Supplementary Data: Table 2

Case J: 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

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 3:

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: WES, Cytoscan HD SNP array (performed on proband, 3 additional carriers, and parents)

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

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

gnomAD: n/a

Supplementary Data: Table 2

Case 2:

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: WES, Cytoscan HD SNP array (performed on proband, 3 additional carriers, and parents)

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

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

gnomAD: n/a

Supplementary Data: Table 2

Case M:

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, partial testing (MYH7, MYBPC3)

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

Supplementary Data: Table 2

Case C: 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, partial testing (MYH7, CSRP3, DES, LMNA, MYBPC3, TNNT2, TNNI3)

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

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

Supplementary Data: Table 2

Case G: proband, Male

DiseaseAssertion: left ventricular noncompaction

CasePresentingHPOs: HP:0030682 (left ventricular noncompaction)

CasePreviousTesting: 12-lead electrocardiogram (ECG), echocardiography, exercise test and 24-hour (or 48-hour) Holter monitoring, cardiac MRI, partial testing (MYH7)

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

Supplementary Data: Table 2

Case I: 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

Case#: D26, female, 54 years

DiseaseAssertion: FDCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: DNA extraction, whole exome sequencing, pyrosequencing, RNA extraction, q-RT-PCR, SDS-PAGE electrophoresis, western blotting and immunofluorescence microscopy

CaseGenotypingMethod: N/A

Variant: NM_000257.4(MYH7):c.4828G>C (p.Glu1610Gln)

ClinVar: 181267 https://www.ncbi.nlm.nih.gov/clinvar/variation/181267/

CAID: N/A

gnomAD: absent

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 1

Case:

DiseaseAssertion: hypertrophic cardiomyopathy

CaseHPOFreeText: maximal wall thickness (MWT) ≥15 mm

CasePreviousTesting: Full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (TNNC1, CSRP3, TCAP, ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CAV3, CRYAB, CTNNA3, DES, DSC2, DSG2, DSP, EMD, FHL1, GLA, JPH2, JUP, LAMA4, LAMP2, LDB3, LMNA, MIB1, MYH6, MYOZ2, MYPN, NEXN, PKP2, PLN, PRDM16, PRKAG2, RBM20, SCN5A, TAZ, TMEM43, TNNC1, TTN, TTR, VCL), electrocardiography

CaseGenotypingMethod: direct sequencing of all coding intron-exon boundaries of 12 genes (prior to 2012), next-generation sequencing (post 2012)

Variant: NM_000257.3(MYH7):c.5786C>T (p.Thr1929Met)

ClinVar: 181397, https://www.ncbi.nlm.nih.gov/clinvar/variation/181397/

gnomAD: n/a

Supplementary Data table 1

Variant noted to be present in 3 individuals

Variant: NM_000257.3(MYH7):c.5135G>A (p.Arg1712Gln)

ClinVar: 36642, https://www.ncbi.nlm.nih.gov/clinvar/variation/36642/

gnomAD: 0.00002125, https://gnomad.broadinstitute.org/variant/14-23884860-C-T

Supplementary Data: S2 Table

Case 8: Spanish, 81yo, Male

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1

CaseGenotypingMethod: genomic DNA obtained from blood or saliva, PCR, Sanger Sequencing

Variant: NM_000257.3(MYH7):c.3056C>A (p.Thr1019Asn)

ClinVar: 195720, https://www.ncbi.nlm.nih.gov/clinvar/variation/195720/

gnomAD: 0.00001591, https://gnomad.broadinstitute.org/variant/14-23892799-G-T

Supplementary Data: S2 Table

Case 4: Spanish, 67yo, Female

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1

CaseGenotypingMethod: genomic DNA obtained from blood or saliva, PCR, Sanger Sequencing

Variant: NM_000257.3(MYH7):c.1324C>T (p.Arg442Cys)

ClinVar: 177897, https://www.ncbi.nlm.nih.gov/clinvar/variation/177897/

gnomAD: 0.00002121, https://gnomad.broadinstitute.org/variant/14-23898247-G-A

Supplementary Data: S2 Table

Case 12: Spanish, 83yo, Female

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1

CaseGenotypingMethod: genomic DNA obtained from blood or saliva, PCR, Sanger Sequencing

Variant: NM_000257.3(MYH7):c.3236G>A (p.Arg1079Gln)

ClinVar: 177826, https://www.ncbi.nlm.nih.gov/clinvar/variation/177826/

gnomAD: 0.000007073, https://gnomad.broadinstitute.org/variant/14-23891398-C-T

Supplementary Data: S2 Table

Case 11: Spanish, 27yo, Male

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1

CaseGenotypingMethod: genomic DNA obtained from blood or saliva, PCR, Sanger Sequencing

Variant: NM_000257.3(MYH7):c.5359G>C (p.Glu1787Gln)

ClinVar: 427207, https://www.ncbi.nlm.nih.gov/clinvar/variation/427207/

gnomAD: n/a

Supplementary Data: S2 Table

Case 3: Spanish, 17yo, Male

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1

CaseGenotypingMethod: genomic DNA obtained from blood or saliva, PCR, Sanger Sequencing

Variant: NM_000257.3(MYH7):c.1207C>G (p.Arg403Gly)

ClinVar: 505562, https://www.ncbi.nlm.nih.gov/clinvar/variation/505562/

gnomAD: n/a

Supplementary Data: S2 Table

Case 126: Spanish, 12yo, Female

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1

CaseGenotypingMethod: genomic DNA obtained from blood or saliva, Next-gen sequencing panels of 55 or 78 genes

Variant: NM_000257.3(MYH7):c.5779A>T (p.Ile1927Phe)

