Case#: proband, young boy

DiseaseAssertion: muscular hypotonia

CasePresentingHPOs: HP:0008947, HP:0008947, HP:0002421, HP:0006829, HP:0008994, HP:0008981

"Infantile muscular hypotonia, delayed motor development, poor head control, severe muscular hypotonia, proximal muscle weakness in lower limbs, calf muscle hypertrophy"

CasePreviousTesting: ENMG at 3.5 months interpreted as normal, but at 6 months showed features of myopathy or muscular dystrophy

GenotypingMethod: Whole exome sequencing (WES) of the parents-offspring trio, Mutation was confirmed as de novo with Sanger sequencing. In silico analysis using both MutationTaster and MutPred Splice predicted the variant to disrupt splicing

Variant: NM_000257.4:c.5655G>A

ClinVar: 378215

CAID: CA16606815

gnomAD: https://gnomad.broadinstitute.org/variant/14-23883216-C-T

Total Allele Frequency: 0.00001193 European (non-Finnish): 0.00002637

Supplementary Data: Online Table 1a

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:c.5773C>G

CAID: CA257807342, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA257807342

gnomAD: n/a

Supplementary Data: Online Table 2a

Case:

CasePresentingHPOs: HP:0010316, HP:0001645 (Ebstein anomaly, sudden cardiac death)

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:c.5754C>G

CAID: CA389034544, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389034544

gnomAD: n/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.732+1G>A

ClinVar: 14127, https://www.ncbi.nlm.nih.gov/clinvar/variation/14127/

gnomAD: 0.000003976, https://gnomad.broadinstitute.org/variant/14-23900793-C-T

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:c.415G>T

CAID: CA389052864, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389052864

gnomAD: n/a

Supplementary Data: Online Table 1a

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.728G>A (p.Arg243His)

ClinVar: 14126, https://www.ncbi.nlm.nih.gov/clinvar/variation/14126/

gnomAD: 0.000007953, https://gnomad.broadinstitute.org/variant/14-23900798-C-T

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:c.3100-2A>C

CAID: CA035633, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA035633

gnomAD: 0.00002475, https://gnomad.broadinstitute.org/variant/14-23891536-T-G

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:c.1915A>G

CAID: CA389049545, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389049545

gnomAD: n/a

Supplementary Data: Online Table 1a

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.1106G>A (p.Arg369Gln)

ClinVar: 42822, https://www.ncbi.nlm.nih.gov/clinvar/variation/42822/

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:c.3928C>G

CAID: CA389041570, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389041570

gnomAD: n/a

Supplementary Data: S2 Table

Case 95: Spanish, 1yo, 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.2608C>T (p.Arg870Cys)

ClinVar: 161326, https://www.ncbi.nlm.nih.gov/clinvar/variation/161326/

gnomAD: 0.00002386, https://gnomad.broadinstitute.org/variant/14-23894049-G-A

MultipleGeneVariants:

(1) TTN Variant:

Variant: NM_133378.4:c.8920A>G

CAID: CA61002480, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_133378.4%3Ac.8920A%3EG

gnomAD: n/a

Supplementary Data: S2 Table

Case 236: Spanish, 37yo, 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.4954G>T (p.Asp1652Tyr)

ClinVar: 43047, https://www.ncbi.nlm.nih.gov/clinvar/variation/43047/

gnomAD: 0.00004774, https://gnomad.broadinstitute.org/variant/14-23885041-C-A

Variant2: NM_000257.3(MYH7):c.4817G>A (p.Arg1606His)

ClinVar: 43039, https://www.ncbi.nlm.nih.gov/clinvar/variation/43039/

gnomAD: 0.00003889, https://gnomad.broadinstitute.org/variant/14-23885349-C-T

Supplementary Data: S2 Table

Case 116: Spanish, 66yo, 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.2167C>G (p.Arg723Gly)

ClinVar: 42885, https://www.ncbi.nlm.nih.gov/clinvar/variation/42885/

gnomAD: n/a

MultipleGeneVariants

(1) TTN Variant:

Variant: NM_133378.4:c.31738G>A

CAID: CA349484668, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_133378.4%3Ac.31738G%3EA

gnomAD: n/a

(2) MYBPC3 Variant:

Variant: NM_000256.3(MYBPC3):c.3676C>T (p.Arg1226Cys)

ClinVar: 42731, https://www.ncbi.nlm.nih.gov/clinvar/variation/42731/

gnomAD: 0.00004815, https://gnomad.broadinstitute.org/variant/11-47353761-G-A

Supplementary Data: S2 Table

Case 1: Spanish, 42yo, 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.427C>T (p.Arg143Trp)

ClinVar: 164401, https://www.ncbi.nlm.nih.gov/clinvar/variation/164401/

gnomAD: 0.00002784, https://gnomad.broadinstitute.org/variant/14-23901923-G-A

Supplementary Data: S2 Table

Case 195: Spanish, 53yo, 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.958G>A (p.Val320Met)

ClinVar: 161328, https://www.ncbi.nlm.nih.gov/clinvar/variation/161328/

gnomAD: 0.00001591, https://gnomad.broadinstitute.org/variant/14-23899810-C-T

Supplementary Data: S2 Table

Case 47: Spanish, 40yo, 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

Variant: NM_000257.3(MYH7):c.4066G>A (p.Glu1356Lys)

ClinVar: 164294, https://www.ncbi.nlm.nih.gov/clinvar/variation/164294/

gnomAD: n/a

Supplementary Data Table S3

Case: 62

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.3158G>A (p.Arg1053Gln)

ClinVar: 155814, https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/

gnomAD: 0.00006010, https://gnomad.broadinstitute.org/variant/14-23891476-C-T

MultipleGeneVariants:

(1) LMNA Variant

Variant: NM_001282625.1:c.1551G>T

CAID: CA342823303, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA342823303

gnomAD: 0.00001100, https://gnomad.broadinstitute.org/variant/1-156106966-G-T

(2) RBM20 Variant

Variant: NM_001134363.3(RBM20):c.2662G>A (p.Asp888Asn)

ClinVar: 43995, https://www.ncbi.nlm.nih.gov/clinvar/variation/43995/

gnomAD: 0.004046, https://gnomad.broadinstitute.org/variant/10-112581039-G-A

Supplementary Data Table S3

Case: 194

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.2770G>A (p.Glu924Lys)

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

gnomAD: Not in gnomAD

MultipleGeneVariants:

(1) DES Variant

Variant: NM_001927.4(DES):c.137C>T (p.Ser46Phe)

ClinVar: 66406 https://www.ncbi.nlm.nih.gov/clinvar/variation/66406/

gnomAD: Not in gnomAD

(2) MYH6 Variant

Variant: NM_002471.3:c.5209A>T (p.Thr1737Ser)

CAID: CA257777730 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA257777730

gnomAD: Not in gnomAD

(3) TNNT2 Variant

Variant: NM_000364.3:c.416G>A (p.Arg139Lys)

CAID: CA028406 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA028406

gnomAD: Not in gnomAD

Supplementary Data Table S3

Case: 17

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.3158G>A (p.Arg1053Gln)

ClinVar: 155814, https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/

gnomAD: 0.00006010, https://gnomad.broadinstitute.org/variant/14-23891476-C-T

MultipleGeneVariants:

