed, and DNA samples of 6 family members carrying the mutation were used to verify the phase and reconstruct the haplotype Supplementary Data: Table 1)

Variant: NM_000257.2(MYH7):c.5754C>R (p.Asn1918Lys)

ClinVar: 66082, https://www.ncbi.nlm.nih.gov/clinvar/variation/66082/

gnomAD: n/a

MultipleGeneVariants:

(1) PRDM16 Variant:

Variant: NM_022114.3(PRDM16):c.2666C>T (p.Pro889Leu)

ClinVar: 487607, https://www.ncbi.nlm.nih.gov/clinvar/variation/487607/

gnomAD: 0.0001771, https://gnomad.broadinstitute.org/variant/1-3331186-C-T

CaseVIII: Brazil, Caucasian

DiseaseAssertion: Hypertrophic cardiomyopathy

FamilyInfo: Family history of HCM, 1 other relative without phenotypes

CasePresentingHPOs: HP:0001712, HP:0001639, HP:0011103 (Left ventricular hypertrophy, Hypertrophic cardiomyopathy, Abnormality of the left ventricular outflow tract)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Cosegregation confirmed for MYH7

CasePreviousTesting: Only MYH7, MYBPC3, and TNNT2 were tested.

CaseGenotypingMethod: DNA was extracted from peripheral blood and the above genes were subject to PCR amplification and directly sequenced. The resulting sequences were compared with the reference and filtered for pathogenicity.

Variant: NM_000257.3:c.4402G>A (p.Glu1468Lys)

ClinVar: 235033 https://www.ncbi.nlm.nih.gov/clinvar/variation/235033/

gnomAD: Not in gnomAD

Multiple Gene Variants

MYBPC3 Variant

Variant: NM_000256.3:c.2686G>A (p.Val896Met)

ClinVar: 42652 https://www.ncbi.nlm.nih.gov/clinvar/variation/42652/

gnomAD: European (Finnish) 0.02794, Overall 0.006194 https://gnomad.broadinstitute.org/variant/11-47357479-C-T

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

CaseAddInfo: 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)

ClinVar: 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)

ClinVar: 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

CaseHCM133: 64 yrs report, Vietnam, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: Family history of sudden cardiac death

CasePresentingHPOs: HP:0100749, HP:0001712, HP:0031295 (Chest pain, Left ventricular hypertrophy, Left atrial enlargement)

HPOsFreeText: Maximal LV thickness 21 mm

CaseNotHPOs: HP:0005110, HP:0001297, HP:0004756 (Atrial fibrillation, Stroke, Ventricular tachycardia)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: The gene panel included 10 sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1, TNNC1, MYH6), 9 genes encoding Z-disk components and Ca2+ homeostasis factors (LDB3, CSRP3, TCAP, VCL, ACTN2, MYOZ2, NEXN, JPH2, PLN), and 4 genes involved in HCM phenocopies (GLA, LAMP2, PRKAG2, TTR), All probands had left ventricular wall thickness >= 15 mm and no other diseases that can cause secondary hypertrophy

CaseGenotypingMethod: The coding region, flanking sequences, and untranslated regions of each gene were enriched by LC-PCR, amplified, and sequenced on the Illumina MiSeq or MiniSeq platform. Identified variants were then filtered for pathogenicity and confirmed by Sanger sequencing.

Variant: NM_000257.4(MYH7):c.3551A>T (p.Gln1184Leu)

ClinVar: 181226 https://www.ncbi.nlm.nih.gov/clinvar/variation/181226/

gnomAD: 0.0006115, http://gnomad.broadinstitute.org/variant/14-23889229-T-A

Multiple Gene Variants

(1) MYH6 Variant

Variant: NM_002471.3(MYH6):c.1252G>A (p.Val418Met)

ClinVar: 44449 https://www.ncbi.nlm.nih.gov/clinvar/variation/44449/

gnomAD: 0.001954, http://gnomad.broadinstitute.org/variant/14-23870076-C-T

Case1: 14 month, female

DiseaseAssertion: dilated cardiomyopathy

FamilyInfo:The three siblings' cases were born to consanguineous parents. They had DCM and died from decompensated heart failure around the age of 12 months

ParentalTesting: Sanger Sequencing determined the parents carried the variant at the heterozygous state (Figure 1)

CasePresentingHPOs: HP:0002094, HP:0002099, HP:0002098, HP:0002090,

CaseHPOFreeText:productive cough, and whining, wheezing, mitral and tricuspid regurgitation

CaseNotHPOs: NR

CaseNotHPOFreeText:no sign of ischemia,

CasePreviousTesting: cardiac ultrasound

Genotyping Method: sanger sequencing

FunctionalAnalysis: NR

Variant: TNNI3 (NM_000363.5): c.204delG;p.(Arg69AlafsTer8)

ClinVar: 179447

gnomAD: not found

Case#: Female, 6 months

DiseaseAssertion: Dilated cardiomyopathy

FamilyInfo: Mother was age 40 at time of birth, which is a high-risk factor for birth defects

ParentalTesting:

CasePresentingHPOs: HP:0031664, HP:0010438, HP:0005162

CaseHPOFreeText: blood pressure of the four limbs was "92/44 mmHg at the right upper limb, 96/58 mmHg at the left upper limb, 101/60 mmHg at the right lower limb, and 103/54 mmHg at the left lower limb." Enlarged heart boundaries. Shifted apex.

CaseNotHPOs: HP:0000975

CaseNotHPOFreeText: decreased milk consumption

CasePreviousTesting: NR

Genotyping Method: genomic sequencing.

FunctionalAnalysis: NR

Variant: NM_001276345.2:c.548G>A

ClinVar:43649

CAID:CA004727

gnomAD: NR

AdditionalInfo:

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.

Case: Female, 19 y.o., ethnicity unknown.

DiseaseAssertion: VWD2N

FamilyInfo: Proband has one older symptomatic sister who shares an identical compound heterozygous genotype, presenting with a mild bleeding tendency, reduced FVIII activity (20-30%), and severely reduced FVIII binding (<2%). The family features one younger unaffected sister who tested negative for both variants, and an unaffected carrier mother. Both parents had normal factor VIII, and there was no male relative with reduced factor VIII or bleeding symptoms.

ParentalGenotype(s): Mother is heterozygous for the c.2561G>A (p.R854Q) variant, negative for the c.2402G>A (p.S801N) variant, and has normal baseline factor VIII levels, confirming the sisters' variants are in trans. Father unavailable/not tested.

CasePresentingHPOs: HP:0004846 (Prolonged bleeding after surgery), HP:0003645 (Prolonged partial thromboplastin time).

CaseHPOFreeText: Index patient experienced bleeding complications following wisdom tooth surgery. Factor VIII binding activity is reduced at 32%. Reduced coagulation factor VIII activity (30%). Prolonged activated partial thromboplastin time (aPTT) of 37 seconds.

CaseNOTHPOs: HP:0001873 (Thrombocytopenia), HP:0012147 (Reduced quantity of von Willebrand factor), HP:0030130 (Impaired von Willebrand factor collagen binding activity).

CaseNOTHPOFreeText: Normal vWF antigen (vWF:Ag) levels (101%), normal vWF activity (116%), normal vWF-collagen-binding activity (104%), normal vWF multimer distribution structures, normal hemoglobin level (128 g/L), and normal Prothrombin Time (PT/QUICK) of 83%.