ClinVar: 487639, https://www.ncbi.nlm.nih.gov/clinvar/variation/487639/

gnomAD: n/a

Supplementary Data: S2 Table

Case 49: Spanish, 18yo, Male

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1

CaseGenotypingMethod: genomic DNA obtained from blood or saliva, Next-gen sequencing panels of 55 or 78 genes

Variant1: NM_000257.3(MYH7):c.2890G>C (p.Val964Leu)

ClinVar: 42938, https://www.ncbi.nlm.nih.gov/clinvar/variation/42938/

gnomAD: 0.0004383, https://gnomad.broadinstitute.org/variant/14-23893148-C-G

Variant2: NM_000257.3(MYH7):c.3613G>A (p.Glu1205Lys)

ClinVar: 179656, https://www.ncbi.nlm.nih.gov/clinvar/variation/179656/

gnomAD: 0.000004004, https://gnomad.broadinstitute.org/variant/14-23889167-C-T

DiseaseAssertion: Hypertrophic Cardiomyopathy

VariantPreviousTesting: ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, and TTR were all tested via NGS.

VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of the 760 HCM probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.

VariantAddInfo: Seen in two HCM probands

Variant: NM_000257.4(MYH7):c.2539A>G (p.Lys847Glu)

ClinVarID: 177757 https://www.ncbi.nlm.nih.gov/clinvar/variation/177757/

gnomAD: Not in gnomAD

DiseaseAssertion: Hypertrophic Cardiomyopathy

VariantPreviousTesting: ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, and TTR were all tested via NGS.

VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of the 760 HCM probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.

VariantAddInfo: Seen in one proband

Variant: NM_000257.4(MYH7):c.1324C>T (p.Arg442Cys)

ClinVarID: 177897 https://www.ncbi.nlm.nih.gov/clinvar/variation/177897/

gnomAD: 0.00005012, http://gnomad.broadinstitute.org/variant/14-23898247-G-A

DiseaseAssertion: Cardiomyopathy

VariantPreviousTesting: ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, ABCC9, CTF1, DES, EMD, LDB3, LMNA, MYH6, RBM20, SGCD, TAZ, TCAP, TTN, VCL, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, TTR, DSC2, DSG2, DSP, JUP, PKP2, RYR2, TMEM43, CASQ2 and RYR2 were all tested in the PanCM panel.

VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of the 305 PanCM probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.

VariantAddInfo: Seen in one PanCM proband

Variant: NM_000257.4(MYH7):c.3157C>T (p.Arg1053Trp)

ClinVar: 181382 https://www.ncbi.nlm.nih.gov/clinvar/variation/181382/

gnomAD: Not in gnomAD

DiseaseAssertion: None

VariantPreviousTesting: Some combination of ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, ABCC9, CTF1, DES, EMD, LDB3, LMNA, MYH6, RBM20, SGCD, TAZ, TCAP, TTN, VCL, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, TTR, DSC2, DSG2, DSP, JUP, PKP2, RYR2, TMEM43, CASQ2 and RYR2 were tested via NGS.

VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.

Variant: NM_000257.4(MYH7):c.4668C>A (p.Gly1556=)

ClinVar: 626810 https://www.ncbi.nlm.nih.gov/clinvar/variation/626810/

gnomAD: 0.0009022, http://gnomad.broadinstitute.org/variant/14-23885498-G-T

Supplementary Data: Online Table 1a

Case:

CaseHPOFreeText: heart transplant

CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)

CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes

Variant: NM_000257.3(MYH7):c.495G>A (p.Met165Ile)

ClinVar: 524948, https://www.ncbi.nlm.nih.gov/clinvar/variation/524948/

gnomAD: n/a

Supplementary Data: Online Table 2b

Case 4:

CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)

CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes

Variant 1: 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

Variant 2: NM_000257.3(MYH7):c.1633G>A (p.Asp545Asn)

ClinVar: 264607, https://www.ncbi.nlm.nih.gov/clinvar/variation/264607/

gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/14-23897049-C-T

variants asserted to be in cis

Supplementary Data: Online Table 2a

Case:

CasePresentingHPOs: HP:0010316 (Ebstein anomaly)

CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)

CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes

Variant: NM_000257.3(MYH7):c.847T>G (p.Tyr283Asp)

ClinVar: 66081, https://www.ncbi.nlm.nih.gov/clinvar/variation/66081/

gnomAD: n/a

Supplementary Data: Online Table 2b

Case 3:

CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)

CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes

Variant 1: 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

Variant 2: NM_000257.3(MYH7):c.1633G>A (p.Asp545Asn)

ClinVar: 264607, https://www.ncbi.nlm.nih.gov/clinvar/variation/264607/

gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/14-23897049-C-T

variants asserted to be in cis

Supplementary Data: Online Table 2a

Case:

CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)

CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes

Variant: NM_000257.3(MYH7):c.4075C>T (p.Arg1359Cys)

ClinVar: 178082, https://www.ncbi.nlm.nih.gov/clinvar/variation/178082/

gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/14-23887513-G-A

Supplementary Data: Online Table 2a

Case:

CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)

CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes

Variant: NM_000257.3(MYH7):c.4125T>A (p.Tyr1375Ter)

ClinVar: 579879, https://www.ncbi.nlm.nih.gov/clinvar/variation/579879/

gnomAD: n/a

Supplementary Data: Online Table 3

Case:

CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)

CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes

Variant: NM_000257.3(MYH7):c.5534G>A (p.Arg1845Gln)

ClinVar: 181286, https://www.ncbi.nlm.nih.gov/clinvar/variation/181286/

gnomAD: 0.000004023, https://gnomad.broadinstitute.org/variant/14-23884229-C-T

Supplementary Data: Table S3

Case 135:

DiseaseAssertion: left ventricular noncompaction

CasePresentingHPOs: HP:0030682 (left ventricular noncompaction)

CaseHPOFreeText: suspected LVNC, >7yo, able to hold breath, non compacted segment = distinct 2-layered appearance of trabeculated and compacted myocardium

CasePreviousTesting: Cardiac MRI using 17-segment model of LV segmentation, ECG, transthoracic echocardiography, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data tables S1 and S2.