(1) NEBL Variant

Variant: NM_006393.2(NEBL):c.2054C>T (p.Ala685Val)

ClinVar: 227732, https://www.ncbi.nlm.nih.gov/clinvar/variation/227732/

gnomAD: 0.0003290, https://gnomad.broadinstitute.org/variant/10-21108354-G-A

(2) RBM20 Variant

Variant: NM_001134363.3(RBM20):c.2662G>A (p.Asp888Asn)

ClinVar: 43995, https://www.ncbi.nlm.nih.gov/clinvar/variation/43995/

gnomAD: 0.004046, https://gnomad.broadinstitute.org/variant/10-112581039-G-A

Supplementary Data Table S3

Case: 212

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.3158G>A (p.Arg1053Gln)

ClinVar: 155814 https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/

gnomAD: 0.0006368, https://gnomad.broadinstitute.org/variant/14-23891476-C-T

MultipleGeneVariants:

(1) PLB1 Variant

Variant: NM_153021.4:c.2981C>G (p.Ser994Cys)

CAID: CA1588372 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_153021.5%3Ac.2981C%3EG

gnomAD: 0.0002632, http://gnomad.broadinstitute.org/variant/2-28828739-C-G

(2) SCN5A Variant

Variant: NM_000335.4(SCN5A):c.1715C>A (p.Ala572Asp)

ClinVar: 67683 https://www.ncbi.nlm.nih.gov/clinvar/variation/67683/

gnomAD: 0.03855, https://gnomad.broadinstitute.org/variant/3-38645378-G-T

Supplementary Data Table S3

Case: 282

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.4901G>A (p.Arg1634His)

ClinVar: 222730 https://www.ncbi.nlm.nih.gov/clinvar/variation/222730/

gnomAD: Not in gnomAD

MultipleGeneVariants:

(1) DSP Variant

Variant: NM_004415.4(DSP):c.1348C>G (p.Pro450Ala)

ClinVar: 222572 https://www.ncbi.nlm.nih.gov/clinvar/variation/222572/

gnomAD: Not in gnomAD

(2) DSP Variant

Variant: NM_004415.4(DSP):c.6208G>A (p.Asp2070Asn)

ClinVar: 44936 https://www.ncbi.nlm.nih.gov/clinvar/variation/44936/

gnomAD: 0.007910, https://gnomad.broadinstitute.org/variant/6-7583703-G-A

(3) GAL Variant

Variant: NM_015973.5(GAL):c.47C>T (p.Ala16Val)

ClinVar: 475915 https://www.ncbi.nlm.nih.gov/clinvar/variation/475915/

gnomAD: 0.01730, https://gnomad.broadinstitute.org/variant/11-68452438-C-T

(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: 0.02794, https://gnomad.broadinstitute.org/variant/11-47357479-C-T

(5) PLB1 Variant

Variant: NM_153021.4:c.275A>G (p.Lys92Arg)

CAID: CA1586810 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_153021.5%3Ac.275A%3EG

gnomAD: 0.03209, https://gnomad.broadinstitute.org/variant/2-28748165-A-G

Supplementary Data Table S3

Case: 107

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.1178C>T (p.Ala393Val)

ClinVar: 222721 https://www.ncbi.nlm.nih.gov/clinvar/variation/222721/

gnomAD: Not in gnomAD

MultipleGeneVariants:

(1) DSP Variant

Variant: NM_004415.4(DSP):c.5498A>T (p.Glu1833Val)

ClinVar: 44929 https://www.ncbi.nlm.nih.gov/clinvar/variation/44929/

gnomAD: 0.02491, https://gnomad.broadinstitute.org/variant/6-7582993-A-T

(2) FHL2 Variant

Variant: NM_201555.1:c.-144C>T

CAID: CA1814921 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA1814921

gnomAD: 0.01323 https://gnomad.broadinstitute.org/variant/2-106006683-G-A

Supplementary Data Table S3

Case: 23

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.3158G>A (p.Arg1053Gln)

ClinVar: 155814, https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/

gnomAD: 0.00006010, https://gnomad.broadinstitute.org/variant/14-23891476-C-T

Supplementary Data Table S3

Case: 67

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.3158G>A (p.Arg1053Gln)

ClinVar: 155814 https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/

gnomAD: 0.0006368, https://gnomad.broadinstitute.org/variant/14-23891476-C-T

Supplementary Data Table S3

Case: 20

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.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) LDB3 Variant

Variant: NM_007078.3(LDB3):c.295C>T (p.Pro99Ser)

ClinVar: 178059, https://www.ncbi.nlm.nih.gov/clinvar/variation/178059/

gnomAD: 0.0009830, https://gnomad.broadinstitute.org/variant/10-88439888-C-T

(2) RBM20 Variant

Variant: NM_001134363.3(RBM20):c.2662G>A (p.Asp888Asn)

ClinVar: 43995, https://www.ncbi.nlm.nih.gov/clinvar/variation/43995/

gnomAD: 0.004046, https://gnomad.broadinstitute.org/variant/10-112581039-G-A

Supplementary Data Table S3

Case: 333

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.3158G>A (p.Arg1053Gln)

ClinVar: 155814 https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/

gnomAD: 0.0006368, https://gnomad.broadinstitute.org/variant/14-23891476-C-T

MultipleGeneVariants:

(1) RBM20 Variant

Variant: NM_001134363.3(RBM20):c.2662G>A (p.Asp888Asn)

ClinVar: 43995 https://www.ncbi.nlm.nih.gov/clinvar/variation/43995/

gnomAD: 0.02090, https://gnomad.broadinstitute.org/variant/10-112581039-G-A

(2) SDHA Variant

Variant: NM_004168.4(SDHA):c.1886A>T (p.Tyr629Phe)

ClinVar: 224949 https://www.ncbi.nlm.nih.gov/clinvar/variation/224949/

gnomAD: 0.5249, https://gnomad.broadinstitute.org/variant/5-254599-A-T

Supplementary Data Table S3

Case: 22

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 1: NM_000257.4(MYH7):c.1816G>A (p.Val606Met)

ClinVar: 14091, https://www.ncbi.nlm.nih.gov/clinvar/variation/14091/

gnomAD: 0.000007070, https://gnomad.broadinstitute.org/variant/14-23896866-C-T

Variant 2: NM_000257.4(MYH7):c.3853+7C>T

ClinVar: 42977, https://www.ncbi.nlm.nih.gov/clinvar/variation/42977/

gnomAD: 0.002253, https://gnomad.broadinstitute.org/variant/14-23888685-G-A

Supplementary Data Table S3

Case: 276

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.1816G>A (p.Val606Met)

ClinVar: 14091 https://www.ncbi.nlm.nih.gov/clinvar/variation/14091/

gnomAD: 0.00001548, https://gnomad.broadinstitute.org/variant/14-23896866-C-T

MultipleGeneVariants:

(1) LAMA4 Variant

Variant: NM_001105206.3(LAMA4):c.3239G>A (p.Arg1080Gln)

ClinVar: 44374 https://www.ncbi.nlm.nih.gov/clinvar/variation/44374/

gnomAD: 0.02400, https://gnomad.broadinstitute.org/variant/6-112460365-C-T

(2) NEBL Variant

Variant: NM_006393.2(NEBL):c.109_110del (p.Leu37fs)

