EGAGenomicsOtherhttps://ega-archive.org/studies/EGAS00001004929EGAEGA study EGAS00001004929Whole genome sequencing delineates regulatory and other genic variants in early onset cardiomyopathyEGArestricted[X]Cardiomyopathy in other diseases classified elsewhere, Disease, Intronic Splice Site Mutation, Secondary Cardiomyopathies, Cardiomyopathy, Secondary Myocardial Diseases, PRIM CARDIOMYOPATHY NEC., Regulatory, Primary Cardiomyopathies, Myocardial Diseases, CARDIOMYOPATH IN OTH DIS, Myocardiopathies, Genome Sequencing, AV265756, Intron Splice Site Mutation, Primary, Cardiomyopathies, Other primary cardiomyopathies (disorder), Fs(3)Sz11, CFC1B, Secondary Myocardial, Complete Genome, Structural, Other primary cardiomyopathy NOS, Cardiomyopathy in other diseases classified elsewhere, Cardiomyopathy NOS (disorder), Secondary Myocardial Disease, Cardiomyopathy NOS, Diseases, Primary Myocardial Disease, NOS, DmF2, Fs(3)Hor, CARDIOMYOPATHIES SECOND, Primary Myocardial, lod, Splice-Site Mutation Abnormality, HTX2, DmelCG2684, Complete, Whole Genome, Regulator, Primary Myocardial Diseases, Complete Genome Sequencing, CRYPTIC, Secondary Cardiomyopathy, Age of onset, Splice-Site Mutation, Myocardial, Splice Region Variant, NTef2, Age symptoms begin, Lds, Structure, cardiomyopathy, Sequencing, early, Other primary cardiomyopathies, Secondary, [X]Cardiomyopathy in other diseases classified elsewhere (disorder), Splice, Primary Cardiomyopathy, cryptic, Horka, Cardiomyopathy (disorder), Whole, DTGA2, CG2684, Fs(3)Horka, Other primary cardiomyopathy NOS (disorder), b2b970Clo, Myocardial Disease, Myocardiopathy, Splice-Juction MutationHeart, CRISPR Locus, [X]Cardiomyopathy in other diseases classified elsewhere, Materials, O-linked Glycosylations, Clustered Regularly Interspaced Short Palindromic Repeat, colony forming unit granulocyte, DG2, A0, Galactosylations, DTN-A, Dystroglycan, DNA replication, Relative, Dystrophin-Associated Glycoprotein 1, Inherited, beta Dystroglycan, Other primary cardiomyopathy NOS, macrophage, Cardiomyopathy in other diseases classified elsewhere, Discover, analysis, Analysis, Fs(3)Hor, Arrays, strong, independent, thymus nucleic acid, Involvement, Genomes, pluripotent stem cell (bone marrow), beta-Dystroglycan, Moods, D830030O17Rik, result, Age of onset, Fishes, NTef2, Sialylation, 3' CMP, AE_PATHOGEN, Independence, CG10849, CD34-positive, Familiar, O-linked, Zebra Fishes, Homo sapiens disease, protein-coding, N-Acetylglucosaminylations, single organism signaling, CRISPR Spacer Sequences, CRISPR Clusters, Secondary Cardiomyopathies, Myocardial Diseases, Ratios, AV265756, Cytidylic Acids, multipotential myeloid stem cell, CRISPR-Cas, Cardiomyopathies, predicted, Fs(3)Sz11, Candidate, heart myocardium, Secondary Myocardial Disease, Cardiomyopathy NOS, Relative Risks, a-DB-1, atomo, Searched, desoxyribose nucleic acid, atome, Confirmed, CARDIOMYOPATHIES SECOND, Acid, HTX2, Moving from wheelchair to bed and return independent, atoms, Contributory, HT-CP, INSDC_feature:gene, Heart Muscles, human, Genomic, Material, DGII|III, ds DNA, Dsc2a, dSc2, D. rerio, CG2684, Acids, Spacer Sequences, Nepal