Table 3 Structural variants identified in panel genes and in the extended gene set
From: Genome sequencing as a first-line genetic test in familial dilated cardiomyopathy
Family ID | Gene | Variant | Database of Genomic Variantsa | Notes | Segregationb |
|---|---|---|---|---|---|
Families “unsolved” after PS | |||||
AA | BAG3 | Chr10:121436136-121436726 del, Chr10:121436139-121436799 dup (g.30254-30844 del, 30257-30917 dup); involves exon 4 (aa.357-533) including BAG domain | Overlap with 2 larger dup, 1 in unaffected subject | BCL associated athanogene 3, chaperone protein. KO mice (-/-): neonatal death Human ventricle: decreased BAG3 expression in heart failure | 3/3 affected, 1/1 unaffected |
BG | TRDN | Chr6:123509665-124330720 dup (821.1 kb); includes TRDN (complete gene) and NKAIN2 (exon 1) | Similar dup in >10 DD patients + unaffected subjects | Triadin, SR protein involved in Ca2+ homeostasis. Tg mice (5-fold overexpression): ↓ contraction | 5/7 affected, 4/4 unaffected |
C | CTNNA3 | Chr10:68286145-68513397 del (227.3 kb); loss of exon 10 (aa 428-458) including vinculin-like domain. | >40 overlapping deletions, known CNV hotspot | α3 catenin, intercalated disc protein. KO mice (-/-): adult DCM | 4/6 affected, 4/17 unaffected |
FK | FRMD3 | Chr9:85906635-85962244 del (55.6 kb); loss of exons 5-12 (aa 125-357, includes partial FERM domain, peptide and lipid-binding regions) | Overlap with 3 del/dup | FERM domain-containing protein 3, cytoskeletal protein | 4/4 affected, 1/4 unaffected |
HB | HPS3 | Chr3:148874313-148882670 del (g.31943-40298 del, 8.4 kb); loss of exon 9-14 (aa.504-863), no identified domains | Overlap with 1 larger dup in 2 DD cases | Hermansky–Pudlak syndrome 3 protein | 1/2 affected 1/2 unaffected |
Families with identified pathogenic/likely pathogenic variants | |||||
BL | DSC2 | Chr18:28681558-28686269 del (g.37617-42327 del, 4.7 kb); loss of first exon + promoter | Absent | Desmocollin 2, desmosomal protein. KO mice (-/-): embryonic lethal | 2/2 affected |
BR | SCN1B | Chr19:35531062-35531134 del (g.14470-14543 del, 73b in 3’ UTR) | Absent | β1 subunit, voltage-gated sodium channel | 1/3 affected, 1/9 unaffected |
DD | XIRP2 | Chr2:167868183-168522158 del/dup (654 kb); del from exon 3/dup (includes whole gene + translocated del segment) | Similar del (exon 4 on), multiple smaller CNV in same region | Xin actin-binding repeat-containing protein 2, intercalated disc protein. KO mice (-/-): postnatal death, ( + /-): normal EF. Human ventricle: expression levels increased (early) or reduced (late) with myocardial stress | 2/2 affected, 1/2 unaffected |
FQ | AK1 | Chr9:130621906-130645663 dup (238 kb); includes complete gene | Overlap with 3 full-gene dup/multiple small del, in unaffected subjects | Adenylate kinase 1, enzyme involved in energy metabolism | 2/2 affected |
