CaseDCM-01: Male, 1 year diagnosis, Caucasian, Germany

CasePresentingHPOs: HP:0001644, HP:0001635 (Dilated cardiomyopathy, Heart failure)

HPOsFreeText: LVEDD at 67 mm, LV-Ejection Fraction at 10%, Cardiac Index at 2.6

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Proband treated with VAD and HTx, No family history of cardiac disease, MYH7 Variant is asserted as de novo, Proband also has a variant in MYL2, 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.5390T>C (p.Leu1797Pro)

ClinVar: 265799 https://www.ncbi.nlm.nih.gov/clinvar/variation/265799/

gnomAD: Not in gnomAD

Multiple Gene Variants

MYL2 Variant

Variant: NM_000432.3:c.401A>C (p.Glu134Ala)

ClinVar: 43475 https://www.ncbi.nlm.nih.gov/clinvar/variation/43475/

gnomAD: European (Non-Finnish) 3.484e-4, Overall 2.015e-4 https://gnomad.broadinstitute.org/variant/12-111350901-T-G

CaseCM1829: Male, 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, Variant is asserted as novel, Mother and father are both 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.2459C>A (p.Ala820Asp)

CAID: CA389048368 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3%3Ac.2459C%3EA

gnomAD: Not in gnomAD

CaseCM1844: 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: No family history of cardiomyopathy or sudden death, Proband found in Supplementary Table 2, Mother and father are both 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.1357C>T (p.Arg453Cys)

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

gnomAD: Not in gnomAD

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)

CaseIII-6: Female, 32 years report, 17 years diagnosis, China, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: Proband's son had the same variant; the father had echocardiograph results but was asymptomatic

CasePresentingHPOs: HP:0001639, HP:0002094, HP:0100749, HP:0001962, HP:0001279, HP:0030879 (Hypertrophic cardiomyopathy, Dyspnea, Chest pain, Palpitations, Syncope, Interlobular septal thickening on pulmonary HRCT)

HPOsFreeText: Septum thickness 25 mm, Left ventricle at 44 mm, Left atrium at 40 mm, Ejection fraction at 54%

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Mutation is classified as de novo

CasePreviousTesting: See list of 26 genes under Target sequence capture sequencing

CaseGenotypingMethod: Genomic DNA was extracted from the proband and other family members. Afterwards, it was subject to PCR amplification and sequencing. Any variants found were confirmed with Sanger sequencing before being filtered 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

Supplementary Data: S2 Table

Case 5: Spanish, 7yo, 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.2146G>A (p.Gly716Arg)

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

gnomAD: n/a

CaseBII-1: Male, 23 years diagnosis, China, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: No family history, pedigree provided

CasePresentingHPOs: HP:0001639, HP:0100749 (Hypertrophic cardiomyopathy, Chest pain)

HPOsFreeText: Interventricular septal thickness at 15.6 mm, Left ventricular posterior wall thickness at 12.1 mm

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Parents tested negative for variant, therefore it is asserted as de novo

CasePreviousTesting: See list of sequenced genes

CaseGenotypingMethod: Genomic DNA was isolated from whole blood of all patients and controls. Whole coding exons and exon-intron boundaries of the 19 HCM-related genes listed above were amplified and sequenced on Ion Torrent PGM. These variants were then filtered for pathogenicity and compared to the controls. Any mutations found were confirmed by conventional dideoxy sequencing and Sanger sequencing.

Variant: NM_000257.3:c.2572C>T (p.Arg858Cys)

ClinVar: 164324 https://www.ncbi.nlm.nih.gov/clinvar/variation/164324/

gnomAD: Not in gnomAD

Case#: 34 year-old Chinese male.

DiseaseAssertion: HAE-C1INH Type 1.

FamilyInfo: Family history of edema (mother passed away due to laryngeal edema, older sister experienced buttock swelling after prolonged sitting, maternal uncle experienced episodic abdominal pain and unilateral upper-limb swelling). Family testing for serum C4 and C1INH concentration and C1INH functional activity indicate that proband’s maternal uncle and asymptomatic daughter exhibit low values for all three of these biochemical markers, consistent with Type 1 HAE. The proband’s daughter and maternal uncle also tested positive for the variant identified in the proband. Pedigree included in figures.

ParentalTesting: Mother passed away before study. Father tested for C4 and C1INH concentration and C1INH function with all values falling in normal ranges.

CasePresentingHPOs: Edema (HP:0000969), Edema of the dorsum of hands (HP:0007514), Edema of the upper limbs (HP:0010742), Non-pitting edema (HP:6000507), Abdominal pain (HP:0002027)

CasePhenotypeFreeText: Onset at approximate age of 26. Episodes of localized edema of limbs, skin, and buttocks lasting two to three days regardless of treatment. Episodes became more frequent at age 34 and were accompanied by abdominal pain triggered by fatigue. Non-pitting edema of right hand observed on physical examination.. The proband’s C4 level was 0.02 g/L (reference range: 0.1–0.4 g/L), C1INH concentration was 0.07 g/L (reference range: 0.21–0.39 g/L), and C1INH functional activity was 4.3% (reference range: ≥68.0%).

CaseNotHPOs: N/A

CaseNotPhenotypeFreeText: N/A

CasePreviousTesting: N/A

GenotypingMethod: PCR amplification with Sanger sequencing.

Variant: NM_000062:c.1067T>A p.(Val356Glu)

LegacyVariant: N/A

ClinVar: N/A

CAID: CA380702482

gnomAD: N/A

MultipleGeneVariants: N/A

PreviouslyPublished: N/A

AdditionalInfo: N/A