CasePreviousTesting: Siblings did not carry any known mutations in the F8 gene or the LMAN1 and MCFD2 genes (which encode for endoplasmic reticulum carrier proteins of coagulation factors V and VIII).

GenotypingMethod: Direct sequence analysis of VWF exons 18-20.

PreviouslyPublished: NA.

Gene: VWF

HGNCID: HGNC:12726

Variant: Heterozygous c.2561G>A (p.R854Q) and heterozygous c.2402G>A (p.S801N).

HGVS: (1) NM_000552.5:c.2561G>A (p.Arg854Gln) (2) NM_000552.5:c.2402G>A (p.Ser801Asn)

ClinVarID: (1) 296 (2) NA

CAID: (1) NA (2) CA383522023

gnomAD: (1) MAF of 0.005974 in the European (non-Finnish) population https://gnomad.broadinstitute.org/variant/12-6034812-C-T?dataset=gnomad_r4

(2) MAF of 0.00001098 in the South Asian population https://gnomad.broadinstitute.org/variant/12-6044331-C-T?dataset=gnomad_r4

Case#:24-year-old male

DiseaseAssertion:non-obstructive HCM and long QTc

FamilyInfo:family history of long QT (mother and maternal grandmother), (family pedigree in Fig. 2)

ParentalTesting:Sanger sequencing done in the father confirming the paternal origin of the variant.

CasePresentingHPOs:HP:0001712, HP:0001657, HP:0005135

CaseNotHPOs:HP:0001654, HP:0006673

CasePreviousTesting: Cardiac MRI, Electrocardiogram, echocardiogram

Genotyping Method:Next Generation Sequencing

FunctionalAnalysis:Pathogenic missense variant

Variant:NM_000363.5(TNNI3):c.592C>G (p.Leu198Val)

ClinVar:177694

CAID:CA022019

gnomAD:chr19-55151875-G-C

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

Case: IP-6

DiseaseAssertion: VWD2

FamilyInfo: Mother is unaffected carrier of F8 Asn2129Ser. The VWF deletion of exons 33-34 segregates in 5 other affected male family members including the father and a full brother of IP-6. The patient’s father displayed a significant decrease in VWF:Ag and VWF:RCo, 13% and 7%, respectively, FVIII: C of 18.5% and the VWF:RCo/VWF:Ag ratio of 0.5 pointing out to type 2 VWD.

ParentalGenotype(s): Mother is heterozygous for F8FAsn2129Ser. Father is heterozygous for VWF deletion of exons 33-34.

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag (17%), VWF:RCo (9%) and FVIII:C (1,9%). Bleedings in the oral cavity, ankle joint and hematomas.

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: Direct sequencing of exons 2–52 including exon/intron boundaries of the VWF gene

GenotypingMethod: multiple ligation‐dependent probe amplification (MLPA; using kit P011 and P012; MRC Holland, Amsterdam, the Netherlands) according to the manufacturer’s instructions. The PCR products were run on an ABI PRISM 3130XL sequencer with the GeneScan 500 LIZ size standard and analyzed using GeneMapper Software 5.0 (Applied Biosystems, Darmstadt, Germany). Dosage analysis based on a comparison between deleted and reference wild‐type DNA samples was performed using the Excel‐based software Coffalyser V9.4 (MRC Holland).

PreviouslyPublished: NA

Gene:VWF

Variant: deletion of exons 33-34

HGVS:

ClinVarID:

CAID:

gnomAD:

MultipleGeneVariants:

GeneName: F8

Variant: Asn2129Ser

ClinVarID or CAID:

gnomAD:

Case: IP-2

DiseaseAssertion: VWD3

FamilyInfo: The mother reported no history of bleeding episodes and the laboratory data were in the border line of the normal range.

ParentalGenotype(s): mother is heterozygous for the p.Gln2551AlafsX16 in the VWF gene

CasePresentingHPOs: HP:0000421

CaseHPOFreeRext: VWF:Ag <6%, VWF:RCo <6% and FVIII:C 2%. Clinically, repetitive severe epistaxis and subcutaneous hematomas were observed.

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: Direct sequencing of exons 2–52 including exon/intron boundaries of the VWF gene

GenotypingMethod: multiple ligation‐dependent probe amplification (MLPA; using kit P011 and P012; MRC Holland, Amsterdam, the Netherlands) according to the manufacturer’s instructions. The PCR products were run on an ABI PRISM 3130XL sequencer with the GeneScan 500 LIZ size standard and analyzed using GeneMapper Software 5.0 (Applied Biosystems, Darmstadt, Germany).

PreviouslyPublished: NA

Gene: VWF

Variant: p.Gln2551AlafsX16

HGVS:

ClinVarID:

CAID:

gnomAD:

MultipleGeneVariants:

GeneName: VWF

Variant: whole gene deletion

ClinVarID or CAID:

gnomAD:

Case1: 17 month onset

DiseaseAssertion: Noncompaction of the ventricular myocardium

FamilyInfo: No known family history of heart disease or sudden cardiac death, Has two sisters with the same MYH7 variant and similar phenotypes, See Fig 3 for pedigree

CasePresentingHPOs: HP:0001279, HP:0001635, HP:0012818, HP:0031295, HP:0030718, HP:0005133, HP:0005180, HP:0001653, HP:0001723, HP:0002092, HP:0004890, HP:0030876, HP:0005168 (Syncope, Heart failure, Biventricular noncompaction cardiomyopathy, Left atrial enlargement, Right atrial enlargement, Right ventricular dilation, Tricuspid regurgitation, Mitral regurgitation, Restrictive cardiomyopathy, Pulmonary arterial hypertension, Elevated pulmonary artery pressure, Increased pulmonary capillary wedge pressure, Elevated right atrial pressure)

HPOsFreeText: Both cardiac ventricles had a coarsely trabeculated and spongy appearance in posterior wall, lateral wall, apical segments, and right ventricle, LVEF at 51%, Short E-wave deceleration time at the transmitral level (85 msec) with a high E/A ratio (2.1), Ratio between the thickness of the noncompacted layer and the myocardial layer was 3.4:1, Underwent cardiac catheterization, Left ventricular systolic pressure and end-diastolic pressure were 95 mmHg and 37 mmHg respectively, Pulmonary vascular resistance was 4.0 Wood Unit m^2

CaseNotHPOs: N/A

NotHPOsFreeText: Normal left ventricle end-diastolic volume (110%), No other congenital heart disease

CaseAddInfo: Died at age 2 yrs of advanced heart failure

CasePreviousTesting: TruSight One sequencing panel was used for testing (Illumina)

CaseGenotypingMethod: Blood samples were collected from the proband and his siblings and genomic DNA was extracted. Target enrichment was performed using the TruSight One sequencing panel (Illumina). Analysis was annotated and filtered, after which the MYH7 pathogenic variant was confirmed using PCR and Sanger sequencing.