ClinVar: 229042 https://www.ncbi.nlm.nih.gov/clinvar/variation/229042/

gnomAD: 0.001673, https://gnomad.broadinstitute.org/variant/10-21185929-TAA-T

Supplementary Data Table S3

Case: 90

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.3158G>A (p.Arg1053Gln)

ClinVar: 155814 https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/

gnomAD: 0.0006368, https://gnomad.broadinstitute.org/variant/14-23891476-C-T

MultipleGeneVariants:

(1) MYBPC3 Variant

Variant: NM_000256.3(MYBPC3):c.977G>A (p.Arg326Gln)

ClinVar: 42813 https://www.ncbi.nlm.nih.gov/clinvar/variation/42813/

gnomAD: 0.01364, https://gnomad.broadinstitute.org/variant/11-47367871-C-T

Supplementary Data Table S3

Case: 218

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.2539_2541del (p.Lys847del)

ClinVar: 42913 https://www.ncbi.nlm.nih.gov/clinvar/variation/42913/

gnomAD: Not in gnomAD

MultipleGeneVariants:

(1) MYBPC3 Variant

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

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

gnomAD: 0.02794, https://gnomad.broadinstitute.org/variant/11-47357479-C-T

(2) PSEN1 Variant

Variant: NM_000021.4(PSEN1):c.953A>G (p.Glu318Gly)

ClinVar: 98094 https://www.ncbi.nlm.nih.gov/clinvar/variation/98094/

gnomAD: 0.03394, https://gnomad.broadinstitute.org/variant/14-73673178-A-G

(3) TMPO Variant

Variant: NM_001032283.2(TMPO):c.859G>C (p.Ala287Pro)

ClinVar: 43693 https://www.ncbi.nlm.nih.gov/clinvar/variation/43693/

gnomAD: 0.04732, https://gnomad.broadinstitute.org/variant/12-98938295-G-C

Supplementary Data Table S3

Case: 26

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.3158G>A (p.Arg1053Gln)

ClinVar: 155814, https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/

gnomAD: 0.00006010, https://gnomad.broadinstitute.org/variant/14-23891476-C-T

MultipleGeneVariants:

(1) FBN1 Variant

Variant: NM_000138.4(FBN1):c.3077T>C (p.Phe1026Ser)

ClinVar: 199948, https://www.ncbi.nlm.nih.gov/clinvar/variation/199948/

gnomAD: 0.0006449, https://gnomad.broadinstitute.org/variant/15-48782053-A-G

(2) SDHA Variant

Variant: NM_004168.4(SDHA):c.1886A>T (p.Tyr629Phe)

ClinVar: 224949, https://www.ncbi.nlm.nih.gov/clinvar/variation/224949/

gnomAD: 0.1547, https://gnomad.broadinstitute.org/variant/5-254599-A-T

Supplementary Data Table S3

Case: 245

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.3158G>A (p.Arg1053Gln)

ClinVar: 155814 https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/

gnomAD: 0.0006368, https://gnomad.broadinstitute.org/variant/14-23891476-C-T

MultipleGeneVariants:

(1) DES Variant

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

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

gnomAD: 0.01512, https://gnomad.broadinstitute.org/variant/2-220284876-C-T

(2) JUP Variant

Variant: NM_002230.4(JUP):c.1942G>A (p.Val648Ile)

ClinVar: 45842 https://www.ncbi.nlm.nih.gov/clinvar/variation/45842/

gnomAD: 0.01341, https://gnomad.broadinstitute.org/variant/17-39913771-C-T

(3) TTN Variant

Variant: NM_001267550.2(TTN):c.33501_33503AGA[6] (p.Glu11172dup)

ClinVar: 46889 https://www.ncbi.nlm.nih.gov/clinvar/variation/46889/

gnomAD: 0.01788, https://gnomad.broadinstitute.org/variant/2-179544685-C-CTCT

Supplementary Data Table S3

Case: 25

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.3158G>A (p.Arg1053Gln)

ClinVar: 155814, https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/

gnomAD: 0.00006010, https://gnomad.broadinstitute.org/variant/14-23891476-C-T

MultipleGeneVariants:

(1) GAL Variant

Variant: NM_015973.5(GAL):c.47C>T (p.Ala16Val)

ClinVar: 475915, https://www.ncbi.nlm.nih.gov/clinvar/variation/475915/

gnomAD: 0.006938, https://gnomad.broadinstitute.org/variant/11-68452438-C-T

Supplementary Data Table S3

Case: 47

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.3158G>A (p.Arg1053Gln)

ClinVar: 155814, https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/

gnomAD: 0.00006010, https://gnomad.broadinstitute.org/variant/14-23891476-C-T

MultipleGeneVariants:

(1) DOLK Variant

Variant: NM_014908.3(DOLK):c.1dup (p.Met1fs)

ClinVar: 167006, https://www.ncbi.nlm.nih.gov/clinvar/variation/167006/

gnomAD: 0.006541, https://gnomad.broadinstitute.org/variant/9-131709581-A-AT

Supplementary Data Table S3

Case: 373

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_000257.3:c.4903A>G (p.Met1635Val)

CAID: CA044177 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA044177

gnomAD: 0.0005972, https://gnomad.broadinstitute.org/variant/14-23885263-T-C

MultipleGeneVariants:

(1) LMNA Variant

Variant: NM_170707.4(LMNA):c.357C>T (p.Arg119=)

ClinVar: 48062 https://www.ncbi.nlm.nih.gov/clinvar/variation/48062/

gnomAD: 0.01294, https://gnomad.broadinstitute.org/variant/1-156100408-C-T

(2) MYBPC3 Variant

Variant: NM_000256.3(MYBPC3):c.3181C>T (p.Gln1061Ter)

ClinVar: 42690 https://www.ncbi.nlm.nih.gov/clinvar/variation/42690/

gnomAD: 0.0001913, https://gnomad.broadinstitute.org/variant/11-47355117-G-A

(3) SCN5A Variant

Variant: NM_000335.4(SCN5A):c.553G>A (p.Ala185Thr)

ClinVar: 67996 https://www.ncbi.nlm.nih.gov/clinvar/variation/67996/

gnomAD: 0.004251, https://gnomad.broadinstitute.org/variant/3-38662392-C-T

(4) VCL Variant

Variant: NM_014000.2(VCL):c.1535G>A (p.Arg512His)

ClinVar: 450167 https://www.ncbi.nlm.nih.gov/clinvar/variation/450167/

gnomAD: 0.0001973, https://gnomad.broadinstitute.org/variant/10-75854211-G-A

Supplementary Data Table S3

Case: 123

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.3158G>A (p.Arg1053Gln)

ClinVar: 155814 https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/

gnomAD: 0.0006368, https://gnomad.broadinstitute.org/variant/14-23891476-C-T

MultipleGeneVariants:

(1) DES Variant

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

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

gnomAD: 0.01512, https://gnomad.broadinstitute.org/variant/2-220284876-C-T

(2) RBM20 Variant

Variant: NM_001134363.3(RBM20):c.2662G>A (p.Asp888Asn)

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

gnomAD: 0.02090, https://gnomad.broadinstitute.org/variant/10-112581039-G-A

Case IV-1: Female, 20mo, carrier with no clinical manifestation

CaseHPOFreeText: interventricular septum = 4mm, posterior wall of left ventricle = 4mm, normal electrocardiogram