CaseGenotypingMethod: WES, variant enrichment analysis

Variant: NM_000257.3(MYH7):c.4010G>A (p.Arg1337Gln)

ClinVar: 181238, https://www.ncbi.nlm.nih.gov/clinvar/variation/181238/

gnomAD: 0.0001207, https://gnomad.broadinstitute.org/variant/14-23887578-C-T

Supplementary Data: Table S3

Case 90:

DiseaseAssertion: left ventricular noncompaction

CasePresentingHPOs: HP:0030682 (left ventricular noncompaction)

CaseHPOFreeText: >7yo, able to hold breath, non compacted segment = distinct 2-layered appearance of trabeculated and compacted myocardium, NC/C ratio > 2.3:1

CasePreviousTesting: Cardiac MRI using 17-segment model of LV segmentation, ECG, transthoracic echocardiography, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data tables S1 and S2.

CaseGenotypingMethod: WES, variant enrichment analysis

Variant: NM_000257.3(MYH7):c.745C>T (p.Arg249Ter)

ClinVar: 407183, https://www.ncbi.nlm.nih.gov/clinvar/variation/407183/

gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/14-23900678-G-A

MultipleGeneVariants:

(1) TPM1 Variant:

Variant: NM_001018004.1(TPM1):c.775A>G (p.Lys259Glu)

ClinVar: 43687, https://www.ncbi.nlm.nih.gov/clinvar/variation/43687/

gnomAD: 0.0008382, https://gnomad.broadinstitute.org/variant/15-63363291-A-G

(2) PRKAG2 Variant:

Variant: p.Lys133Ile no ClinVar or CAID

Supplementary Data: Table S3

Case 12:

DiseaseAssertion: left ventricular noncompaction

CasePresentingHPOs: HP:0030682 (left ventricular noncompaction)

CaseHPOFreeText: >7yo, able to hold breath, non compacted segment = distinct 2-layered appearance of trabeculated and compacted myocardium, NC/C ratio > 2.3:1

CasePreviousTesting: Cardiac MRI using 17-segment model of LV segmentation, ECG, transthoracic echocardiography, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data tables S1 and S2.

CaseGenotypingMethod: WES, variant enrichment analysis

Variant: NM_000257.3(MYH7):c.5786C>T (p.Thr1929Met)

ClinVar: 181397, https://www.ncbi.nlm.nih.gov/clinvar/variation/181397/

gnomAD: 0.00005308, https://gnomad.broadinstitute.org/variant/14-23882972-G-A

CaseMYH7-19: Australia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

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.2539A>G (p.Lys847Glu)

ClinVar: 177757 https://www.ncbi.nlm.nih.gov/clinvar/variation/177757/

gnomAD: Not in gnomAD

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

CaseMYH7-11: Australia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

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.3325A>G (p.Lys1109Glu)

ClinVar: 492984 https://www.ncbi.nlm.nih.gov/clinvar/variation/492984/

gnomAD: Not in gnomAD

CaseMYH7-10: Australia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

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.3592G>T (p.Asp1198Tyr)

ClinVar: 520451 https://www.ncbi.nlm.nih.gov/clinvar/variation/520451/

gnomAD: Not in gnomAD

CaseMYH7-31: Australia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: 1 other proband shares this genotype

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

CaseMYH7-18: Australia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

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.2578A>G (p.Lys860Glu)

ClinVar: 192312 https://www.ncbi.nlm.nih.gov/clinvar/variation/192312/

gnomAD: Not in gnomAD

CaseMYH7-2: Australia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

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.5287G>A (p.Ala1763Thr)

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

gnomAD: European (Non-Finnish) 1.238e-4, Overall 7.423e-5 https://gnomad.broadinstitute.org/variant/14-23884476-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

Supplementary Data Table S3

Case: 33

DiseaseEntity: HCM

HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm

InheritancePattern: n/a

CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)

CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing

Variant: NM_000257.4(MYH7):c.5656-4G>A

ClinVar: 516360, https://www.ncbi.nlm.nih.gov/clinvar/variation/516360/

gnomAD: 0.00006011, https://gnomad.broadinstitute.org/variant/14-23883106-C-T

MultipleGeneVariants:

(1) CRYAB Variant

Variant: c.331G>A (p.Gly111Ser) unregistered variant

(2) DES Variant

Variant: NM_001927.4(DES):c.638C>T (p.Ala213Val)

ClinVar: 44265, https://www.ncbi.nlm.nih.gov/clinvar/variation/44265/

gnomAD: 0.009280, https://gnomad.broadinstitute.org/variant/2-220284876-C-T

(3) FKTN Variant

Variant: NM_006731.2(FKTN):c.1336A>G (p.Asn446Asp)

ClinVar: 36138, https://www.ncbi.nlm.nih.gov/clinvar/variation/36138/

gnomAD: 0.01093, https://gnomad.broadinstitute.org/variant/9-108397495-A-G

(4) MYBPC3 Variant

Variant: NM_000256.3(MYBPC3):c.2686G>A (p.Val896Met)

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

gnomAD: 0.006194, https://gnomad.broadinstitute.org/variant/11-47357479-C-T

Supplementary Data Table S3

Case: 52

DiseaseEntity: HCM

HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm

InheritancePattern: n/a

CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)

CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing

Variant: NM_000257.4(MYH7):c.2451C>A (p.Asn817Lys)

ClinVar: 235029, https://www.ncbi.nlm.nih.gov/clinvar/variation/235029/

gnomAD: absent

MultipleGeneVariants:

(1) TTN Variant

Variant: NM_001267550.2(TTN):c.74597_74599CAA[1] (p.Thr24867del)

ClinVar: 165840, https://www.ncbi.nlm.nih.gov/clinvar/variation/165840/

gnomAD: absent

Case 7: 47 year old male

DiseaseAssertion: novel MYH7 R1832C in the index case

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

ParentalTesting:NR

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

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

CaseNotHPOs:NR

CaseNotHPOFreeText:NR

CasePreviousTesting:NR

Genotyping Method:NR

FunctionalAnalysis:NR

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

ClinVar:161322

CAID:CA016134

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

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

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

CasePT-110: United States

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001650, HP:0001658 (Aortic valve stenosis, Myocardial infarction)

NotHPOsFreeText: N/A

CaseAddInfo:

CaseGenotypingMethod: DNA was collected from the participants using blood samples. 18 genes suspected on contributing to HCM were targeted and sequenced. The variants were then located and filtered for pathogenicity.