Bhasa, Myocardiopathy, DNA, Dsc2b, Monophosphate, DSC4, CRISPR-Cas Loci, Clinical Batch, Labeled, DNS, (Deoxyribonucleotide)n, Effects, CARDIOMYOPATH IN OTH DIS, CFU-GEMM, Analytical, CRISPR Array, N-linked Glycosylations, Thirty-Nine, Cytidylic Acid, Other primary cardiomyopathies (disorder), Human, N-linked, CDHF2, CDHF3, Secondary Myocardial, CDHF5, Cardiac, New Lesion, CMP, Deoxyribonucleic Acid, Core Genome, tough, disease or disorder, myeloid stem cell, Medical, Higher, Man, Primary Myocardial, Pediatric, DSC1, DSC2, DSC3, l(3)05634, D18S892E, Negation, Complete, Whole Genome, Clinical, Supply, MDDGB4, Accessory Genome, Complete Genome Sequencing, Tagged, Double Stranded, Deoxyribonucleic acid, Expressions, Sequencing, outcome, CRISPR Sequences, Odds, Primary Cardiomyopathy, Dag-1, cryptic, MDDGC4, Supplied, Phosphoglycosylation, Whole, Loci, Panel, genome, (Deoxyribonucleotide)m, Expression, Independent for Wheelchair Transfer, atom, DmelCG10849, N-linked Glycosylation, Spacer Sequence, common myeloid precursor, New, NEW, Zebra Fish, Protein Glycosylation, DNAn+1, Affects, Result, Myocardiopathies, disorders, Heart Muscle, DSC, Primary, function, Pangenome, CFC1B, Sequences, Discovery, Confirmatory, matrilin-1, Cytidine, erythrocyte, Primary Myocardial Disease, condition, clinical, GlcNAcylations, Dystroglycan 1, Cross Product Ratio, Relative Risk, Dtn, DTN, New Lesion Identification, Regulator, Danio frankei, Myocardial, Childhood, danio, Negated, Lds, Independent for Transfer Between Wheelchair and Bed, Locus, High, No, desmocollin-3, Pan-genome, signalling process, Cardiomyopathy (disorder), Desoxyribonukleinsaeure, Array, Other primary cardiomyopathy NOS (disorder), Independent, inherited, 2'-CMP, CRISPR Loci, Primary Cardiomyopathies, Reporter Substance, CRISPR Spacer, Galactosylation, clinical data, Highly, element, Cardiac Muscle, Odds Ratios, 15, Cardiac Muscles, Tracer, diseases, Cardiomyopathy NOS (disorder), diseases and disorders, Newari, Effect, alpha-Dystroglycan, Risk Ratio, D. rerios, gene expression, Group, human disease, DmelCG2684, Gene Expressions, Man (Taxonomy), CFU-S, Elements, Zebrafishes, Provide, N-Acetylglucosaminylation, Pathogenic, Myocardia, Pathogenic Variant, Panel Device, CRISPRs, Novel, 39, CMD1BB, Muscles, alpha Dystroglycan, Analyzed, Double-Stranded DNA, deoxyribonucleic acids, Outcome, DNAn, 5'-Cytidylic acid, common myeloid precursor., Cardiomyopathy, Secondary Myocardial Diseases, leopard danio, Label, pediatric, Modern, Genome Sequencing, Glycosylations, scan tracer used, CRISPR Arrays, Search, Double-Stranded, Clusters, Fucosylations, (Deoxyribonucleotide)n+m, Gm19389, Gene Expression, heart muscle, CRISPR Element, Complete Genome, Involved, Phosphoglycosylations, ARVC10, Non, MDDGA4, Diseases, muscle of heart, Genetic Materials, Not, Brachydanio rerio, NOS, Genetic Material, Confirmation, Clinical Data, Element, Danio rerio, Risk, Fifteen, Primary Myocardial Diseases, N linked Glycosylation, DRP3, Exomes, Sialylations, Mat1, cardiomyopathy, early, disease, l(3)SH4, Patient, Expressed, Cluster, N Acetylglucosaminylation, Horka, Reporter Object, Spacers, Fs(3)Horka, Cistron, and