Variant: NM_000257.4(MYH7):c.5740G>A (p.Glu1914Lys)

ClinVar: 43088 https://www.ncbi.nlm.nih.gov/clinvar/variation/43088/

gnomAD: Not in gnomAD

MultipleGeneVariants

(1) PLEC Variant

Variant: NM_000445.4:c.3005-8T>C

CAID: CA187619061 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA187619061

gnomAD: Not in gnomAD

CaseIII:2: 44 year old male, South Asian

DiseaseAssertion: HCM, septal hypertrophic obstructive cardiomyopathy

FamilyInfo: family history of two sudden cardiac deaths at ages 35 and 19, and three family members with septal hypertrophic obstructive cardiomyopathy

CasePresentingHPOs: HP:0001279, HP:0002094, HP:0001962

"Syncope, Dyspnea, Palpitations"

CasePreviousTesting: screened sarcomeric thin filament protein gene, α-tropomyosin (TPM1), screening of seven other sarcomeric genes: MYH7, MYBPC3, TNNT2, TNNI3, MYL2, MYL3, and ACTC

GenotypingMethod: sequences covering all the exons and exon–intron boundaries of TPM1 and seven other sarcomeric genes (MYH7, MYBPC3, TNNT2, TTN, TNNI3, MYL2, MYL3, and ACTC) were synthesized

MultipleGeneVariants:

VariantMYH7: NM_000257.4:c.2686G>A

ClinVar: 132908

CAID: CA012857

gnomAD: not found

VariantMYH7: NP_000248.2:p.Ile524Lys

ClinVar: not found

CAID: valid allele but not present in the registry

gnomAD: not found

VariantTPM1: NM_000366.6:c.644C>T

ClinVar: 31883

CAID: CA018243

gnomAD: https://gnomad.broadinstitute.org/variant/15-63354418-C-T

0.000008806 European (non-Finnish)

CaseII-9: Male, 38 years diagnosis, China, Asian

DiseaseAssertion: Hypertrophic cardiomyopathy

FamilyInfo: Proband's father (I-1) and mother (I-2) had histories of mild episodes of dizziness, no other symptoms reported in the other family members

CasePresentingHPOs: HP:0001279, HP:0001712, HP:0001639 (Syncope, Left ventricular hypertrophy, Hypertrophic cardiomyopathy)

HPOsFreeText: Heart rate 62 bpm, PR interval 172 ms, QRS complex duration 88 ms, Diffuse repolarization changes with a late-onset inverted T-wave pattern, LVMI 109.55 g/m2, MLVWT 24 mm, Ejection Fraction 70%

CaseNotHPOs: HP:0030148 (Heart murmur)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: See Table 1

CaseGenotypingMethod: Genomic DNA was extracted from blood and amplified. It was then subjected to a sequencing panel with an Illumina sequencer based on the 96 genes related to cardiac function. All readings were aligned, with any variants confirmed by Sanger sequencing and filtered for pathogenicity.

Variant: NM_000257.3:c.5151T>A (p.His1717Gln)

CAID: CA389036862 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3%3Ac.5151T%3EA

gnomAD: Not in gnomAD

Multiple Gene Variants:

KCNQ1 Variant

Variant: NM_000218.2:c.568C>T (p.Arg190Trp)

ClinVar: 53070 https://www.ncbi.nlm.nih.gov/clinvar/variation/53070/

gnomAD: Latino 2.896e-5, Overall 4.011e-6 https://gnomad.broadinstitute.org/variant/11-2591948-C-T

MYLK2 Variant

Variant: NM_033118.3:c.970A>G (p.Lys324Glu)

ClinVar: CA408526793 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_033118.3%3Ac.970A%3EG

gnomAD: African 6.453e-5, Overall 4.087e-6 https://gnomad.broadinstitute.org/variant/20-30412153-A-G

TMEM70 Variant

Variant: NM_017866.5:c.440T>C (p.Ile147Thr)

ClinVar: 571761 https://www.ncbi.nlm.nih.gov/clinvar/variation/571761/

gnomAD: East Asian 4.893e-4, Overall 3.579e-5 https://gnomad.broadinstitute.org/variant/8-74893513-T-C

Case#: II-9, male, Asian, 38 yr, proband

DiseaseAssertion: HCM, LQT1

FamilyInfo: HCM passed on in family (figure 1)

CasePresentingHPOs: HP:0001279, HP:0001712, HP:0001639 (Syncope, Left ventricular hypertrophy, Hypertrophic cardiomyopathy)

CaseHPOFreeText: physical examination; 12-lead ECG (SR, HR 57 bpm, P 80 ms, PR 164 ms, QRS 102 ms, QTc 423 ms); 2D echocardiographic study with S5-1 probe (MLVWT 14 mm, EF 62%, LVMI 94.27 g/m^2);

CaseNotHPOs: HP:0030148 (Heart murmurs)

CaseNotHPOFreeText: No inverted T wave: Normal QTc 440 ms

CasePreviousTesting: Additional Sanger sequencing for KCNQ1, MKLY2, TMEM70

CaseGenotypingMethod: Illumina-SolexaHiSeq 2000 sequencing from peripheral blood leococytes; bi-directional Sanger sequencing;

Variant: absent

ClinVar: absent

CAID: CA389036862 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389036862

gnomAD: absent

MultipleGeneVariants:

(1) KCNQ1 Variant:

Variant: NM_181798.1(KCNQ1):c.187C>T (p.Arg63Trp)

ClinVar: 53070 https://www.ncbi.nlm.nih.gov/clinvar/variation/53070/

CAID: n/a

gnomAD: absent

(2) MKLY2 Variant:

Variant: absent

ClinVar: absent

CAID: CA408526793 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA408526793

gnomAD: African 0.00006453 https://gnomad.broadinstitute.org/variant/20-30412153-A-G

(3) TMEM70 Variant:

Variant: NM_017866.6(TMEM70):c.440T>C (p.Ile147Thr)

ClinVar: 571761 https://www.ncbi.nlm.nih.gov/clinvar/variation/571761/

CAID: n/a

gnomAD: East Asian 0.0004893 https://gnomad.broadinstitute.org/variant/8-74893513-T-C

CaseHCM006: 15 yrs report, Vietnam, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: Family history of sudden cardiac death

CasePresentingHPOs: HP:0002875, HP:0001712, HP:0031295, HP:0011103, HP:0001653 (Exertional dyspnea, Left ventricular hypertrophy, Left atrial enlargement, Abnormality of the left ventricular outflow tract, Mitral regurgitation)

HPOsFreeText: Maximal LV thickness 33 mm

CaseNotHPOs: HP:0005110, HP:0001297, HP:0004756 (Atrial fibrillation, Stroke, Ventricular tachycardia)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: The gene panel included 10 sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1, TNNC1, MYH6), 9 genes encoding Z-disk components and Ca2+ homeostasis factors (LDB3, CSRP3, TCAP, VCL, ACTN2, MYOZ2, NEXN, JPH2, PLN), and 4 genes involved in HCM phenocopies (GLA, LAMP2, PRKAG2, TTR), All probands had left ventricular wall thickness >= 15 mm and no other diseases that can cause secondary hypertrophy

CaseGenotypingMethod: The coding region, flanking sequences, and untranslated regions of each gene were enriched by LC-PCR, amplified, and sequenced on the Illumina MiSeq or MiniSeq platform. Identified variants were then filtered for pathogenicity and confirmed by Sanger sequencing.