Variant: NM_000257.3:c.5326A>G (p.Ser1776Gly)

ClinVar: 177629 https://www.ncbi.nlm.nih.gov/clinvar/variation/177629/

gnomAD: East Asian 3.007e-4, Overall 4.595e-5 https://gnomad.broadinstitute.org/variant/14-23884437-T-C

Multiple Gene Variants:

MYBPC3 Variant:

Variant is reported as below, but the nucleotide sequence is incorrect. Unable to register

Variant: NM_000256.3:c.76A>G (p.Ser236Gly)

CasePT-99: United States

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001650, HP:0001658 (Aortic valve stenosis, Myocardial infarction)

NotHPOsFreeText: N/A

CaseAddInfo:

CaseGenotypingMethod: DNA was collected from the participants using blood samples. 18 genes suspected on contributing to HCM were targeted and sequenced. The variants were then located and filtered for pathogenicity.

Variant: NM_000257.3:c.4199C>G (p.Ala1400Gly)

ClinVar: 181248 https://www.ncbi.nlm.nih.gov/clinvar/variation/181248/

gnomAD: Not in gnomAD

CasePT-42: United States

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001650, HP:0001658 (Aortic valve stenosis, Myocardial infarction)

NotHPOsFreeText: N/A

CaseAddInfo: 2 other siblings share the same genotype

CaseGenotypingMethod: DNA was collected from the participants using blood samples. 18 genes suspected on contributing to HCM were targeted and sequenced. The variants were then located and filtered for pathogenicity.

Variant: NM_000257.3:c.5317C>A (p.Gln1773Lys)

ClinVar: 181277 https://www.ncbi.nlm.nih.gov/clinvar/variation/181277/

gnomAD: Not in gnomAD

CasePT-33: United States

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001650, HP:0001658 (Aortic valve stenosis, Myocardial infarction)

NotHPOsFreeText: N/A

CaseAddInfo: PT-34 is the proband's sibling in Family 17 with the same genotype

CaseGenotypingMethod: DNA was collected from the participants using blood samples. 18 genes suspected on contributing to HCM were targeted and sequenced. The variants were then located and filtered for pathogenicity.

Variant: NM_000257.3:c.1615A>G (p.Met539Val)

ClinVar: 181409 https://www.ncbi.nlm.nih.gov/clinvar/variation/181409/

gnomAD: Not in gnomAD

CasePT-30: United States

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001650, HP:0001658 (Aortic valve stenosis, Myocardial infarction)

NotHPOsFreeText: N/A

CaseAddInfo:

CaseGenotypingMethod: DNA was collected from the participants using blood samples. 18 genes suspected on contributing to HCM were targeted and sequenced. The variants were then located and filtered for pathogenicity.

Variant: NM_000257.3:c.2606G>A (p.Arg869His)

ClinVar: 177667 https://www.ncbi.nlm.nih.gov/clinvar/variation/177667/

gnomAD: African 1.230e-4, Overall 2.386e-5 https://gnomad.broadinstitute.org/variant/14-23894051-C-T

CasePT-76: United States

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001650, HP:0001658 (Aortic valve stenosis, Myocardial infarction)

NotHPOsFreeText: N/A

CaseAddInfo:

CaseGenotypingMethod: DNA was collected from the participants using blood samples. 18 genes suspected on contributing to HCM were targeted and sequenced. The variants were then located and filtered for pathogenicity.

Variant: NM_000257.3:c.2334C>G (p.Asp778Glu)

ClinVar: 265252 https://www.ncbi.nlm.nih.gov/clinvar/variation/265252/

gnomAD: Not in gnomAD

CasePT-97: United States

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001650, HP:0001658 (Aortic valve stenosis, Myocardial infarction)

NotHPOsFreeText: N/A

CaseAddInfo:

CaseGenotypingMethod: DNA was collected from the participants using blood samples. 18 genes suspected on contributing to HCM were targeted and sequenced. The variants were then located and filtered for pathogenicity.

Variant: NM_000257.3:c.4159G>A (p.Glu1387Lys)

ClinVar: 181244 https://www.ncbi.nlm.nih.gov/clinvar/variation/181244/

gnomAD: South Asian 3.266e-5, Overall 3.977e-6 https://gnomad.broadinstitute.org/variant/14-23887429-C-T

Supplementary Data, Table 2

Case: Australian

DiseaseAssertion: HCM

CaseHPOFreeText: maximum left ventricular wall thickness of ≥15 mm

CasePreviousTesting: electrocardiography, echocardiography, Full testing (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1)

CaseGenotypingMethod: DNA isolated from peripheral blood or buccal swabs, PCR, Sanger sequencing, segregation analysis, haplotype analysis of MYBPC3 and MYH7

Variant: NM_000257.3(MYH7):c.1324C>T (p.Arg442Cys)