CasePreviousTesting: same as proband

CaseGenotypingMethod: same as proband

Variant: NM_000257.3:c.1172A>C

CAID: CA389051191, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389051191

gnomAD: n/a

Case III-15: Male, 18yo, diagnosed at 16yo

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePresentingHPOs: HP:0012250 (ST segment depression

CaseHPOFreeText: abnormal Q wave, interventricular septum = 15mm, posterior wall of left ventricle = 9mm

CaseNotHPOs: HP:0005135 (abnormal T wave)

CaseNotHPOFreeText: no clinical manifestations

CasePreviousTesting: same as proband

CaseGenotypingMethod: same as proband

Variant: NM_000257.3:c.1172A>C

CAID: CA389051191, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389051191

gnomAD: n/a

Case IV-1: Female, 10mo, carrier with no clinical manifestation

CaseHPOFreeText: interventricular septum = 4mm, posterior wall of left ventricle = 4mm, normal electrocardiogram

CasePreviousTesting: same as proband

CaseGenotypingMethod: same as proband

Variant: NM_000257.3:c.1172A>C

CAID: CA389051191, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389051191

gnomAD: n/a

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)

CaseCM0934: 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, Mother tested negative for the 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.1357C>T (p.Arg453Cys)

ClinVar: 14089 https://www.ncbi.nlm.nih.gov/clinvar/variation/14089/

gnomAD: Not in gnomAD

CaseCM1762: Female, 12 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, Father shows positive for this variant with no symptoms while Mother shows negative for this variant with no symptoms

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.1845G>C (p.Lys615Asn)

CAID: CA389049696 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3%3Ac.1845G%3EC

gnomAD: Not in gnomAD

CaseCM1824: Female, 13 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, Father afflicted with HCM and also positive for same 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.2146G>A (p.Gly716Arg)

ClinVar: 14105 https://www.ncbi.nlm.nih.gov/clinvar/variation/14105/

gnomAD: Not in gnomAD

CaseCM1811: Female, 15 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 shows positive for this variant with no symptoms while Father shows negative for this variant with no symptoms

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.1988G>A (p.Arg663His)

ClinVar: 42875 https://www.ncbi.nlm.nih.gov/clinvar/variation/42875/

gnomAD: European (Non-Finnish) 3.097e-5, Overall 1.414e-5 https://gnomad.broadinstitute.org/variant/14-23896042-C-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.2104A>G (p.Ile702Val) listed in paper as p.Arg719Gln

ClinVar: 217470, https://www.ncbi.nlm.nih.gov/clinvar/variation/217470/

gnomAD: n/a

Supplementary Data table 1

Variant noted to be present in 4 individuals

Variant: NM_000257.3(MYH7):c.4130C>T (p.Thr1377Met)

ClinVar: 42992, https://www.ncbi.nlm.nih.gov/clinvar/variation/42992/

gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/14-23887458-G-A

Supplementary Data table 1

Variant noted to be present in 2 individuals

Variant: NM_000257.3(MYH7):c.1063G>A (p.Ala355Thr)

ClinVar: 42820, https://www.ncbi.nlm.nih.gov/clinvar/variation/42820/

gnomAD: n/a

Supplementary Data table 1

Variant noted to be present in 3 individuals

Variant: NM_000257.3(MYH7):c.1207C>T (p.Arg403Trp)

ClinVar: 14102, https://www.ncbi.nlm.nih.gov/clinvar/variation/14102/

gnomAD: n/a

PMID: 32461996

Gene: MYH7

HGNC: 7577

PMID: 23674365

Gene: MYH7

HGNC: 7577

Supplementary Data: Table S3

Case 1:

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.3286G>T (p.Asp1096Tyr)

ClinVar: 42963, https://www.ncbi.nlm.nih.gov/clinvar/variation/42953/

gnomAD: 0.0001414, https://gnomad.broadinstitute.org/variant/14-23890217-C-A

MultipleGeneVariants:

(1) ACTN2 Variant:

Variant: NM_001103.3(ACTN2):c.893G>A (p.Arg298His)

ClinVar: 43951, https://www.ncbi.nlm.nih.gov/clinvar/variation/43951/

gnomAD: 0.0004457, https://gnomad.broadinstitute.org/variant/1-236902618-G-A

Supplementary Data: Table S3

Case 87:

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:c.332C>T

CAID: CA389053057, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389053057

gnomAD: n/a

MultipleGeneVariants:

(1) DMD Variant:

Variant: NM_004011.3:c.3062C>A

CAID: CA10378350, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA10378350

gnomAD: 0.0001133, https://gnomad.broadinstitute.org/variant/X-31893318-G-T

Supplementary Data: Table S3

Case 7:

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.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

MultipleGeneVariants:

(1) TTN Variant:

Variant: p.Arg12731Ter no ClinVar or CAID

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 HCM proband

Variant: NM_000257.4(MYH7):c.1816G>A (p.Val606Met)

ClinVarID: 14091 https://www.ncbi.nlm.nih.gov/clinvar/variation/14091/

gnomAD: 0.00001548, http://gnomad.broadinstitute.org/variant/14-23896866-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 one HCM proband

Variant: NM_000257.3:c.2714G>A (p.Cys905Tyr)

CAID: CA389047298 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389047298

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.2945T>C (p.Met982Thr)

ClinVar: 42941 https://www.ncbi.nlm.nih.gov/clinvar/variation/42941/

gnomAD: 0.001416, http://gnomad.broadinstitute.org/variant/14-23892910-A-G

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 HCM probands

Variant: NM_000257.4(MYH7):c.958G>A (p.Val320Met)

ClinVar: 161328 https://www.ncbi.nlm.nih.gov/clinvar/variation/161328/

gnomAD: 0.00006154, http://gnomad.broadinstitute.org/variant/14-23899810-C-T

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 two PanCM probands

Variant: NM_000257.4(MYH7):c.4498C>T (p.Arg1500Trp)

ClinVar: 164284 https://www.ncbi.nlm.nih.gov/clinvar/variation/164284/

gnomAD: Not in gnomAD

CasePT-80: 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.2546T>C (p.Met849Thr)

ClinVar: 42914 https://www.ncbi.nlm.nih.gov/clinvar/variation/42914/

gnomAD: Not in gnomAD

CasePT-35: 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-36 and PT-37 are the proband's siblings in Family 18 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.1491G>T (p.Glu497Asp)

ClinVar: 14124 https://www.ncbi.nlm.nih.gov/clinvar/variation/14124/

gnomAD: Ashkenazi Jewish 1.984e-4, Overall 7.953e-6 https://gnomad.broadinstitute.org/variant/14-23897796-C-A

Case III-1: Male, 11yo, proband, died at 12yo

DiseaseAssertion: Left ventricular hypertrophy

CasePresentingHPOs: HP:0002018, HP:0000969, HP:0003388, HP:0001640, HP:0002240, HP:0002240, HP:0005135, HP:0031295 (nausea, edema, fatigability, cardiomegaly, hepatomegaly, left ventricular hypertrophy, abnormal T-wave, left atrial enlargement)

