Table 1.
mtDNA variants identified by NGS in p.R453C-β-MHC isogenic lines used for HCM modeling (WT, healthy; het, heterozygous; HOM, homozygous; KO, knockout). In silico pathogenicity prediction algorithms used: § MitoTIP; * Polyphen-2; † CAROL; ‡ APOGEE. Phenotypically severe hPSC-CM line is highlighted in red and less severe ones in green.
| Isogenic hPSC-CM Set(s) | Locus | mtDNA Mutation | Percent Heteroplasmy (WT-Het-HOM-KO) | In silico Prediction (Score) | Potential HCM Effect |
|---|---|---|---|---|---|
| AT1 | MT-HV2, MT-OHR | m.152T > C | 99.9 (all lines) | N/A (non-coding) |
Aggravator (present only in AT1s) |
| REBL-PAT + HUES7 | MT-HV2, MT-OHR, MT-CSB2 | m.309_310insCCT |
REBL-PAT: 28.9–26.4–27.2 HUES7: 17.4–13.8–15.6 |
N/A (non-coding) |
Protective (absent in AT1) |
| HUES7 | MT-HV2, MT-OHR, MT-CSB2 | m.309_310insCCCT | 11.7–11.6–13.3 | N/A (non-coding) |
Protective (absent in AT1) |
| AT1 + REBL-PAT + HUES7 | MT-HV2, MT-OHR, MT-CSB2 | m.310T > C |
AT1: 15.0–17.1–14.5–17.0; REBL-PAT: 61.2–63.2–61.9; HUES7: 61.6–56.4–57.6 |
N/A (non-coding) |
Protective (less prevalent in AT1) |
| AT1 + REBL-PAT + HUES7 | MT-HV2, MT-OHR, MT-CSB2 | m.310_311insC |
AT1: 67.8–64.2–65.6–63.9 REBL-PAT: 30.1–26.7–27.2 HUES7: 26.1–32.0–33.3 |
N/A (non-coding) |
Aggravator (more prevalent in AT1s) |
| AT1 | MT-HV3 | m.514_515delCA | 60.1–53.5–53.6–53.7; | N/A (non-coding) |
Aggravator only present in AT1s) |
| REBL-PAT | MT-RNR2 | m.2203G > A | 14.5% | N/A (non-coding) |
None: acquired during reprogramming |
| AT1 | MT-RNR2 | m.2525C > T | Fibroblasts: 12.1% iPSCs + iPSC-CMs: 99.9% |
N/A (non-coding) |
None: increased upon nuclear reprogramming |
| AT1 + REBL-PAT + HUES7 | MT-TA | m.5597A > C |
AT1: 5.4–12.4–6.5–11.4; REBL-PAT: 11.1–14.3–13.2; HUES7: 24.8–7.8–8.8 |
Possibly pathogenic (73.80%) § | None: acquired during reprogramming/culture |
| HUES7 | MT-CO1 | m.5938A > C | 12.2–1.2–1.1 | Probably damaging (1.000) * Deleterious (1) † Neutral (0.45) ‡ |
None: acquired during culture |
| REBL-PAT | MT-HV1 | m.16319G > A | 99.7–99.7–99.6 | N/A (non-coding) |
Protective (absent in AT1) |