ClinVar: 177897, https://www.ncbi.nlm.nih.gov/clinvar/variation/177897/

gnomAD: 0.00002121, https://gnomad.broadinstitute.org/variant/14-23898247-G-A

Supplementary Data, Table 2

Case: Australian

DiseaseAssertion: HCM

CaseHPOFreeText: maximum left ventricular wall thickness of ≥15 mm

CasePreviousTesting: electrocardiography, echocardiography, Full testing (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1)

CaseGenotypingMethod: DNA isolated from peripheral blood or buccal swabs, PCR, Sanger sequencing, segregation analysis, haplotype analysis of MYBPC3 and MYH7

Variant: NM_000257.3(MYH7):c.1478T>A (p.Met493Lys)

ClinVar: 192308, https://www.ncbi.nlm.nih.gov/clinvar/variation/192308/

gnomAD: n/a

Table V

Case 902: Italian, Female, 25yo at onset

DiseaseAssertion: HCM

CasePresentingHPOs: HP:0001712, HP:0000821, HP:0006682, HP:0004756 (left ventricular hypertrophy, hypothyroidism, premature ventricular contractions, ventricular tachycardia)

CaseHPOFreeText: maximum left ventricular wall thickness of ≥15 mm, LVWT = 19mm, automatic implantable cardioverter defibrillator, LV ejection fraction = 64%

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_000256.3(MYBPC3):c.2507T>C (p.Met836Thr) written in paper as p.Ile836Thr

ClinVar: 454315, https://www.ncbi.nlm.nih.gov/clinvar/variation/454315/

gnomAD: n/a

Case#: HCM516, male, 23 years,

DiseaseAssertion: HCM

FamilyInfo: Yes, father and mother has HCM

CasePresentingHPOs: syncope, chest tightness (HP:0001279, HP:0031352)

CaseHPOFreeText: inverted T-waves, ST-segment depression, 28mm MLVWT, 67% LVE F, 0.64 E/A ratio, LVOT-PG 44mm

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseGenotypingMethod: sequencing, physical examination, ECG, 3D modeling, statistical analysis

MultipleGeneVariants:

(1) Variant: NM_000257.4(MYH7):c.2631G>A (p.Met877Ile)

ClinVar: 955476 https://www.ncbi.nlm.nih.gov/clinvar/variation/955476/

CAID: N/A

gnomAD: absent

(2) Variant: NM_000257.4(MYH7):c.3134G>A (p.Arg1045His)

ClinVar: 651054 https://www.ncbi.nlm.nih.gov/clinvar/variation/651054/

CAID: N/A

gnomAD: absent

Case#: 6, female, 45 yr at onset, 66 yr at diagnosis

DiseaseAssertion: Myopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0100595, HP:0003202, HP:0003715, HP:0100301 (Camptocormia, skeletal muscle atrophy, myofibrillar myopathy, muscle fiber tubular inclusions)

CaseHPOFreeText: muscle atrophy specifically paraspinal, no clinical signs of the atrophy

CaseNotHPOs: HP:0003701, HP:0000508, HP:0000602, HP:0002015 (proximal muscle weakness, ptosis, ophthalmoplegia, dysphagia)

CaseNotHPOFreeText: No ALS, MG, or Parkinson's disease

CasePreviousTesting: spinal cord imaging, EMG, deltoid muscle, repetitive nerve stimulation, intravenous Prostigmin therapeutic text, screening for anti-ancetylcholine receptor and anti-muscle specific kinase antibodies, left deltoid muscle biopsy

CaseGenotypingMethod: N/A

Variant: NM_000257.4(MYH7):c.5329G>A (p.Ala1777Thr)

ClinVar: 177697 https://www.ncbi.nlm.nih.gov/clinvar/variation/177697/

CAID: N/A

gnomAD: 0.0001316 (European/non-Finnish) https://gnomad.broadinstitute.org/variant/14-23884434-C-T

CaseHCM4.1: Mixed ancestry

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: HP:0000819 (Diabetes mellitus)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: See Table 1

CaseGenotypingMethod: DNA was extracted from the probands' blood, followed by sequencing of the coding regions and exon/intron boundaries of 15 genes associated with HCM. From there, they were amplified by PCR ampliication and variants were filtered by pathogenicity. Every unclassified variant was confirmed by Sanger sequencing afterwards.

Variant: NM_000257.3:c.2282C>A (p.Thr761Asn)

ClinVar: 546292 https://www.ncbi.nlm.nih.gov/clinvar/variation/546292/

gnomAD: Not in gnomAD

Case2: Male, 43 years diagnosis, China, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePresentingHPOs: HP:0001639, HP:0001667, HP:0005110 (Hypertrophic cardiomyopathy, Right ventricular hypertrophy, Atrial fibrillation)

HPOsFreeText: 0 SCD risk factors, NYHA class is II, Right ventricular wall thickness 14.9 mm

CaseNotHPOs: HP:0002092, HP:0001642, HP:0030680 (Pulmonary arterial hypertension, Pulmonary stenosis, Congenital heart disease)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CaseGenotypingMethod: Probands' genomic DNA was extracted from blood samples. WES was performed, with the resulting sequence data mapped to a reference genome and variants filtered for pathogenicity and predicted effects. All variants identified were confirmed via Sanger sequencing of the respective genes.