megakaryocyte, HDGC, Contribute, zebrafish, Provided, zebra fish, other disease, Non-, LVNC1, nuclear mRNA cis splicing, human being, GlcNAcylation, Independent for Transfer, Gene, Coding, Fcmd, Deoxyribonucleic acids, O-linked Glycosylation, zebra danio, glycosylation, Homo sapiens, resilient, Glycosylation, Mood, FCMD, CMD1X, DmF2, Cyprinus rerio, 2' CMP, Pathogen, CRISPR Spacers, PRIM CARDIOMYOPATHY NEC, lod, Cross-Product Ratio, Risk Ratios, 2210407P21Rik, Genetic, ANALYSIS, Protein Glycosylations, Medical Coding, CRISPR Spacer Sequence, Ratio, Positive Surgical Margin, CRISPR Cluster, non-neoplastic, CRISPR, [X]Cardiomyopathy in other diseases classified elsewhere (disorder), Heritable, CRISPR-Cas Locus, via U2-type spliceosome, Loss, Reporter, Crtm, ARVD10, Newar Language, DNA Replication, ARVD11, Clients, B. rerio, 3'-CMP, disorder, Myocardial Disease, b2b970Clo, elements, Known, Fucosylation, Tag, Brachydanio rerio frankei, WGS, adbn, Disease, Cross-Product, CRISPR Sequence, Regulatory, LGMD2M, Dystrophin Associated Glycoprotein 1, l(3)63Eb, medical condition, Muscle, Cistrons, Client, cardiac muscle, Testing, Cross-Product Ratios, O linked Glycosylation, Clinical Lot, DGII/III, tracer, Sequence, Protein, Danio rerio frankei, CRISPR Elements, atomus, Cytidylic, Spacer, ds-DNA, Replication, Contributing, Zebra, Reported By, Risks, Secondary Cardiomyopathy, CRYPTIC, patient, Age symptoms begin, ucp14, Zebra danios, Thirty Nine, Other primary cardiomyopathies, Secondary, Zebra danio, Relative Odds, scan_tracer_used, Cranin, DTGA2, Modern Man, CRISPR Cas Loci, Additional, Experimental Result, AW228162, Genome, Contribution, Positive MarginsfalseWhole genome sequencing delineates regulatory, structural, and cryptic splice variants in early onset cardiomyopathyCardiomyopathy (CMP) is a heritable disorder. Over 50% cases are gene-elusive on clinical gene panel testing. The contribution of variants in non-coding DNA elements that result in cryptic splicing and regulate gene expression has not been explored. We analyzed whole genome sequencing (WGS) data in a discovery cohort of 209 pediatric CMP patients and 1,953 independent replication genomes and exomes. We searched for protein-coding variants, and non-coding variants predicted to affect the function or expression of genes. Thirty-nine % cases harbored pathogenic coding variants in known CMP genes, and 5% harbored high-risk loss-of-function (LoF) variants in additional candidate CMP genes. Fifteen % harbored high-risk regulatory variants in promoters and enhancers of CMP genes (Odds ratio 2.25, p=6.70×10-7 versus controls). Genes involved in α-dystroglycan glycosylation (FKTN, DTNA) and desmosomal signaling (DSC2, DSG2) were most highly enriched for regulatory variants (Odds ratio 6.7-58.1). Functional effects were confirmed in patient myocardium and reporter assays in human cardiomyocytes, and in zebrafish CRISPR knockouts. We provide strong evidence for the genomic contribution of functionally active variants in new genes and in regulatory elements of known CMP genes to early-onset CMP.2022-02-07 10:47:13EGAS000010049299606EGAD00001008477EGAC00001001885