Variant: NM_000257.4(MYH7):c.2207T>C (p.Ile736Thr)

ClinVar: 164342 https://www.ncbi.nlm.nih.gov/clinvar/variation/164342/

gnomAD: Not in gnomAD

Multiple Gene Variants

(1) NEXN Variant

Variant: NM_144573.3(NEXN):c.835C>T (p.Arg279Cys)

ClinVar: 30994 https://www.ncbi.nlm.nih.gov/clinvar/variation/30994/

gnomAD: 0.006303, http://gnomad.broadinstitute.org/variant/1-78392548-C-T

CaseHCM125: 39 yrs report, Vietnam, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: Family history of sudden cardiac death

CasePresentingHPOs: HP:0002875, HP:0001712, HP:0031295, HP:0011103, HP:0001653, HP:0006698 (Exertional dyspnea, Left ventricular hypertrophy, Left atrial enlargement, Abnormality of the left ventricular outflow tract, Mitral regurgitation, Dilatation of the ventricular cavity)

HPOsFreeText: Maximal LV thickness 22 mm

CaseNotHPOs: HP:0005110, HP:0001297, HP:0004756 (Atrial fibrillation, Stroke, Ventricular tachycardia)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: The gene panel included 10 sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1, TNNC1, MYH6), 9 genes encoding Z-disk components and Ca2+ homeostasis factors (LDB3, CSRP3, TCAP, VCL, ACTN2, MYOZ2, NEXN, JPH2, PLN), and 4 genes involved in HCM phenocopies (GLA, LAMP2, PRKAG2, TTR), All probands had left ventricular wall thickness >= 15 mm and no other diseases that can cause secondary hypertrophy

CaseGenotypingMethod: The coding region, flanking sequences, and untranslated regions of each gene were enriched by LC-PCR, amplified, and sequenced on the Illumina MiSeq or MiniSeq platform. Identified variants were then filtered for pathogenicity and confirmed by Sanger sequencing.

Variant: NM_000257.4(MYH7):c.2207T>C (p.Ile736Thr)

ClinVar: 164342 https://www.ncbi.nlm.nih.gov/clinvar/variation/164342/

gnomAD: Not in gnomAD

Multiple Gene Variants

(1) MYH6 Variant

Variant: NM_002471.3(MYH6):c.5410C>A (p.Gln1804Lys)

ClinVar: 312843 https://www.ncbi.nlm.nih.gov/clinvar/variation/312843/

gnomAD: 0.002807, http://gnomad.broadinstitute.org/variant/14-23853806-G-T

CaseHCM047: 59 yrs report, Vietnam, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: Family history of hypertrophic cardiomyopathy, Has a sister with MYBPC3 mutation with asymptomatic HCM (did not mention MYH7 mutation)

CasePresentingHPOs: HP:0002875, HP:0001712 (Exertional dyspnea, Left ventricular hypertrophy)

HPOsFreeText: Maximal LV thickness 20 mm

CaseNotHPOs: HP:0005110, HP:0001297, HP:0004756 (Atrial fibrillation, Stroke, Ventricular tachycardia)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: The gene panel included 10 sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1, TNNC1, MYH6), 9 genes encoding Z-disk components and Ca2+ homeostasis factors (LDB3, CSRP3, TCAP, VCL, ACTN2, MYOZ2, NEXN, JPH2, PLN), and 4 genes involved in HCM phenocopies (GLA, LAMP2, PRKAG2, TTR), All probands had left ventricular wall thickness >= 15 mm and no other diseases that can cause secondary hypertrophy

CaseGenotypingMethod: The coding region, flanking sequences, and untranslated regions of each gene were enriched by LC-PCR, amplified, and sequenced on the Illumina MiSeq or MiniSeq platform. Identified variants were then filtered for pathogenicity and confirmed by Sanger sequencing.

Variant: NM_000257.4(MYH7):c.1322C>T (p.Thr441Met)

ClinVar: 14122 https://www.ncbi.nlm.nih.gov/clinvar/variation/14122/

gnomAD: 0.002556, http://gnomad.broadinstitute.org/variant/14-23898249-G-A

Multiple Gene Variants

(1) MYBPC3 Variant

Variant: NM_000256.3(MYBPC3):c.2308G>A (p.Asp770Asn)

ClinVar: 36604 https://www.ncbi.nlm.nih.gov/clinvar/variation/36604/

gnomAD: 0.00008693, http://gnomad.broadinstitute.org/variant/11-47360071-C-T

CaseHCM051: 39 yrs report, Vietnam, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: Family history of hypertrophic cardiomyopathy, Has 2 siblings where the MYH7 and MYOZ2 mutations are solely present in the brother and sister respectively, Brother has LVH and palpitations while sister has no symptoms whatsoever

CasePresentingHPOs: HP:0100749, HP:0001712, HP:0031295 (Chest pain, Left ventricular hypertrophy, Left atrial enlargement)

HPOsFreeText: Maximal LV thickness 18 mm

CaseNotHPOs: HP:0005110, HP:0001297, HP:0004756 (Atrial fibrillation, Stroke, Ventricular tachycardia)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: The gene panel included 10 sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1, TNNC1, MYH6), 9 genes encoding Z-disk components and Ca2+ homeostasis factors (LDB3, CSRP3, TCAP, VCL, ACTN2, MYOZ2, NEXN, JPH2, PLN), and 4 genes involved in HCM phenocopies (GLA, LAMP2, PRKAG2, TTR), All probands had left ventricular wall thickness >= 15 mm and no other diseases that can cause secondary hypertrophy

CaseGenotypingMethod: The coding region, flanking sequences, and untranslated regions of each gene were enriched by LC-PCR, amplified, and sequenced on the Illumina MiSeq or MiniSeq platform. Identified variants were then filtered for pathogenicity and confirmed by Sanger sequencing.

Variant: NM_000257.4(MYH7):c.3424G>A (p.Glu1142Lys)

ClinVar: 181222 https://www.ncbi.nlm.nih.gov/clinvar/variation/181222/

gnomAD: Not in gnomAD

Multiple Gene Variants

(1) MYOZ2 Variant

Variant: NM_016599.4:c.326C>G (p.Pro109Arg)

CAID: CA104971226 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA104971226

gnomAD: Not in gnomAD

Table 1 and 4

Case A13: Male, 10yo, proband (III-2)

DiseaseAssertion: malignant HCM

FamilyInfo: positive family history (fig 1), grandfather died at 42yo from heart disease, father died at 40yo due to sudden cardiac death, mother (A11, II-1) had no clinical symptoms, sister (A12, III-1) diagnosed at 21yo with severe HCM

CasePresentingHPOs: HP:0100749, HP:0001279 (chest pain, syncope)

CaseHPOFreeText: interventricular septum thickness = 21.0mm, left ventricular posterior wall thickness = 12.0mm, left atrium = 40.0mm, left ventricular ejection fraction = 48%, septal asymmetry, decreased left ventricular systolic and diastolic function

CasePreviousTesting: 12-lead ECG, echocardiography, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing (LMNA, PRKAG2, SCN5A, MYH6)

CaseGenotypingMethod: genomic DNA collected from peripheral whole blood samples, PCR, high-throughput sequencing using PGM Sequencing 400 kit, variants verified via Sanger Sequencing

Variant: NM_000257.3(MYH7):c.2155C>T (p.Arg719Trp)

ClinVar: 14104, https://www.ncbi.nlm.nih.gov/clinvar/variation/14104/

gnomAD: 0.00003185, https://gnomad.broadinstitute.org/variant/14-23895180-G-A

MultipleGeneVariants:

(1) PRKAG2 Variant:

Variant: NM_016203.3(PRKAG2):c.298G>A (p.Gly100Ser)

