Case342: Female, Birth onset, Japan, Asian

DiseaseAssertion: Left ventricular noncompaction

CasePresentingHPOs: HP:0030682, HP:0025169, HP:0001635, HP:0001663 (Left ventricular noncompaction, Left ventricular systolic dysfunction, Heart failure, Ventricular fibrillation)

HPOsFreeText: Left Ventricular Ejection Fraction at 38%, LVDD-Z score at 1.72

CaseNotHPOs: N/A

NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes

CaseAddInfo: No family history

CasePreviousTesting: Genes tested include the 8 sarcomere genes as well as 65 more listed in Table S1.

CaseGenotypingMethod: Genomic DNA was extracted from whole blood from each of the probands. Next Generation Sequencing of 73 genes related to cardiac function was performed, incorporating PCR amplification, and any variants found were subjected to filtering for frequency and pathogenicity. Any variants suggested to be pathogenic were confirmed by Sanger sequencing afterwards.

Variant: NM_000257.3:c.2513C>T (p.Pro838Leu)

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

gnomAD: Not in gnomAD

MultipleGeneVariants:

BMPR1A Variant

Variant: NM_004329.2:c.851G>T (p.Arg284Leu)

CAID: CA377458781 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_004329.2:c.851G%3ET

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)