Variant: NM_000257.3:c.2123G>C (p.Gly708Ala)

ClinVar: 42882 https://www.ncbi.nlm.nih.gov/clinvar/variation/42882/

gnomAD: Not in gnomAD

MultipleGeneVariants:

MYBPC3 Variant:

Variant: NM_000256.3:c.1000G>A (p.Glu334Lys)

ClinVar: 177902 https://www.ncbi.nlm.nih.gov/clinvar/variation/177902/

gnomAD: East Asian 3.338e-3, Overall 2.368e-4 https://gnomad.broadinstitute.org/variant/11-47367848-C-T

**TTN Variant

Unknown Variant

Variant: TTN-E23808K

CAID: N/A

gnomAD: N/A

ACTN2 Variant

Unknown Variant

Variant: ACTN2-P32fs

CAID: N/A

gnomAD: N/A

DSC2 Variant

Unknown Variant, as 3 possible mutations can be responsible for this protein change

Variant: DSC2-S574R

CAID: N/A

gnomAD: N/A

LAMA4 Variant

Unknown Variant

Variant: LAMA4-L1040P

CAID: N/A

gnomAD: N/A

SYNEC2 Variant

Unknown Variant, as 3 possible mutations can be responsible for this protein change

Variant: SYNE2-W5861C

CAID: N/A

gnomAD: N/A

CaseARVC-02: Male, 35 year diagnosis, Caucasian, Germany

CasePresentingHPOs: HP:0011663, HP:0001635 (Right ventricular cardiomyopathy, Heart failure)

HPOsFreeText: RVEDD at 61 mm

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Proband treated with HTx and ICD, Father died of cardiac issues, Brother has heart disease, Patient is heterozygous for MYH7 variant

CaseGenotypingMethod: Using a Cardiomyopathy gene panel of 46 genes, the proband's DNA was screened for variants. Afterwards, the variants were classified based on pathogenicity and modeled using predictive software.

Variant: NM_000257.3:c.3715A>G (p.Ile1239Val)

ClinVar: 265831 https://www.ncbi.nlm.nih.gov/clinvar/variation/265831/

gnomAD: Not in gnomAD

CaseMYH7-27: N/A

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CaseGenotypingMethod: Testing for all 8 sarcomeric genes, plus GLA, LAMP2, and PRKAG2 was initiated in all probands. After the direct sequencing, the variants were filtered for pathogenicity and classified.

Variant: NM_000257.3:c.505A>G (p.Arg169Gly)

ClinVar: 177664 https://www.ncbi.nlm.nih.gov/clinvar/variation/177664/

gnomAD: Not in gnomAD

CaseMYH7-5: N/A

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CaseGenotypingMethod: Testing for all 8 sarcomeric genes, plus GLA, LAMP2, and PRKAG2 was initiated in all probands. After the direct sequencing, the variants were filtered for pathogenicity and classified.

Variant: NM_000257.3:c.2198G>T (p.Gly733Val)

ClinVar: 181177 https://www.ncbi.nlm.nih.gov/clinvar/variation/181177/

gnomAD: Not in gnomAD

Case IV-8: Female, Iranian, 36yo

DiseaseAssertion: DCM

FamilyInfo: consanguineous family, pedigree in fig. 1

CasePresentingHPOs: HP:0005162 (left ventricular dysfunction)

CaseHPOFreeText: New York Heart Association Class = I, left ventricular ejection fraction = 60%, left ventricular internal end-diastolic diameter = 5.0cm, left ventricular internal end-systolic diameter = 3.1cm, interventricular septum = 0.7cm, posterior wall = 0.7cm, normal sinus rhythm, Normal heart valve function

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

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

DOI: 10.64898/2026.10.01.756008

Resource: Caenorhabditis Genetics Center (RRID:SCR_007341)

Curator: @Apiekniewska

SciCrunch record: RRID:SCR_007341

What is this?

DOI: 10.64898/2026.09.28.755163

Resource: (WB Cat# WBStrain00041969,RRID:WB-STRAIN:WBStrain00041969)

Curator: @Apiekniewska

SciCrunch record: RRID:WB-STRAIN:WBStrain00041969

What is this?

DOI: 10.64898/2026.09.28.755163

Resource: (WB Cat# WBStrain00000001,RRID:WB-STRAIN:WBStrain00000001)

Curator: @Apiekniewska

SciCrunch record: RRID:WB-STRAIN:WBStrain00000001

What is this?

DOI: 10.64898/2026.09.17.752367

Resource: Caenorhabditis Genetics Center (RRID:SCR_007341)

Curator: @Apiekniewska

SciCrunch record: RRID:SCR_007341

What is this?

DOI: 10.64898/2026.09.13.751219

Resource: RRID:WB-STRAIN:WBStrain00033148

Curator: @Apiekniewska

SciCrunch record: RRID:WB-STRAIN:WBStrain00033148

What is this?

DOI: 10.64898/2026.09.13.751219

Resource: (WB Cat# WBStrain00000001,RRID:WB-STRAIN:WBStrain00000001)

Curator: @Apiekniewska

SciCrunch record: RRID:WB-STRAIN:WBStrain00000001

What is this?

DOI: 10.64898/2026.08.10.743574

Resource: RRID:WB-STRAIN:WBStrain00034902

Curator: @Apiekniewska

SciCrunch record: RRID:WB-STRAIN:WBStrain00034902

What is this?

DOI: 10.64898/2026.08.10.743574

Resource: (WB Cat# WBStrain00000001,RRID:WB-STRAIN:WBStrain00000001)

Curator: @Apiekniewska

SciCrunch record: RRID:WB-STRAIN:WBStrain00000001

What is this?

CaseCM1832: Male, 0 years diagnosis, Japan, Asian

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001939 (Abnormality of metabolism/homeostasis)

NotHPOsFreeText: Neuromuscular disease, Malformation syndromes

CaseAddInfo: No family history of cardiomyopathy or sudden death, Proband found in Supplementary Table 2, Mother is negative for this variant

CasePreviousTesting: 8 patients with HCM and one with RCM were analyzed by NGS for the eight sarcomere-encoding genes and MYP.

CaseGenotypingMethod: Probands were subject to PCR amplification and direct sequencing of 64 cardiomyopathy-associated genes, including the eight sarcomere-encoding genes. The variants were then filtered for rarity and tested for pathogenicity.

Variant: NM_000257.3:c.2609G>T (p.Arg870Leu)

ClinVar: 235031 https://www.ncbi.nlm.nih.gov/clinvar/variation/235031/

gnomAD: Not in gnomAD

CaseCM0969: Male, 6 years diagnosis, Japan, Asian

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001939 (Abnormality of metabolism/homeostasis)

NotHPOsFreeText: Neuromuscular disease, Malformation syndromes

CaseAddInfo: Positive family history of cardiomyopathy or sudden death, Proband found in Supplementary Table 2, Variant is asserted as novel, Both father and sister with HCM tested positive for this variant

CasePreviousTesting: 8 patients with HCM and one with RCM were analyzed by NGS for the eight sarcomere-encoding genes and MYP.

CaseGenotypingMethod: Probands were subject to PCR amplification and direct sequencing of 64 cardiomyopathy-associated genes, including the eight sarcomere-encoding genes. The variants were then filtered for rarity and tested for pathogenicity.

Variant: NM_000257.3:c.2777T>C (p.Leu926Pro)

ClinVar: 525005 https://www.ncbi.nlm.nih.gov/clinvar/variation/525005/

gnomAD: Not in gnomAD

DOI: 10.64898/2026.07.10.737828

Resource: RRID:WB-STRAIN:WBStrain00007961

Curator: @Apiekniewska

SciCrunch record: RRID:WB-STRAIN:WBStrain00007961

What is this?

DOI: 10.64898/2026.07.10.737828

Resource: RRID:WB-STRAIN:WBStrain00034895

Curator: @Apiekniewska

SciCrunch record: RRID:WB-STRAIN:WBStrain00034895

What is this?

DOI: 10.64898/2026.07.10.737828

Resource: (WB Cat# WBStrain00034068,RRID:WB-STRAIN:WBStrain00034068)

Curator: @Apiekniewska

SciCrunch record: RRID:WB-STRAIN:WBStrain00034068

What is this?

DOI: 10.64898/2026.07.10.737828

Resource: (WB Cat# WBStrain00034065,RRID:WB-STRAIN:WBStrain00034065)

Curator: @Apiekniewska

SciCrunch record: RRID:WB-STRAIN:WBStrain00034065

What is this?

DOI: 10.64898/2026.07.10.737828

Resource: RRID:WB-STRAIN:WBStrain00007977

Curator: @Apiekniewska

SciCrunch record: RRID:WB-STRAIN:WBStrain00007977

What is this?

DOI: 10.64898/2026.07.10.737828

Resource: RRID:WB-STRAIN:WBStrain00040174

Curator: @Apiekniewska

SciCrunch record: RRID:WB-STRAIN:WBStrain00040174

What is this?

DOI: 10.64898/2026.07.10.737828

Resource: RRID:WB-STRAIN:WBStrain00007966

Curator: @Apiekniewska

SciCrunch record: RRID:WB-STRAIN:WBStrain00007966

What is this?

DOI: 10.64898/2026.07.10.737828

Resource: RRID:WB-STRAIN:WBStrain00021974

Curator: @Apiekniewska

SciCrunch record: RRID:WB-STRAIN:WBStrain00021974

What is this?

DOI: 10.64898/2026.07.10.737828

Resource: RRID:WB-STRAIN:WBStrain00000264

Curator: @Apiekniewska

SciCrunch record: RRID:WB-STRAIN:WBStrain00000264

What is this?

DOI: 10.64898/2026.07.10.737828

Resource: RRID:WB-STRAIN:WBStrain00004861

Curator: @Apiekniewska

SciCrunch record: RRID:WB-STRAIN:WBStrain00004861

What is this?

DOI: 10.64898/2026.07.10.737828

Resource: (WB Cat# WBStrain00005102,RRID:WB-STRAIN:WBStrain00005102)

Curator: @Apiekniewska

SciCrunch record: RRID:WB-STRAIN:WBStrain00005102

What is this?

DOI: 10.64898/2026.07.10.737828

Resource: (WB Cat# WBStrain00000001,RRID:WB-STRAIN:WBStrain00000001)

Curator: @Apiekniewska

SciCrunch record: RRID:WB-STRAIN:WBStrain00000001

What is this?

DOI: 10.64898/2026.07.10.737828

Resource: RRID:WB-STRAIN:WBStrain00046813

Curator: @Apiekniewska

SciCrunch record: RRID:WB-STRAIN:WBStrain00046813

What is this?

DOI: 10.64898/2026.07.10.737828

Resource: RRID:WB-STRAIN:WBStrain00007962

Curator: @Apiekniewska

SciCrunch record: RRID:WB-STRAIN:WBStrain00007962

What is this?

Case#: male, 43 yrs,

DiseaseAssertion: FDCM

FamilyInfo: Family B; sister also proband; brother died of SCD; daughter and father asymptomatic

CasePresentingHPOs: HP:0012250 (ST segment depression)

CaseHPOFreeText: severe cardiac enlargement, increased LVEDD (77.8 mm), decreased LVESD (69.8 mm), decreased LVEF (21% < 50%), heart rate 78 beats/min, widened QRS complex (120 ms > 110 ms)

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: N/A

CaseGenotypingMethod: Sanger sequencing, Genome Analyzer IIx, ECG,

Variant: NM_000257.4(MYH7):c.3134G>A (p.Arg1045His)

ClinVar: 651054 https://www.ncbi.nlm.nih.gov/clinvar/variation/651054/

CAID: N/A

gnomAD: absent

Case#: female

DiseaseAssertion: FDCM

FamilyInfo: Family B; brother also proband; brother died of SCD, niece and father asymptomatic

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseGenotypingMethod: Sanger sequencing, Genome Analyzer IIx, ECG,

Variant: NM_000257.4(MYH7):c.3134G>A (p.Arg1045His)

ClinVar: 651054 https://www.ncbi.nlm.nih.gov/clinvar/variation/651054/

CAID: N/A

gnomAD: absent

CaseHCM014: 43 yrs report, Vietnam, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