ClinVar: 36697, https://www.ncbi.nlm.nih.gov/clinvar/variation/36697/

gnomAD: 0.006770, https://gnomad.broadinstitute.org/variant/7-151478406-C-T

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

Case: Pedigree 5 proband, 28yo at diagnosis, Turkish-Jewish

CasePresentingHPOs: HP:0001639, HP:0001645, HP:0001712, HP:0001279, HP:0001653 (hypertrophic cardiomyopathy, sudden cardiac death, left ventricular hypertrophy, syncope, mild mitral regurgitation)

HPOsFreeText: clinical severity: asymptomatic, LVOT obstruction, anterior septal thickness of 16 mm with dynamic obstruction, normal EF of 60%, asymmetrical hypertrophy on MRI, septal wall thickness of 25 mm, normal sinus rhythm, ventricular premature beats

CaseNotHPOs:

NotHPOsFreeText: skeletal involvement

CasePreviousTesting: exact genes sequenced not specified

CaseGenotypingMethod: NGS (Health in Code, commercial 7-gene panel), contains genes known to cause HCM

Variant: NM_000257.4:c.2605C>T (p.Arg869Cys)

CAID: CA012714, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA012714

gnomAD: n/a

MultipleGeneVariants:

(1) MYL2 Variant:

Variant: NM_000432.3(MYL2):c.304G>A (p.Ala102Thr)

ClinVar: 626792, https://www.ncbi.nlm.nih.gov/clinvar/variation/626792/

gnomAD: 0.00001193, https://gnomad.broadinstitute.org/variant/12-111351099-C-T

FamilyInfo: no family history of cardiomyopathy, maternal grandfather died suddenly at 52yo

Case III.4: Female, age 30

DiseaseAssertion: Distal myopathy

FamilyInfo: Figure 1, similar distal muscle weakness in four relatives. Patients I.2 and II.2 experienced foot drop while walking. Patient III.2 muscle biopsy findings suggestive of core myopathy suggested a disorder similar to his youngest sister. Patient IV.1 displayed a less progressive muscular phenotype than her older relatives and tested negative for the mutation in RYR1

CasePresentingHPOs: HP:0001761, HP:0008994, HP:0002650

"Pes cavus, Proximal muscle weakness in lower limbs, Scoliosis"

CaseHPOFreeText: stepping gait

CasePreviousTesting: muscle biopsy showed fiber size variability, increased internal nuclei and histochemical evidence of eccentric core-like lesions, Analysis of RYR1 revealed a heterozygous c.880G > A:p.(Glu294Lys) mutation

GenotypingMethod: Amplicon-based Sanger sequencing, MotorPlex used to analyze a large set of genes that cause known forms of non-syndromic muscle disorders

MultipleGeneVariants:

(1) MHY7Variant: Novel

Variant: NM_000257.4:c.4303T>C

ClinVar: not found

CAID: CA389040164

gnomAD: not found

(2) RYR1Variant:

Variant: NM_000540.2:c.880G>A

ClinVar: 590621

CAID: CA072725

gnomAD: https://gnomad.broadinstitute.org/variant/19-38939074-G-A?dataset=gnomad_r2_1

Total allele frequency: 0.00006159 European (non-Finnish)

Table 5

Case EO9: Italian

DiseaseAssertion: HCM (early-onset)

FamilyInfo: positive family history

CasePreviousTesting: echocardiography, Full testing (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1), additional testing: (GLA, LAMP2, PRKAG2, TNNC1, MYH6, CSPR3, PLN, TCAP, CAV3), electrocardiography

CaseGenotypingMethod: Genomic DNA extracted from periphera whole blood, emulsion PCR, 17 HCM genes sequenced using Personal Genome Machine (PGM) IonTorrent sequencer, variants confirmed via Sanger sequencing

Variant: NM_000257.3:c.2146G>C

CAID: CA389049033, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389049033

gnomAD: n/a

MultipleGeneVariants:

(1) MYBPC3 Variant:

Variant: NM_000256.3(MYBPC3):c.1483C>T (p.Arg495Trp)

ClinVar: 164114, https://www.ncbi.nlm.nih.gov/clinvar/variation/164114/

gnomAD: n/a

Case: proband, 2mo

DiseaseEntity: Left ventricular noncompaction (LVNC)

CasePresentingHPOs: HP:0001635 (congestive heart failure)

HPOsFreeText: required mechanical ventilation and inotropic support, depressed left ventricular function, deep left ventricle trabeculations

FamilyInfo: sibling with fetal demise at 24wks gestation due to pulmonary hypoplasia and biventricular noncompaction with deep recesses in myocardial walls of both ventricles, right ventricular dilation, and widespread fibrosis; signs of LVNC also present in 4yo sibling and father, paternal grandfather had history of arrhythmia

CaseGenotypingMethod: WES

Variant: NM_000257.4(MYH7):c.1159C>T (p.Leu387Phe)

ClinVar: 524975, https://www.ncbi.nlm.nih.gov/clinvar/variation/524975/

gnomAD: absent from gnomAD

MultipleGeneVariants:

(1) MLK2 Variant

Variant: NM_001308142.1:c.2010G>C

CAID: CA394829003, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA394829003

gnomAD: absent

(2) NKX2-5 Variant

Variant: NM_004387.4(NKX2-5):c.355G>T (p.Ala119Ser)

ClinVar: 9018, https://www.ncbi.nlm.nih.gov/clinvar/variation/9018/

gnomAD: 0.0009792, https://gnomad.broadinstitute.org/variant/5-172660192-C-A?dataset=gnomad_r2_1

Case1: patient 1, 68 years old, male

DiseaseAssertion: HCM

FamilyInfo: positive family history of SCD and end stage heart failure

CasePresentingHPOs: n/a

CaseHPOFreeText: n/a

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

GenotypingMethod: multiplex targeted high‐throughput sequencing, DNA capture assay including all exons from 130 genes involved in cardiovascular Mendelian disorders and analysed simultaneously four samples by multiplexing

VariantMYH7: NM_000257.4:c.4130C>A

ClinVar: not found

CAID: CA389040836

gnomAD: not found

VariantMYBPC3:

ClinVar: 42813

CAID: CA016212

gnomAD: https://gnomad.broadinstitute.org/variant/11-47367871-C-T

0.01364 European (Finnish)

CaseDW: 16 years diagnosis, Australia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: One affected relative, Father, died suddenly

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: Maximum left ventricular hypertrophy at 21 mm

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: 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.937A>T (p.Ile313Phe)

CAID: CA389051713 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3%3Ac.937A%3ET

gnomAD: Not in gnomAD

Multiple Gene Variants:

MYBPC3 Variant

Variant: NM_000256.3:c.2372_2373insG (p.Trp792Valfs)

ClinVar: 42619 https://www.ncbi.nlm.nih.gov/clinvar/variation/42619/

gnomAD: European (Non-Finnish) 4.277e-5, Overall 1.744e-5 https://gnomad.broadinstitute.org/variant/11-47359280-A-AC

Case: proband, 9mo at presentation

DiseaseAssertion: Idiopathic dilated cardiomyopathy

CasePresentingHPOs: HP:0001635, HP:0001695, HP:0001263, HP:0007018, HP:0007018, HP:0002059, HP:0031332 (congestive heart failure, cardiac arrest, global developmental delay, attention deficit, autism, cerebral atrophy, myocyte degeneration)