CaseHPOFreeText: inability to lie down, double chambered left ventricle, protrusion of precordium, soft heart sounds, grade 3/6 systolic murmur at the cardiac apex, liver enlarged to 3cm below right costal margin, left ventricle divided into apical and basal chambers by an incomplete fibromuscular septum, basal chamber was enlarged (ball-shaped) and had end-diastolic diameter of 80.7mm, impaired contraction of of left ventricular wall and septum, reduction of left ventricular ejection fraction = 35%, diameter of communication between 2 chambers of left ventricle = 16.0mm, the apical chamber of the left ventricle had a thinning wall, relative dullness of cardiac enlargement, normal thickness of septum and left ventricular wall, upper and middle section of ventricular septum expanded to right ventricle, died due to multiple system organ failure

FamilyInfo: 8 family members with double-chambered left ventricles

CasePreviousTesting: transthoracic echocardiography, ECG, cardiac MRI

CaseGenotypingMethod: WES, Affymetrix Cytoscan 750K Array to check potential candidate copy number variations, segregation analysis using the results from Sanger sequencing

Variant: NM_000257.3:c.998A>T

CAID: CA389051586, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389051586

gnomAD: n/a

Case II-3: Female, 40yo

DiseaseAssertion: Left ventricular hypertrophy

CasePresentingHPOs: HP:0001712 (left ventricular hypertrophy)

CaseHPOFreeText: double-chambered left ventricle, reduced exercise capacity for 13yrs, mild heart failure symptoms, normal thickness of septum and left ventricle, 2 chambers of left ventricle have 18.5mm diameter of communication and they contract almost normally, left ventricle ventricle end-diastolic diameter = 74.3mm, left ventricular ejection fraction = 45%

CasePreviousTesting: same as proband

CaseGenotypingMethod: segregation analysis using the results from Sanger sequencing

Variant: NM_000257.3:c.998A>T

CAID: CA389051586, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389051586

gnomAD: n/a

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

Table III

Case 94: Italian, 30yo,

DiseaseAssertion: HCM

CasePresentingHPOs: HP:0001712 (left ventricular hypertrophy)

CaseHPOFreeText: LVWT = 24mm, LV ejection fraction = 65%

CasePreviousTesting: echocardiography, Full testing (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1), additional testing Sanger: (GLA, LAMP2, PRKAG2), additional testing 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:c.161G>T

CAID: CA028998, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA028998

gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/14-23902781-C-A

MultipleGeneVariants:

(1) MYBPC3 Variant:

Variant: NM_000256.3(MYBPC3):c.1174delG (p.Ala392Leufs)

ClinVar: 568945, https://www.ncbi.nlm.nih.gov/clinvar/variation/568945/

gnomAD: n/a

(2) TNNT2 Variant:

Variant: NM_000364.3(TNNT2):c.853C>T (p.Arg285Cys)

ClinVar: 12411, https://www.ncbi.nlm.nih.gov/clinvar/variation/12411/

gnomAD: 0.0003556, https://gnomad.broadinstitute.org/variant/1-201328373-G-A

(3) MYOM1 Variant:

Variant: NM_003803.3(MYOM1):c.2087G>A (p.Arg696His)

ClinVar: 525100, https://www.ncbi.nlm.nih.gov/clinvar/variation/525100/

gnomAD: 0.0002032, https://gnomad.broadinstitute.org/variant/18-3135667-C-T

CaseBJJ: 16 years diagnosis, Australia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: No family history of HCM or Sudden Cardiac Death

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: Maximum left ventricular hypertrophy at 22 mm,

CaseNotHPOs: N/A

NotHPOsFreeText: Sudden cardiac death events

CaseAddInfo: Cis/trans status is unknown

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.

Variant1: NM_000257.3:c.2389G>A (p.Ala797Thr)

ClinVar: 42901 https://www.ncbi.nlm.nih.gov/clinvar/variation/42901/

gnomAD: African 1.230e-4, Overall 2.386e-5 https://gnomad.broadinstitute.org/variant/14-23894525-C-T

Variant2: NM_000257.3:c.2420G>A (p.Arg807His)

ClinVar: 391904 https://www.ncbi.nlm.nih.gov/clinvar/variation/391904/

gnomAD: Latino 5.644e-5, Overall 1.414e-5 https://gnomad.broadinstitute.org/variant/14-23894494-C-T

CaseMYH7-39: 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.952A>C (p.Thr318Pro)

CAID: CA389051682 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3%3Ac.952A%3EC

gnomAD: Not in gnomAD

CaseMYH7-26: 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.2167C>T (p.Arg723Cys)

ClinVar: 14095 https://www.ncbi.nlm.nih.gov/clinvar/variation/14095/

gnomAD: South Asian 3.266e-5, Overall 1.194e-5 https://gnomad.broadinstitute.org/variant/14-23895023-G-A

CaseMYH7-3: 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.5222_5223del (p.Val1741Glyfs*11)

CAID: CA913184899 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913184899

gnomAD: Not in gnomAD

CaseMYH7-15: 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.2738T>C (p.Ile913Thr)

CAID: CA389047215 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3%3Ac.2738T%3EC

gnomAD: Not in gnomAD

CaseMYH7-1: 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.5452C>T (p.Arg1818Trp)

ClinVar: 217826 https://www.ncbi.nlm.nih.gov/clinvar/variation/217826/

gnomAD: Latino 5.782e-5, Overall 7.956e-6 https://gnomad.broadinstitute.org/variant/14-23884311-G-A

Case: Male, 43yo

DiseaseAssertion: HCM

FamilyInfo: Variant (p.Val698Ala) segregates with HCM in 5 family members and 2 others are unaffected carriers

CaseHPOFreeText: left ventricular wall thickness = 28 mm

CasePreviousTesting: n/a

CaseGenotypingMethod: n/a

Variant: NM_000257.3(MYH7):c.2093T>C (p.Val698Ala) heterozygous

ClinVar: 42878, https://www.ncbi.nlm.nih.gov/clinvar/variation/42878/

gnomAD: n/a

Case#: Case III-2, 42 yr, female, early childhood onset

DiseaseAssertion: DCM

FamilyInfo: Family D, her father (II-5) had late-onset foot drop and hand weakness, died at age 51 from a myocardial infarction, her son (IV-3) had a severe generalized weakness since childhood, never walked and had prominent neck extensor contractures, died at age 19 years from a presumed cardiopulmonary event, 2 sisters (III-1 and III-3) had early-onset weakness and foot drop, her nephew (IV-1) had severe weakness and was wheelchair dependent, muscle biopsy, diagnosed with an unspecified muscular dystrophy, her niece (IV-2) had severe congenital weakness and died in her teens, all affected family members had contractures of neck extensors, heel cords, knee flexors, and elbow flexors

CasePresentingHPOs: progressive muscle weakness, lower limb muscle weakness, gait disturbance, slender build, scapular winging, thoracic scoliosis, weakness of facial musculature, generalized limb muscle atrophy, sinus tachycardia (HP:0003323, HP:0007340, HP:0001288, HP:0001533, HP:0003691, HP:0002943, HP:0030319, HP:0009055, HP:0011703)

CaseHPOFreeText: weakness and gait at age 5, nonambulatory by late-teens, wheelchair dependent, neck muscle atrophy, hypoactive myotatic reflexes

CaseNotHPOs: respiratory distress, syncope, chest pain, palpitations (HP:0002098, HP:0001279, HP:0100749, HP:0001962)

CaseNotHPOFreeText: normal sensory

CasePreviousTesting: Analysis included most of the other congenital myopathy genes and was otherwise negative

CaseGenotypingMethod: neurological examination, serum creatine kinase, nerve conduction studies, concentric needle electromyography, electrocardiogram, echocardiogram, forced vital capacity, muscle biopsy, immunohistochemical analyses, strength testing (MRC 3/2), arm flexors (MRC 4/4), arm extensors (MRC 3/3), wrist flexors (MRC 3/3), wrist extensors (MRC 1/3), finger flexors (MRC 2/2), finger extensors (MRC 2/2), finger adductors and abductors (MRC 4/4), hip flexors (MRC 2/2), hip abductors and adductors (MRC 3/3), knee flexors (MRC 2/2), knee extensors (MRC 2/2), foot dorsiflexors (MRC 0/0), plantar flexors (MRC 3/3) toe flexors (MRC 2/2), and toe extensors (MRC 1/1), normal 0.82 L (25%) FVC, 25% left ventricular ejection fraction, normal NCSs, increased small polyphasic MUAP, occasional fibrillation potentials, positive sharp waves, and brief myotonic discharges, facioscapulohumeral muscular dystrophy type 1, Emery–Dreifuss muscular dystrophy (EMD, LMNA, and FHL1 gene disorders), and limb-girdle muscular dystrophy type 1C were negative

Variant: NM_000257.2

ClinVar: absent

CAID: absent

gnomAD: absent

Case#: Case III-2, female, 64 yr, early childhood onset

DiseaseAssertion: None

FamilyInfo: Family C, her mother (II-1) and maternal grandmother (I-1) had late-onset leg weakness (Fig. 1C), her brother (III-4) had severe generalized weakness and was diagnosed with an unspecified muscular dystrophy

CasePresentingHPOs: Gait disturbance, lower limb muscle weakness, hypertension, osteoarthritis, hyperlipidemia, glaucoma, neck flexor weakness, weakness of facial musculature, weakness of long finger extensor muscles, foot dorsiflexor weakness (HP:0001288, HP:0007340, HP:0000822, HP:0002758, HP:0003077, HP:0000501, HP:0003722, HP:0030319, HP:0009077, HP:0009027)

CaseHPOFreeText: mild heel cord contractures, mild eye closure weakness, unable to stand on heels, limb weakness

CaseNotHPOs: Scoliosis, scapular winging, generalized muscle hypertrophy (HP:0002650, HP:0003691, HP:0003720)

CaseNotHPOFreeText: hand or foot deformities, normal knee bend and stand on tiptoes, normal reflexes and sensory

CasePreviousTesting: N/A

CaseGenotypingMethod: neurological examination, serum creatine kinase, nerve conduction studies, concentric needle electromyography, electrocardiogram, echocardiogram, forced vital capacity, muscle biopsy, immunohistochemical analyses, CK 156 unit/L (n < 143), FVC 2.13 L (68%), ECG and echo normal, left ventricular ejection fraction 65%, normal NCS except low-amplitude peroneal and tibial compound muscle action potential, abnormal increase of small polyphasic MUAP in tibialis anterior, no fibrillation potentials, no positive sharp waves, no myotonic discharges

Variant: NM_182476.3(COQ6):c.115G>A (p.Val39Met) & NM_000257.4(MYH7):c.4844_4846AGA[2] (p.Lys1617del)

ClinVar: 214236 https://www.ncbi.nlm.nih.gov/clinvar/variation/214236/ & 190401 https://www.ncbi.nlm.nih.gov/clinvar/variation/190401/

CAID: N/A

gnomAD: 0.00006720 African https://gnomad.broadinstitute.org/variant/14-74417150-G-A & absent

PMID: 28491642

Gene: ACTC1

HGNC ID: 143

PMID: 28491642 Gene: ACTC1 HGNC ID: 143

PMID: 28491642

Gene: ACTC1

HGNC ID: 143

PMID: 28491642

Gene: ACTC1

HGNC ID: 143

A novel ACTC1 mutation in a young boy with left ventricular noncompaction and arrhythmias PMID: 28491642

Gene: ACTC1

HGNC ID: 143

Supplementary Data, Table 2

Variant noted to be present in 16 individuals

Variant: NM_000257.3(MYH7):c.2681A>G (p.Glu894Gly)

ClinVar: 42922, https://www.ncbi.nlm.nih.gov/clinvar/variation/42922/

gnomAD: n/a

Supplementary Data, Table 2

Variant noted to be present in 9 individuals

Variant: NM_000257.3(MYH7):c.4135G>A (p.Ala1379Thr)

ClinVar: 42993, https://www.ncbi.nlm.nih.gov/clinvar/variation/42993/

gnomAD: n/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.4066G>A (p.Glu1356Lys)

ClinVar: 164294, https://www.ncbi.nlm.nih.gov/clinvar/variation/164294/

gnomAD: n/a

Supplementary Data, Table 2

Variant noted to be present in 2 individuals

Variant: NM_000257.3(MYH7):c.1208G>A (p.Arg403Gln)

ClinVar: 14087, https://www.ncbi.nlm.nih.gov/clinvar/variation/14087/

gnomAD: n/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.1051A>G (p.Lys351Glu)

ClinVar: 181335, https://www.ncbi.nlm.nih.gov/clinvar/variation/181335/

gnomAD: n/a

Supplementary Data, Table 2

Variant noted to be present in 4 individuals

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

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

gnomAD: n/a

Supplementary Data, Table 2

Variant noted to be present in 5 individuals

Variant: NM_000257.3(MYH7):c.1816G>A (p.Val606Met)

CinVar: 14091, https://www.ncbi.nlm.nih.gov/clinvar/variation/14091/

gnomAD: 0.000007070, https://gnomad.broadinstitute.org/variant/14-23896866-C-T

PMID: 20301725

Gene: MYH7

HGNC: 7577

"The purpose of this overview is to increase clinician awareness of the genetic basis of hypertrophic cardiomyopathy (HCM) and the benefits of early diagnosis and management to individuals with genetic HCM."