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

HPOsFreeText: Maximal LV thickness 27 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.5135G>A (p.Arg1712Gln)

ClinVar: 36642 https://www.ncbi.nlm.nih.gov/clinvar/variation/36642/

gnomAD: 0.00004657, http://gnomad.broadinstitute.org/variant/14-23884860-C-T

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

CaseHCM083: 53 yrs report, Vietnam, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0002875, HP:0001712, HP:0001667, HP:0001705 (Exertional dyspnea, Left ventricular hypertrophy, Right ventricular hypertrophy, Right ventricular outlet obstruction)

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.4159G>A (p.Glu1387Lys)

ClinVar: 181244 https://www.ncbi.nlm.nih.gov/clinvar/variation/181244/

gnomAD: 0.00003266, http://gnomad.broadinstitute.org/variant/14-23887429-C-T

Case: Case 9, male, 69yo

CasePresentingHPOs: HP:0031318 (myocardial fiber disarray)

HPOsFreeText: BMI = 25.2kg/m^2, cause of death: accidental head injury, heart weight = 624g, left ventricular thickness = 1.8cm, distribution of myocyte disarray in ventricular septum, area of disarray = 7.8%, grade of fibrosis = 3

CaseNotHPOs: HP:0031296 (atrial septal hypertrophy)

CasePreviousTesting: NGS of 81 cardiovascular disorder-related genes (Supplemental Table S1)

CaseGenotypingMethod: genomic DNA extracted from whole blood, PCR, NGS of 81 cardiovascular disorder-related genes (Supplemental Table S1)

Variant: NM_000257.4(MYH7):c.2822G>A (p.Arg941His)

ClinVar: 636633, https://www.ncbi.nlm.nih.gov/clinvar/variation/636633/

gnomAD: 0.00001590, https://gnomad.broadinstitute.org/variant/14-23893216-C-T?dataset=gnomad_r2_1

DOI: 10.64898/2026.07.04.736516

Resource: RRID:WB-STRAIN:WBStrain00004027

Curator: @Apiekniewska

SciCrunch record: RRID:WB-STRAIN:WBStrain00004027

What is this?

DOI: 10.64898/2026.07.04.736516

Resource: RRID:WB-STRAIN:WBStrain00027527

Curator: @Apiekniewska

SciCrunch record: RRID:WB-STRAIN:WBStrain00027527

What is this?

DOI: 10.64898/2026.07.04.736516

Resource: (WB Cat# WBStrain00000001,RRID:WB-STRAIN:WBStrain00000001)

Curator: @Apiekniewska

SciCrunch record: RRID:WB-STRAIN:WBStrain00000001

What is this?

DOI: 10.64898/2026.07.01.734387

Resource: RRID:WB-STRAIN:WBStrain00031400

Curator: @Apiekniewska

SciCrunch record: RRID:WB-STRAIN:WBStrain00031400

What is this?

DOI: 10.64898/2026.07.01.734387

Resource: RRID:WB-STRAIN:WBStrain00026779

Curator: @Apiekniewska

SciCrunch record: RRID:WB-STRAIN:WBStrain00026779

What is this?

DOI: 10.64898/2026.06.29.735219

Resource: Caenorhabditis Genetics Center (RRID:SCR_007341)

Curator: @Apiekniewska

SciCrunch record: RRID:SCR_007341

What is this?

DOI: 10.64898/2026.05.28.728331

Resource: (WB Cat# WBStrain00000001,RRID:WB-STRAIN:WBStrain00000001)

Curator: @Apiekniewska

SciCrunch record: RRID:WB-STRAIN:WBStrain00000001

What is this?

DOI: 10.64898/2026.05.28.728331

Resource: Caenorhabditis Genetics Center (RRID:SCR_007341)

Curator: @Apiekniewska

SciCrunch record: RRID:SCR_007341

What is this?

DOI: 10.64898/2026.05.19.726147

Resource: Caenorhabditis Genetics Center (RRID:SCR_007341)

Curator: @Apiekniewska

SciCrunch record: RRID:SCR_007341

What is this?

DOI: 10.64898/2026.05.08.723815

Resource: RRID:WB-STRAIN:WBStrain00041978

Curator: @Apiekniewska

SciCrunch record: RRID:WB-STRAIN:WBStrain00041978

What is this?

DOI: 10.64898/2026.05.08.723815

Resource: (WB Cat# WBStrain00041969,RRID:WB-STRAIN:WBStrain00041969)

Curator: @Apiekniewska

SciCrunch record: RRID:WB-STRAIN:WBStrain00041969

What is this?

DOI: 10.64898/2026.04.22.720250

Resource: Caenorhabditis Genetics Center (RRID:SCR_007341)

Curator: @Apiekniewska

SciCrunch record: RRID:SCR_007341

What is this?

Supplemental data table e-1

Case: MYH7 Case 2

InheritancePattern: autosomal recessive

DiseaseEntity: n/a

PreviouslyPublished: PMID: 16858239, PMID: 27247418

PreviousTesting: Not specified

CaseGenotypingMethod: paper notes single gene, NGS, and WES were used, but does not specify which method was used for each individual family

Variant: NM_000257.4(MYH7):c.2594A>G (p.Lys865Arg)

ClinVar: 524996, https://www.ncbi.nlm.nih.gov/clinvar/variation/524996/

gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/14-23894063-T-C

DOI: 10.64898/2026.04.13.718277

Resource: Caenorhabditis Genetics Center (RRID:SCR_007341)

Curator: @Apiekniewska

SciCrunch record: RRID:SCR_007341

What is this?

DOI: 10.64898/2026.04.09.717484

Resource: RRID:WB-STRAIN:WBStrain00032090

Curator: @Apiekniewska

SciCrunch record: RRID:WB-STRAIN:WBStrain00032090

What is this?