CaseHPOFreeText: had transvenous pacemaker for complete heart block and left ventricular assist device, ABO-incompatible heart transplant at 1yo, walked at 2.5yo, sensory and behavioral deficits, suspected mitochondrial disorder

FamilyInfo: Parents underwent Sanger Sequencing to confirm variant was de novo in proband (Fig. 2)

CasePreviousTesting: MRI, metabolic evaluation, Full testing (MYPBC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (TruSight One Gene List)

CaseGenotypingMethod: chromosomal microarray, trio analysis with fluorescent in situ hybridization, next-gen sequencing of 4813 genes (TruSight One Sequencing Panel), Sanger Sequencing

Variant: NM_000257.3(MYH7):c.2513C>T (p.Pro838Leu) (previously reported as de novo, PMID: 18380764)

ClinVar: 42910, https://www.ncbi.nlm.nih.gov/clinvar/variation/42910/

gnomAD: n/a

MultipleGeneVariants:

(1) NRXN1 Variant:

Variant: 181,000bp copy number loss within chr 2:6.3, build NCBI 37/hg19 (from position 51201593-51382885)

Case2: Male, 46 yrs onset, China, Asian

DiseaseAssertion: Arrhythmogenic Cardiomyopathy

FamilyInfo: Brother has ACM with dyskinesia and enlargement in RVOT and frequent VES, PKP2 variant segregated with disease but MYH7 variant was detected in 9 unaffected relatives (See Fig 3)

CasePresentingHPOs: HP:0001638, HP:0011675, HP:0010872, HP:0011712, HP:0004756, HP:0001962, HP:0002321, HP:0006682, HP:0001707 (Cardiomyopathy, Arrhythmia, T-wave inversion, Right bundle branch block, Ventricular tachycardia, Palpitations, Vertigo, Ventricular extrasystoles, Abnormality of the right ventricle)

HPOsFreeText: Task force score of 5, Regional right ventricular dyskinesia, PLAX RVOT is 43 mm, 1897 VES / 24 h, LVEF of 64%, LVEDD at 51 mm, IVS at 8 mm

CaseNotHPOs: HP:0001639, HP:0001711 (Hypertrophic cardiomyopathy, Abnormal morphology of the left ventricle)

NotHPOsFreeText: Depolarization abnormalities

CasePreviousTesting: Tested genes include MYH7, MYBPC3, TNNT2, TNNI3, TPM1, ACTC1, TTN, TCAP, ACTN2, LDB3, MYH6, TNNC1, MYPN and NEBL.

CaseGenotypingMethod: The coding sequences of 15 genes were directly captured and sequenced. Candidate variants were then filtered by pathogenicity and confirmed via sanger sequencing. Family members were tested via Sanger sequencing afterwards.

CaseAddInfo: Proband is heterozygous for both variants

Variant: NM_000257.3:c.5116C>G (p.Leu1706Val)

CAID: CA389036928 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389036928

gnomAD: Not in gnomAD

Multiple Gene Variants

(1) PKP2 Variant

Variant: NM_004572.3(PKP2):c.2489+1G>A

ClinVar: 6757 https://www.ncbi.nlm.nih.gov/clinvar/variation/6757/

gnomAD: 0.00008012, http://gnomad.broadinstitute.org/variant/12-32949042-C-T

Case3: Male, 24 yrs onset, China, Asian

DiseaseAssertion: Arrhythmogenic Cardiomyopathy

FamilyInfo: 62 yr old mother and 37 yr old sister carry both the variants but do not have ACM phenotype (See Figure 3)

CasePresentingHPOs: HP:0001638, HP:0011675, HP:0004756, HP:0006682, HP:0025074, HP:0001279, HP:0001645 (Cardiomyopathy, Arrhythmia, Ventricular tachycardia, Ventricular extrasystoles, Abnormal QRS complex, Syncope, Sudden cardiac death)

HPOsFreeText: Task force score of 6, Regional right ventricular dyskinesia, PLAX RVOT is 36 mm, 59,065 VES / 24 h, LVEF of 58%, LVEDD at 46 mm, IVS at 8 mm, Epsilon wave in V1–3

CaseNotHPOs: HP:0001639, HP:0001711 (Hypertrophic cardiomyopathy, Abnormal morphology of the left ventricle)

NotHPOsFreeText: Repolarization abnormalities

CasePreviousTesting: Tested genes include MYH7, MYBPC3, TNNT2, TNNI3, TPM1, ACTC1, TTN, TCAP, ACTN2, LDB3, MYH6, TNNC1, MYPN and NEBL.

CaseGenotypingMethod: The coding sequences of 15 genes were directly captured and sequenced. Candidate variants were then filtered by pathogenicity and confirmed via sanger sequencing. Family members were tested via Sanger sequencing afterwards.

CaseAddInfo: Proband is heterozygous for both variants

Variant: NM_000257.3:c.3134G>A (p.Arg1045His)

CAID: CA035801 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000257.3%3Ac.3134G%3EA

gnomAD: 0.0002005, http://gnomad.broadinstitute.org/variant/14-23891500-C-T

Multiple Gene Variants

(1) PKP2 Variant

Variant: NM_004572.3:c.2146delA (p.Met716Cysfs*30)

CAID: CA915940300 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA915940300

gnomAD: Not in gnomAD

Case: Family A proband, female, Saudi Arabia, 10mo at presentation

CasePresentingHPOs: HP:0001635, HP:0001644, HP:0005185, HP:0012664, HP:0006677, HP:0011713 (heart failure, dilated cardiomyopathy, global systolic dysfunction, reduced ejection fraction, prolonged QRS complex, left bundle branch block)

HPOsFreeText: decompensated heart failure, diastolic dysfunction, left ventricle end-diastolic diameter = 120cm, left ventricular end systolic diameter = 0.4cm, left ventricular ejection fraction = 25%, left ventricular posterior wall thickness = 0.4cm, heat rate = 140bpm

CaseNotHPOs: HP:0011703 (sinus tachycardia)

FamilyInfo: consanguineous, family history of heart disease, pedigree in Fig. 1

CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, TPM1, ACTC1; 181 genes, Supplementary Data Table S1

CaseGenotypingMethod: genomic DNA extracted from peripheral blood, NGS (181 genes, Supplementary Data Table S1), variants confirmed via Sanger sequencing, parents tested

InheritancePattern: autosomal dominant

Variant: NM_000257.3(MYH7):c.2770G>A (p.Glu924Lys)

ClinVar: 14092, https://www.ncbi.nlm.nih.gov/clinvar/variation/14092/

gnomAD: n/a

MultipleGeneVariants:

(1) LAMA4 Variant

Variant: NM_001105206.2:c.3925G>A

CAID: CA365374078, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA365374078

gnomAD: n/a

Case8: Female, 12 yrs onset, Slovakia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: Affected family members

CasePresentingHPOs: HP:0001639 (Hypertrophic Cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: Normal LV ejection fraction

CasePreviousTesting: ABCC9, ACTC1, ACTN2, ANKRD1, CASQ2, CAV3, CRYAB, CSRP3, CTF1, DES, DSC2, DSG2, DSP, DTNA, EMD, FHL2, GLA, JUP, LAMA4, LAMP2, LDB3, LMNA, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYOZ2, NEXN, PKP2, PLN, PRKAG2, RBM20, RYR2, SGCD, TAZ, TCAP, TMEM43, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, VCL were all tested on NGS panel

CaseGenotypingMethod: Genomic DNA was extracted from whole blood and samples were purified and amplified. The coding exons for the above genes were enriched and sequenced. The resulting variants were analyzed and filtered for predicted pathogenicity.

CaseAddInfo: N/A

Variant: NM_000257.4(MYH7):c.746G>A (p.Arg249Gln)

ClinVar: 14088 https://www.ncbi.nlm.nih.gov/clinvar/variation/14088/

gnomAD: Not in gnomAD

MultipleGeneVariants

(1) DSP Variant

Variant: NM_004415.4(DSP):c.484C>G (p.Arg162Gly)

ClinVar: 546994 https://www.ncbi.nlm.nih.gov/clinvar/variation/546994/

gnomAD: 0.00006152, http://gnomad.broadinstitute.org/variant/6-7559520-C-G

CaseII.1: 67 year old female, proband

DiseaseAssertion: progressive asymmetric distal limb weakness - Welander distal myopathy

FamilyInfo: 66-year-old sister has a mild distal myopathy, supraventricular tachycardia and hypertrophic cardiomyopathy. Both sisters carry the only known pathogenic TIA1 mutation and a heterozygous MYH7 variant (c.5459G > A; p.Arg1820Gln). Another sibling with isolated distal myopathy carries only the TIA1 mutation.

CasePresentingHPOs: HP:0002460, HP:0003805

"distal limb weakness, rimmed vacuoles"

CaseHPOFreeText: congophilic inclusions

CaseNotHPOFreeText: cardiac involvement

CasePreviousTesting: Electromyography - showed myopathic changes in distal upper and lower limb muscles with fibrillation potentials and rare myotonic discharges. Neurological examination - asymmetric weakness limited to distal muscles.

ANO5, BAG3, CAV3, CRYAB, DES, DNAJB6, DYSF, FHL1, FLNC, GNE, LDB3, MATR3, MYH7, MYOT, TCAP, TIA1, TTN and VCP were tested, all coding regions plus 20 bp flanking non-coding regions were analyzed through a combination of targeted next generation sequencing and Sanger sequencing

MultipleGeneVariants:

(1) MYH7Variant: NM_000257.4:c.5459G>A

ClinVar: 419278

CAID: CA046848

gnomAD:https://gnomad.broadinstitute.org/variant/14-23884304-C-T

Allele Frequency: East Asian 0.00005437

(2) TIA1Variant: NM_022173.4:c.1150G>A

ClinVar: 41480

CAID: CA1697383

gnomAD: https://gnomad.broadinstitute.org/variant/2-70439862-C-T?dataset=gnomad_r2_1

Total Allele Frequency: Other 0.0001629

GenotypingMethod: Targeted next generation sequencing and Sanger sequencing

Table V

Case 905: Italian, Male, 30yo at onset

DiseaseAssertion: HCM

FamilyInfo: family history of HCM

CasePresentingHPOs: HP:0001712 (left ventricular hypertrophy)

CaseHPOFreeText: maximum left ventricular wall thickness of ≥15 mm, automatic implantable cardioverter defibrillator, heart transplantation

CasePreviousTesting: echocardiography, Full testing (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1), additional testing: (GLA, LAMP2, PRKAG2), additional genes added with NGS: (TNNC1, MYH6, MYOM1, MYOZ2, ANKRD1, VCL, CALR3, CAV3)

CaseGenotypingMethod: Genomic DNA extracted from peripheral leukocytes, Sanger sequencing (73 samples), Next-gen sequencing (19 samples)

Variant: NM_000257.3(MYH7):c.2302G>A (p.Gly768Arg)

ClinVar: 164337, https://www.ncbi.nlm.nih.gov/clinvar/variation/164337/

gnomAD: n/a

MultipleGeneVariants:

(1) MYOM1 Variant:

Variant: NM_003803.3:c.1655G>A

CAID: CA401714383, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401714383

gnomAD: n/a

Case1: Female, 74 years old

DiseaseAssertion: Hypertrophic cardiomyopathy

FamilyInfo: family history negative for HC and SCD

CasePresentingHPOs: HP:0001962

"Palpitations"

CaseHPOFreeText: Age 25 at diagnosis, double heterozygote

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: Genomic DNA of peripheral blood was harvested from all subjects and their family members. The sequence of all coding sequences (exon 2-39 of MYH7, exon 1-35 of MYBPC3, exon 2-17 of TNNT2) for selected genes was studied by polymerase chain reaction (PCR), and direct sequencing. Maximal LVWT 21.3 mm

GenotypingMethod: Direct sequencing of MYH7

VariantMYH7: NM_000257.4:c.77C>T

ClinVar: 37375

CAID: CA016817

gnomAD: https://gnomad.broadinstitute.org/variant/14-23902865-G-A

0.006515 East Asian

VariantMYBPC3: NM_000256.3:c.1000G>A

ClinVar: 177902

CAID: CA009667

gnomAD: https://gnomad.broadinstitute.org/variant/11-47367848-C-T

0.003338 East Asian

CaseIII-15: Male, 47 years report, China, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: 25 people from 74 family members were positively identified for having HCM, Some of them only carried a single variant while others carried multiple, Many other family members died from sudden cardiac death at various ages

CasePresentingHPOs: HP:0001639, HP:0031352 ( Hypertrophic cardiomyopathy, Chest tightness)

HPOsFreeText: Left atrial diameter at 38 mm, Left ventricular end-diastolic diameter at 52 mm, Interventricular septum thickness maximum at 20 mm, Left ventricular posterior wall thickness maximum at 8 mm

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: All below variants are heterozygous with the wild-type

CaseGenotypingMethod: The above family members, along with IV:14 to serve as a control to compare to, were processed through Whole Exome Sequencing. Any variants found were mapped and filtered for pathogenicity, and any that were detected were confirmed by Sanger sequencing.

Variant: NM_000257.3:c.2155C>T (p.Arg719Trp)

ClinVar: 14104 https://www.ncbi.nlm.nih.gov/clinvar/variation/14104/

gnomAD: European (Non-Finnish) 6.481e-5, Overall 3.185e-5 https://gnomad.broadinstitute.org/variant/14-23895180-G-A

MultipleGeneVariants:

(1) MYOZ2 Mutation

Variant: NM_016599.4:c.505A>C (p.Lys169Gln)

CAID: CA16609625 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_016599.4%3Ac.505A%3EC

gnomAD: Not in gnomAD

(2) DNAJC19 Mutation

Variant: NM_145261.3:c.59G>A (p.Arg20His)

ClinVar: 466328 https://www.ncbi.nlm.nih.gov/clinvar/variation/466328/

gnomAD: South Asian 4.246e-4, Overall 5.304e-5 https://gnomad.broadinstitute.org/variant/3-180705881-C-T

(3) CTNNA3 Mutation

Variant: NM_001127384.2:c.2441T>A (p.Leu814Ter)

CAID: CA377089103 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_013266.3%3Ac.2441T%3EA

gnomAD: Not in gnomAD

Case1: male fetus

DiseaseAssertion: LVNC

FamilyInfo: first two pregnancies had resulted in miscarriages due to cervical insufficiency. The third pregnancy (after cerclage) resulted in a healthy nondysmorphic female with mild Ebstein anomaly of the tricuspid valve. The father was reported to have a history of a cardiac murmur and possible “hole in the heart.” Fetal echocardiography revealed that our patient's second child (fourth pregnancy) also had mild Ebstein anomaly. Father also has Ebstein anomaly, with significant apical displacement of the tricuspid valve, moderate tricuspid valve insufficiency, and right heart enlargement

CasePresentingHPOs: HP:0010316, HP:0031195

"Ebstein anomaly of the tricuspid valve, Apical hypertrabeculation of the left ventricle"

CaseHPOFreeText: mild apical displacement of the tricuspid valve, presence of multiple trabeculations on parasternal short‐axis and apical 4‐chamber views, with deep intertrabecular recesses

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: echocardiogram, Peripheral blood samples use to test 46 genes initially (including MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1)

GenotypingMethod: Testing was performed by oligonucleotide‐based target capture, followed by next generation sequencing. Sanger sequencing was used to provide data in areas with insufficient coverage and confirm clinically significant and novel variants. Heterozygous.

