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A large series of patients with the MYH7 p.(Arg1712Gln) variant showed: (1) a consistent hypertrophic cardiomyopathy (HCM) phenotype, (2) women developing HCM at a later age, and (3) development of HCM after the sixth decade.
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Describing a series of individuals with a single pathogenic variant is important to establish variant-specific screening protocols to prevent unnecessary cardiac evaluations.
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For healthy MYH7 p.(Arg1712Gln) carriers, longer screening intervals could be appropriate for women younger than 30 years and follow-up should be continued after the age of 60 years.
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Our data also showed that MYH7 p.(Arg1712Gln) is a founder variant in a subset of French and Dutch patients.
Introduction
Methods
Subjects
Molecular data
Clinical data
Haplotype analysis
Results
Molecular data
Clinical data
ID | Sex | AAD | ALE | Signs and symptoms at presentation | Maximum LV wall thickness | Left atrial dilatation | Obstruction of LV outflow | LVEF | AF | Events | FH of HCM | Variant identified in family member | FH of SCD |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | M | 61 | 62 | Chest pain and dyspnoea (61) | 19–20 mm (IRM, 61); 19 mm (echo, 62) | Mild dilatation (echo, 62) | Yes, 13 mm Hg at Valsalva manoeuvre increasing to 30 mm Hg after extrasystole (62) | Normal (61) / 75.2% (62) | Yes (61) | Myocardial ischaemia under stress, coronary angiography: atheromatous arteries without significant stenosis (61) | No | No, none tested | U (35) |
2 | F | NA | 84 | NA | 24 mm (echo, 72) 28 mm (echo, 84) | No, 19 cm2 (72) / yes, 29.3 cm2 (84) | Yes (72) | 79% (72) / slightly altered (84) | No | No | Yes | No, none tested | NA |
3 | M | 45 | 46 | Pulmonary embolism | 22 mm (echo, 45) | Yes, 437 ml/m2 (44) | NA | 73% (44) | No | No | No | No | No |
4 | M | 28 | NA | NA | NA | NA | NA | NA | NA | No | Yes | Yes | No |
5 | M | 16 | 37 | Chest pain (14) | 18 mm (MRI, 32); 25 mm (MRI, 37) | No | No | 78%, (32) | No | NA | Yes | Yes | No |
6 | F | 67 | 68 | Heart murmur, dyspnoea, chest pain, dizziness | 19 mm | Normal | Severe (6 m/s), SAM | Normal | Yes | No | Yes | Yes | Yes? (suspected in father) |
7 | F | 68 | 76 | Out-of-hospital cardiac arrest during exercise; VF | 19 mm (MRI, 68) | Mild dilatation LA, borderline dimensions right atrium(68) / biatrial dilatation (76) | Midventricular obstruction with a dynamic systolic and diastolic gradient (76) | 59% on MRI (68) | Yes (69) | VF (68), ICD (68), AF (69), persistent AF (75), repolarisation abnormalities (68) | Yes | Yes | Yes |
8 | M | 48 | 63 | Presyncope | 19 mm (48); 20 mm | NA(48); mild dilatation(63) | No (48); no (63) | Normal | No | Some PVC (Holter) | Yes | Yes | No |
9 | M | 51 | 51 | Arrhythmias during exercise | NA | NA | NA | NA | No | Repolarisation abnormalities | Yes | Yes | No |
10 | M | 29 | 71 | NA | NA | NA | NA | NA | Yes | LBBB, pacemaker for asystolia and bradycardia (54), NSVT (59), ICD (59), ICD therapy (62), TIA (58), atrial flutter ablation (69) | Yes | Yes | M (30), S (18), B (40) |
11 | F | 34 | 62 | NA | 18 mm (34) | NA | NA | NA | Yes | Borderline AV block, ablation for atrial flutter (62) | NA | No | No |
12 | F | 74 | 76 | None | 21 mm (MRI, 74) | NA | NA | NA | NA | Intraventricular conduction delay | NA | No | NA |
13 | F | NA | 72 | NA | NA | NA | NA | NA | NA | Intraventricular conduction delay, ICD (72) | NA | NA | NA |
14 | M | 40 | 40 | None | 16 mm | Dilated (45 ml/m2) | No | Normal | No | Borderline first-degree AV block (Holter) | No | No | F (48), U (42), GF |
15 | M | 8 | 48 | NA | 18 mm (48) | NA | NA | NA | Yes | Myectomy (8), TIA (10), chronic heart failure (43), RBBB | NA | NA | NA |
16 | F | 44 | 49 | Chest pain, dyspnoea, dizziness, bradychardia | 18 mm (44); 19 mm (echo, 49); 24 mm (MRI, 49) | NA | NA | NA | No | Septal reduction by myectomy (44), LBBB | NA | NA | NA |
17 | M | 33 | 37 | SVT | 16 mm (echo, 33); 17 mm (echo, 37); 15 mm (MRI) | Normal (echo); dilated (MRI, 29 cm2) | NA / 13.5 mm Hg | NA / normal | No | SVT, ablation of posteroseptal accessory pathway (19 and 33) | No | No | No |
18 | M | 66 | 71 | NA | 13 mm (66); 17 mm (71) | NA | NA | NA | No | NA | Yes | No | Yes (33) |
19 | F | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
20 | M | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
21 | F | 60 | 76 | NA | 19 mm (echo, MRI) | NA | Slightly faster blood flow LVOT (61) | 75% (70) | Yes (69) | Left anterior hemi block, tachycardia-bradycardia syndrome | Yes | No, none tested | NA |
22 | F | 68 | 78 | NA | 17 mm (echo and MRI, 73); 14 mm (MRI, 78) | NA | Yes | Normal (73); 49% (78) | No | NSVT (78), aortic valve insufficiency, hypertension | Yes | No | No |
Probands
Family members
Penetrance
Haplotype analysis
Discussion
Number of patients | Phenotype | Additional informations | Reference |
---|---|---|---|
1 | HCM | Childhood-onset, familial HCM | Morita, et al. N Engl J Med. 2008;358:1899–908 |
1 | HCM | 44-year-old female; apical aneurysm, MWT 14 mm, ECG abnormalities, negative T wave; positive family history; also carrried TNNI3 variant p.(Arg162Gln) (gnomAD allele frequency 10/249030) | Gruner, et al. Circ Cardiovasc Genet. 2011;4:288–95 |
4 | Unknown | 4 unrelated individuals from published data, a reported clinical cohort, and clinical laboratory data provided in genetic test report | Pan, et al. Circ Cardiovasc Genet. 2012;5:602–10 |
1 | HCM | Age at diagnosis: 19 years | Miller, et al. J Genet Couns. 2013;22:258–67 |
1 | HCM | None | Mook, et al. J Med Genet. 2013;50:614–26 |
7 | HCM? | Study on 427 unrelated, ostensibly healthy individuals from various racial and ethnic backgrounds and HCM case cohort of 2178 individuals | Kapplinger, et al. J Cardiovasc Transl Res. 2014;7:347–61 |
3 | Asymptomatic | Asymptomatic, pre-hypertrophic mutation carriers | Witjas-Paalberends, et al. Cardiovasc Res. 2014;103:248–57 |
1 | HCM | None | Lopes, et al. Heart. 2015;101:294–301 |
3 | Cardiomyopathy | 3 patients from Russia/Belarus | Glotov, et al. Clin Chim Acta. 2015;446:132–40 |
7 | HCM | None | