Numbers of subjects with a TTNtv are shown for each group. TTNtv are classified by type, the affected transcript, and expression level of the variant-encoding exon. Comparisons between groups were assessed by Fisher’s exact test. Cohort ethnicity: Caucasian: healthy volunteer, 75%; FHS, 100%; JHS, 0%; unselected DCM, 88%; end-stage, DCM 85%; African American: healthy volunteer, 2%; FHS, 0%; JHS, 100%; unselected DCM, 4%; end-stage DCM, 6%.
| Discovery cohorts | Replication cohorts | |||||||||
| Healthy volunteers (n = 308) | FHS (n = 1623) | JHS (n = 1980) | Unselected DCM (n = 371)* | End-stage DCM (n = 155) | P value DCM versus controls | WHI (n = 667) | Familial DCM (n = 163) | P value DCM versus controls | ||
| Unselected DCM | All DCM | |||||||||
| Transcript affected by truncation | ||||||||||
| N2BA and N2B | 4 | 11 | 20 | 42 | 34 | 1.7 × 10−25 | 5.5 × 10−46 | 2 | 31 | 3.8 × 10−21 |
| N2BA only | 4 | 2 | 8 | 7 | 0 | 0.0014 | 0.0083 | 2 | 0 | 1 |
| Neither N2BA or N2B (novex-3 terminal exon only†) | 1 (0) | 8 (5) | 4 (1) | 1 (1) | 1 (1) | 1 | 0.7 | 5 (4) | 0 (0) | 1 |
| Totals | 9 | 21 | 32 | 50 | 35 | 9 | 31 | |||
| Sarcomere domain | ||||||||||
| A-band (18,235 amino acids) | 2 | 7 | 12 | 32 | 29 | 0.011 | 0.00014 | 1 | 25 | 0.015 |
| Non–A-band (17,756 amino acids) | 7 | 9 | 19 | 18 | 8 | 4 | 6 | |||
| Totals | 9 | 16 | 31 | 49‡ | 34‡ | 5 | 31 | |||
| Usage§ of exon containing truncation | ||||||||||
| Low (PSI <0.15) | 1 | 4 | 4 | 2 | 0 | 0.25 | 0.38 | 1 | 0 | 1 |
| Intermediate (PSI 0.15 to 0.9) | 4 | 1 | 7 | 5 | 0 | 0.012 | 0.042 | 2 | 0 | 1 |
| High (PSI >0.9) | 4 | 11 | 20 | 42 | 34 | 1.7 × 10−25 | 5.5 × 10−46 | 2 | 31 | 3.8 × 10−21 |
| Totals | 9 | 16 | 31 | 49‡ | 34‡ | 5 | 31 | |||
| Variant type | ||||||||||
| Frameshift variant | 2 | 3 | 7 | 22 | 15 | 4.9 × 10−16 | 4.0 × 10−25 | 1 | 15 | 1.9 × 10−10 |
| Stop gained | 3 | 7 | 6 | 15 | 12 | 7.3 × 10−09 | 2.3 × 10−15 | 2 | 16 | 2.8 × 10−10 |
| Canonical splice sites¶ | 2 | 3 | 7 | 9 | 5 | 2.9 × 10−05 | 2.3 × 10−07 | 1 | 0 | 1 |
| Splice variant predictions|| | 2 | 3 | 11 | 4 | 5 | 0.089 | 0.0015 | 1 | 0 | 1 |
| Totals | 9 | 16 | 31 | 49‡ | 34‡ | 1.4 × 10−25 | 2.8 × 10−43 | 5 | 31 | 1.6 × 10−18 |
*Three of 374 subjects were excluded from these analyses due to relatedness to other subjects.
†Variants that only affect the alternative terminal exon of novex-3 are excluded elsewhere.
‡Total number of individuals with TTNtv; four individuals with DCM (one unselected, three end-stage) carry a second TTNtv, which is a splice variant prediction in three cases.
§Exon usage levels are displayed categorically on the basis of PSI.
¶Canonical splice sites refer to the two intronic base pairs at the 5′ and 3′ splice junctions.
||Variants close to canonical splice sites that are predicted in silico to alter splicing.