Table 2 WGS-identified LOF variants in the extended gene set
From: Genome sequencing as a first-line genetic test in familial dilated cardiomyopathy
Family ID | Gene | Variant | ExAC variant frequency; PLi score | Notes | Segregationa |
|---|---|---|---|---|---|
Families ”unsolved” after PS | |||||
AJ | RYR2 | c.8209_-4T>C | Absent; 1.00 | Ryanodine receptor 2, SR protein involved in Ca2+ homeostasis. KO mice (-/-): embryonic lethal, (+/-): adults, normal baseline EF, ↓ contraction post-TAC; cKO mice (-/-): adults, transient ↓ contraction. CPVT families with exon 3 deletion: DCM in a subset of individuals | 1/1 affected 0/1 unaffected |
AT | MYO18B | c.1692+1_1692+29del | Absent; 0 | Myosin 18B, Z-disc protein. KO mice (-/-): embryonic lethal, disordered myofibrils | 1/2 affected 0/3 unaffected |
BF | BDKRB1 | p.R282* | 0.002883; 0.07 | Bradykinin receptor B1. KO mice (-/-): adults, mild ventricular dilation, normal EF | 2/3 affected 2/10 unaffected |
BG | TTN b | c.31763-1G>A | 0.0002733; 0 | Titin, sarcomeric protein. Titin-truncating transgenic mice (-/-): embryonic lethal, (+/-): adults, stress-induced DCM. Zebrafish (+/-): adults, spontaneous DCM | 3/7 affected 0/4 unaffected |
BP | RYR2 | c.14757-7_14757-6delTCinsAT | Absent; 1.00 | Ryanodine receptor 2 (see above) | 2/3 affected 2/5 unaffected |
SCN4A | p.Y600* | Absent; 0.01 | α4 subunit, voltage-gated sodium channel. KO mice (-/-): adults, no heart defects reported | 1/3 affected 0/5 unaffected | |
MYBPHL b | p.R255* | 0.001450; 0 | Myosin binding protein H-like, sarcomeric protein. KO mice (-/-, +/-): adults, DCM; p.R255* variant: altered MyBP-HL localization in transfected neonatal mouse cardiomyocytes | 1/3 affected, 2/5 unaffected | |
DF | FLNC | p.C2369* | Absent; 1.00 | Filamin C, actin crosslinking protein in Z-disc and sarcolemma. KO mice (-/-): neonatal death; zebrafish MO: cardiac developmental defects | 2/2 affected 2/3 unaffected |
Families with identified pathogenic/likely pathogenic variants | |||||
AM | ADRA1A | RRHQA341-345* | Absent; 0 | α1A adrenoceptor. KO mice (-/-): adults, normal EF | 3/3 affected 3/12 unaffected |
PLEC | p.Q2360* | 0.0002591; 0.02 | Plectin, cytoskeletal protein. KO mice (-/-): neonatal death, Z-disc disorganization | 2/3 affected 8/12 unaffected | |
BK | TRIM63 | p.Q247* | 0.000486; 0 | Tripartite motif containing 63, E3 ubiquitin ligase p.Q247* variant: transfected cells, ↓autoubiquitination; transgenic mice, adults, ↑ LV mass, ↑ LVEDD, normal EF | 2/2 affected 0/1 unaffected |
BR | TLL2 | p.V441* | Absent; 0 | Tolloid like 2, zinc-dependent metalloprotease. KO mice (-/-): adults, no heart defects reported | 1/2 affected 1/9 unaffected |
CS | ANO5 | p.N64fs | 0.001027; 0 | Anoctamin 5, transmembrane protein. KO mice (-/-): adults, normal EF (baseline, isoproterenol stress) | 6/6 affected 0/6 unaffected. |
CZ | PDE4DIP | p.C18* | 0.0000698; NA | Phosphodiesterase 4D interacting protein, A-kinase anchoring protein, contributes to phosphorylation of cMyBPC and cTNI | 4/4 affected 0/2 unaffected |
DO | SYNE2 | p.A6022A* | Absent; 0 | Spectrin repeat-containing nuclear envelope protein 2, nuclear membrane protein. KO mice (-/-): adults, normal EF | 2/3 affected 1/2 unaffected |
EA | ASB15 | p.G403* | 0.0000906; 0 | Ankyrin repeat and SOCS box containing 15, involved in muscle differentiation and protein turnover | 2/3 affected 1/3 unaffected |
MO | ACADVL | c.1077_+1G>T | Absent; 0 | Very long chain acyl-CoA dehydrogenase c.1077_+1G>T variant: 36% residual enzyme activity (predicted to be asymptomatic) | 2/2 affected 0/1 unaffected |
MYOM2 | p.Q18* | 0.0006355; 0 | Myomesin 2, sarcomeric protein. Neonatal rat cardiomyocytes (-/-): ↓ rate of contraction | 1/2 affected 0/1 unaffected | |
R | FLNC | c.3791_-8G>A | 0.0001607; 1.00 | Filamin C (see above) | 1/5 affected 1/2 unaffected |