VariantMYH7: NM_000257.4:c.3658_3660del

ClinVar: 42968

CAID: CA013921

gnomAD: not reported

**VariantTTN: c.25722_25724delAGA (p.Glu8576del)

Allele registry currently not working

Case N3: Tunisia, Female, 28yo at onset, 30yo at study

DiseaseAssertion: hypertrophic cardiomyopathy

CasePresentingHPOs: HP:0100749 (chest pain)

CaseHPOFreeText: left ventricular septum (LVS) ≥15 mm, septum size = 25mm

FamilyInfo: Family history of HCM and sudden cardiac death

CasePreviousTesting: Full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (FLNC, TNNC1), electrocardiogram, echocardiography

CaseGenotypingMethod: PCR, Next-generation sequencing, identified variants confirmed via Sanger Sequencing

Variant: NM_000257.3:c.5639G>A

CAID: CA257807907, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA257807907

gnomAD: n/a

MultipleGeneVariants:

(1) MYBPC3 Variant:

Variant: NM_000256.3(MYBPC3):c.772G>A (p.Glu258Lys)

ClinVar: 42792, https://www.ncbi.nlm.nih.gov/clinvar/variation/42792/

gnomAD: 0.00001656, https://gnomad.broadinstitute.org/variant/11-47369975-C-T

Case#: Male, mid-40s

DiseaseAssertion: STGD1

FamilyInfo: Retinal disease reported in sibling and material grandfather. Mother exhibited decreased visual acuity, BEM in right eye, and tapetal reflex in both eyes.

CasePresentingHPOs: HP:0000622, HP:0000613, HP:0000662, HP:0011504, HP:0007663, HP:0011463

CaseHPOFreeText: n/a

CaseNotHPOs: HP:0007843, HP:0011507

CaseNotHPOFreeText: Autofluorescence(qAF): 381.5. The Case's qAF was noted to be in the range observed in healthy eyes, and also lower than many other STGD1 patients with the same age. There were no flecks, intraretinal pigment migration, retinal vessel attenuation, or optic nerve pallor (Figure 1).

Genotyping Method: Sanger Sequencing

PreviouslyPublished: n/a

Variant: NM_000350.3(ABCA4):c.1411G>A (p.Glu471Lys), NM_001034853.2(RPGR):c.3070G>T (p.Glu1024Ter)

ClinVar: 99052, 1275798

SupplementalData: n/a

Case#:5-year-old girl

DiseaseAssertion: Asymptomatic

FamilyInfo: Mother was diagnosed with STGD1 and She was homozygous for a (severe) splice site mutation, IVS 35+2 T>C, Maternal uncle was diagnosed with STGD1. Father passed down the G1961E variant.

CasePresentingHPOs: HP:0030630, HP:0011504

CaseHPOFreeText: The ELM in the central macula appeared thickened with indistinct borders, particularly along its inner border (Fig. 2C), horizontal diameter for the region of thickened ELM was 1113 μm, FAF revealed Bull’s Eye Maculopathy (BEM) (Fig. 2B),

CaseNotHPOs:

CaseNotHPOFreeText: No retinal, vasculature, pigmentary or optic nerve head abnormalities were detected on clinical examination, no focal abnormality observed in the outer nuclear layer (ONL) or RPE (Fig. 2C), There was no FAF evidence of flecks or GA

Genotyping Method:

PreviouslyPublished: No

Variant:NM_000350.3:c.5882G>,

ClinVar:7888

CAID:CA119132

SupplementalData:

Case#: 1 male, 6 years old, from Taiwanese and Korean decent.

DiseaseAssertion: ABCA4-related retinopathy Stargardt disease

FamilyInfo: Single affected individual. Paternal uncle presented with Stargart disease previously, and Taiwanese and Korean descent underwent genetic testing to identify two pathogenic variants in the ABCA4 gene. One of the variants found was the same ABCA4 variant from the originally affected individual. No additional family information is provided in text.

CasePresentingHPOs: HP:0000529 - progressive visual loss, HP:0025010 - Foveal atrophy, HP:0000603 - Central scotoma, HP:0007663 - Decreased visual acuity, HP:0030602 - Abnormal fundus autofluorescence imaging, HP:0007984 - ERG: Reduced dark-adapted b-wave amplitude, HP:0000512 - Abnormal electroretinogram, HP:0020032 - Hyperreflective retinal dots on OCT

CaseHPOFreeText: peripapillary sparing was observed on fundus autofluorescence imaging.

CaseNotHPOs: HP:0012045 - Retinal flecks

CaseNotHPOFreeText: N/A

Genotyping Method: Genetic testing was used and after sequencing two variants were found on the ABCA4 gene.

PreviouslyPublished: N/A

Variant: NM_000350.3(ABCA4):c.3523-2A>G

Variant: NM_000350.3(ABCA4):c.2249T>C (p.Leu750Pro)

ClinVar: Variation ID: 866764

ClinVar: Variation ID: 417984

CAID: N/A

SupplementalData: N/A

• Gene Name: DICER1 Syndrome (OMIM 606241, 601200)
• PMID: 34599283
• Hugo Gene Nomenclature Committee (HGNCID): N/A
• Inheritance Pattern: Autosomal Dominant
• Disease Entity: pleuropulmonary blastoma (PPB), Sertoli-Leydig cell tumor, gynandroblastoma, embryonal rhabdomyosarcomas of the cervix and other sites, multinodular goiter, differentiated and poorly differentiated thyroid carcinoma, cervical-thyroid teratoma, cystic nephroma-anaplastic sarcoma of kidney, nasal chondromesenchymal hamartoma, intestinal juvenile-like hamartomatous polyp, ciliary body medulloepithelioma, pituitary blastoma, pineoblastoma, primary central nervous system sarcoma, embryonal tumor with multilayered rosettes-like cerebellar tumor, PPB-like peritoneal sarcoma, DICER1-associated presacral malignant teratoid neoplasm and other non-neoplastic associations.
• Mutation: Germline
• Zygosity: Heterozygous
• Variant: has multiple variants associated with it
• Family Information: Germ cell tumors have been reported in family members
• Case: identified affected families w/ pleuropulmonary blastoma (PPB): germline and somatic DICER1 mutations also identified in other familial associated tumors
• CasePreviousTesting: numerous studies confirmed relationship b/t DICER1 variants in carriers and development of range neoplasms and non-neoplastic conditions