Table 1 and 4

Case 64: Male, 42yo

DiseaseAssertion: HCM

FamilyInfo: negative family history

CaseHPOFreeText: interventricular septum thickness = 18.1mm, left ventricular end diastolic diameter = 51.7mm, left ventricular end systolic diameter = 34.4mm, left ventricular posterior wall thickness = 9.8mm, left atrium = 44mm, left ventricular ejection fraction = 61%

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.1987C>T (p.Arg663Cys)

ClinVar: 42874, https://www.ncbi.nlm.nih.gov/clinvar/variation/42874/

gnomAD: n/a

Case: Pedigree 4 proband, congenital (abnormalities noticed at 24wks gestation), Yemenite Jewish

CasePresentingHPOs: HP:0012817, HP:0010316 (noncompaction cardiomyopathy, Ebstein anomaly)

HPOsFreeText: clinical severity: moderate to asymptomatic

CaseNotHPOs:

NotHPOsFreeText: skeletal involvement

CasePreviousTesting: none

CaseGenotypingMethod: MYH7 sequencing

Variant: NM_000257.4:c.1859T>C (p.Leu620Pro)

CAID: CA389049669, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389049669

gnomAD: n/a

FamilyInfo: father, the paternal grandmother, and paternal uncle had a known history of Ebstein anomaly and NCCM, proband's 2 sisters are healthy with no evidence of cardiomyopathy, 7 other family members diagnosed with Ebstein anomaly and NCCM, but most were asymptomatic, variant segregated with all affected members in heterozygous state, no unaffected members were genotype positive

Case: Pedigree 3 proband, female, 3mo at diagnosis, North African and Jewish

CasePresentingHPOs: HP:0001644 (dilated cardiomyopathy)

HPOsFreeText: clinical severity: severe (fatal)

CaseNotHPOs:

NotHPOsFreeText: skeletal involvement

CasePreviousTesting: exact genes sequenced not specified

CaseGenotypingMethod: DCM CardioChip, included 19 genes known to cause DCM

Variant 1: NM_000257.3(MYH7):c.427C>T (p.Arg143Trp)

ClinVar: 164401, https://www.ncbi.nlm.nih.gov/clinvar/variation/164401/

gnomAD: 0.00002784, https://gnomad.broadinstitute.org/variant/14-23901923-G-A

Variant 2: NM_000257.4(MYH7):c.4588C>T (p.Arg1530Ter)

ClinVar: 43029, https://www.ncbi.nlm.nih.gov/clinvar/variation/43029/

gnomAD: 0.00001591, https://gnomad.broadinstitute.org/variant/14-23886133-G-A

FamilyInfo: mother is of North African and Iraqi‐Jewish descent, while the father is of North African and Balkan Jewish descent, probands brother died at 3.5mo and also carried both variants, maternal cousin died of RCM in early childhood, maternal aunt carried p.R143W

PMID: 32830170

Gene: MYH7

HGNC: 7577

Case12: Female, 60 years diagnosis, China, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: One sibling and one child died of SCD in their 30s, with child having confirmed HCM

CasePresentingHPOs: HP:0001639, HP:0030148 (Hypertrophic cardiomyopathy, Heart murmur)

HPOsFreeText: Mixed features of apical and classic HCM

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: Probands were only genotyped for MYH7 and MYBPC3 in that order, stopping once a positive finding was detected.

CaseGenotypingMethod: Genomic DNA was extracted from peripheral blood. Each gene's coding exons and flanking introns were subject to PCR amplification and sequencing. From there, any variants found were filtered for pathogenicity and low frequencies.

Variant: NM_000257.3:c.1273G>A (p.Gly425Arg)

ClinVar: 42834 https://www.ncbi.nlm.nih.gov/clinvar/variation/42834/

gnomAD: Not in gnomAD

Case15: Female, 48 years diagnosis, China, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: One parent died of cardiomyopathy/sudden death, one offspring had a heart murmur and found to have HCM

CasePresentingHPOs: HP:0001639, HP:0001279, HP:0005162, HP:0003546 (Hypertrophic cardiomyopathy, Syncope, Left ventricular failure, Poor exercise tolerance)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Heart transplantation done

CasePreviousTesting: Probands were only genotyped for MYH7 and MYBPC3 in that order, stopping once a positive finding was detected.

CaseGenotypingMethod: Genomic DNA was extracted from peripheral blood. Each gene's coding exons and flanking introns were subject to PCR amplification and sequencing. From there, any variants found were filtered for pathogenicity and low frequencies.

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

Supplementary Material 4

Case M-10: Japanese

DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)

CasePreviousTesting: Clinical evaluation, chest radiography, electrocardiography, echocardiography, cardiac catheterization, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1)

CaseGenotypingMethod: 8 sarcomeric genes amplified from genomic DNA via PCR then screened using bidirectional direct sequencing

Variant: NM_000257.3(MYH7):c.1987C>T (p.Arg663Cys)

ClinVar: 42874, https://www.ncbi.nlm.nih.gov/clinvar/variation/42874/

gnomAD: n/a

Supplementary Material 4

Case M-6: Japanese

DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)

CasePreviousTesting: Clinical evaluation, chest radiography, electrocardiography, echocardiography, cardiac catheterization, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1)

CaseGenotypingMethod: 8 sarcomeric genes amplified from genomic DNA via PCR then screened using bidirectional direct sequencing

Variant 2: NM_000257.3(MYH7):c.1357C>T (p.Arg453Cys)

ClinVar: 14089, https://www.ncbi.nlm.nih.gov/clinvar/variation/14089/

gnomAD: n/a

Supplementary Material 4

Case M-23: Japanese

DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)

CasePreviousTesting: Clinical evaluation, chest radiography, electrocardiography, echocardiography, cardiac catheterization, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1)

CaseGenotypingMethod: 8 sarcomeric genes amplified from genomic DNA via PCR then screened using bidirectional direct sequencing

Variant: NM_000257.3(MYH7):c.2546T>C (p.Met849Thr)

ClinVar: 42914, https://www.ncbi.nlm.nih.gov/clinvar/variation/42914/

gnomAD: n/a

Supplementary Material 4

Case M-30: Japanese

DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)

CasePreviousTesting: Clinical evaluation, chest radiography, electrocardiography, echocardiography, cardiac catheterization, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1)

CaseGenotypingMethod: 8 sarcomeric genes amplified from genomic DNA via PCR then screened using bidirectional direct sequencing

Variant: NM_000257.3(MYH7):c.2803G>A (p.Glu935Lys)

ClinVar: 14106, https://www.ncbi.nlm.nih.gov/clinvar/variation/14106/

gnomAD: n/a

Supplementary Material 4

Case M-9: Japanese

DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)

CasePreviousTesting: Clinical evaluation, chest radiography, electrocardiography, echocardiography, cardiac catheterization, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1)

CaseGenotypingMethod: 8 sarcomeric genes amplified from genomic DNA via PCR then screened using bidirectional direct sequencing

Variant: NM_000257.3(MYH7):c.1987C>T (p.Arg663Cys)

ClinVar: 42874, https://www.ncbi.nlm.nih.gov/clinvar/variation/42874/

gnomAD: n/a

Supplementary Material 4

Case M-26: Japanese

DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)

CasePreviousTesting: Clinical evaluation, chest radiography, electrocardiography, echocardiography, cardiac catheterization, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1)

CaseGenotypingMethod: 8 sarcomeric genes amplified from genomic DNA via PCR then screened using bidirectional direct sequencing

Variant: NM_000257.3(MYH7):c.2609G>A (p.Arg870His)

ClinVar: 14120, https://www.ncbi.nlm.nih.gov/clinvar/variation/14120/

gnomAD: 0.000007072, https://gnomad.broadinstitute.org/variant/14-23894048-C-T

Case#: HCM443, female, 28 years, not a smoker

DiseaseAssertion: HCM

FamilyInfo: None

CasePresentingHPOs: 46mm LAD, 17mm LVST, 44mm LVEDD, 69% LVEF, 18mm Maxi LVWT, 68mmHg Maxi LVOTG, 103385170 raw RNA-seq reads, 96969874 HQ reads (93.79%), 96.18% mapping rate, 707524 total variant, 33016 exonic variant

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseGenotypingMethod: RNA-seq, read mapping, variant calling, identify functional variants, differential expression analysis, miRWalk miRNA target prediction, LncRNA annotation, Co-expression network analysis, PPI network analysis, gene over-representation analysis,

Variant: NM_000257.4(MYH7):c.2221G>T (p.Gly741Trp)

ClinVar: 177665 https://www.ncbi.nlm.nih.gov/clinvar/variation/177665/

CAID: N/A

gnomAD: absent

Case#: HCM431, male, 24 years, not a smoker

DiseaseAssertion: HCM

FamilyInfo: None

CasePresentingHPOs: 57mm LAD, 18mm LVST, 49mm LVEDD, 80% LVEF, 21mm Maxi LVWT, 80mmHg Maxi LVOTG, 95467544 raw RNA-seq reads, 91611504 HQ reads (95.96%), 96.60% mapping rate, 701266 total variant, 33263 exonic variant

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseGenotypingMethod: RNA-seq, read mapping, variant calling, identify functional variants, differential expression analysis, miRWalk miRNA target prediction, LncRNA annotation, Co-expression network analysis, PPI network analysis, gene over-representation analysis,

Variant: NM_000257.4(MYH7):c.4066G>A (p.Glu1356Lys)

ClinVar: 164294 https://www.ncbi.nlm.nih.gov/clinvar/variation/164294/

CAID: N/A

gnomAD: absent

Case#: HCM483, male, 37 years, smoker

DiseaseAssertion: HCM

FamilyInfo: None

CasePresentingHPOs: 57mm LAD, 23mm LVST, 40mm LVEDD, 72% LVEF, 26mm Maxi LVWT, 70mmHg Maxi LVOTG, 132375212 raw RNA-seq reads, 125845538 HQ reads (95.07%), 96.52% mapping rate, 838862 total variant, 35806 exonic variant

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseGenotypingMethod: RNA-seq, read mapping, variant calling, identify functional variants, differential expression analysis, miRWalk miRNA target prediction, LncRNA annotation, Co-expression network analysis, PPI network analysis, gene over-representation analysis,

Variant: NM_000257.4(MYH7):c.1816G>A (p.Val606Met)

ClinVar: 14091 https://www.ncbi.nlm.nih.gov/clinvar/variation/14091/

CAID: N/A

gnomAD: 0.00001548 European (non-finnish) https://gnomad.broadinstitute.org/variant/14-23896866-C-T

Case#: 8th case, male, 49 years

DiseaseAssertion: SHCM

FamilyInfo: No

CasePresentingHPOs: Mycardial fibrosis (HP:0001685)

CaseHPOFreeText: 630 g heart, IVST to LVWT ratio 1.38, IVST 2.2 cm, LVWT 1.6 cm, hypertrophy of myocardial fibers, stenosis in lumens,

CaseNotHPOs: N/A

CaseNotHPOFreeText: no pathological changes found in major organs besides heart

CasePreviousTesting: N/A

CaseGenotypingMethod: physical examination, ECG, 2D and Doppler echocardiography, histological examinations, genomic DNA extraction, DNA cloning, sequence analysis

Variant: NC_000014.9:g.23429026T>G (Thr446Pro)

ClinVar: absent

CAID: CA257823360

gnomAD: absent

PMID: 32380038

Gene: MYH7

HGNC: 7577

Table 5

Case EO23: Italian

DiseaseAssertion: HCM (early-onset)

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

Variant1: NM_000257.3:c.3973G>A

CAID: CA389041353, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389041353

gnomAD: n/a

Variant2: NM_000257.3(MYH7):c.2804A>T (p.Glu935Val)

ClinVar: 181207, https://www.ncbi.nlm.nih.gov/clinvar/variation/181207/

gnomAD: n/a

Table 5

Case LO13: Italian

DiseaseAssertion: HCM (late-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(MYH7):c.1816G>A (p.Val606Met)

ClinVar: 14091, https://www.ncbi.nlm.nih.gov/clinvar/variation/14091/

gnomAD: 0.000007070, https://gnomad.broadinstitute.org/variant/14-23896866-C-T

Case: Patient 16, female, 39yo, symptom onset in adulthood

CasePresentingHPOs: HP:0030237, HP:0003327, HP:0003701, HP:0002460, HP:0003458 (hand muscle weakness, axial muscle weakness, proximal muscle weakness, distal muscle weakness, EMG: myopathic abnormalities)

HPOsFreeText: normal CK values

CaseNotHPOs: HP:0002650 (scoliosis)

NotHPOsFreeText: no respiratory or cardiac involvement

FamilyInfo: no family history

DiseaseEntity: no assertion

InheritancePattern: no assertion

CasePreviousTesting: see below

CaseGenotypingMethod: 9 cases underwent targeted Sanger sequencing of MYH7, 12 cases underwent Motorplex analysis (NGS of 93 myopathy-related genes - PMID:25214167), all MYH7 variants confirmed via Sanger sequencing, segregation analysis performed on available family members, which cases received which sequencing technique is not specified

Variant: NM_000257.3:c.1780C>A

CAID: CA389049833, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389049833

gnomAD: absent

Case: Patient 7, male, 8yo, congenital onset of symptoms

CasePresentingHPOs: HP:0003327, HP:0002650, HP:0030682, HP:0003458 (axial muscle weakness, scoliosis, left ventricular noncompaction, EMG: myopathic abnormalities)

HPOsFreeText: minicores present on muscle biopsy

FamilyInfo: no family history

DiseaseEntity: no assertion

InheritancePattern: no assertion

CasePreviousTesting: see below

CaseGenotypingMethod: 9 cases underwent targeted Sanger sequencing of MYH7, 12 cases underwent Motorplex analysis (NGS of 93 myopathy-related genes - PMID:25214167), all MYH7 variants confirmed via Sanger sequencing, segregation analysis performed on available family members, which cases received which sequencing technique is not specified

Variant: NM_000257.3:c.5655+1G>A

CAID: CA389034770, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389034770

gnomAD: absent

CaseMYH7-5: Japan, Asian

CasePresentingHPOs: HP:0001639, HP:0006685 (Hypertrophic cardiomyopathy, Endomyocardial fibrosis)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo:

CaseGenotypingMethod: Genomic DNA was extracted from whole blood from each proband. They each had 95 genes associated with DCM, HCM, and other inherited cardiovascular diseases sequenced with a panel, including both the exons and spicing regions. Variants were then filtered for rarity and pathogenicity.

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

CaseMYH7-1: Japan, Asian

CasePresentingHPOs: HP:0001639, HP:0006685 (Hypertrophic cardiomyopathy, Endomyocardial fibrosis)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo:

CaseGenotypingMethod: Genomic DNA was extracted from whole blood from each proband. They each had 95 genes associated with DCM, HCM, and other inherited cardiovascular diseases sequenced with a panel, including both the exons and spicing regions. Variants were then filtered for rarity and pathogenicity.

Variant: NM_000257.3:c.2803G>A (p.Glu935Lys)

ClinVar: 14106 https://www.ncbi.nlm.nih.gov/clinvar/variation/14106/

gnomAD: Not in gnomAD

Case2: female, 16 years old

DiseaseAssertion: Myopathy

FamilyInfo:

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

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

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

CaseNotHPOs:

CaseNotHPOFreeText:

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

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

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

ClinVar: not found

CAID: CA389037627

gnomAD: not found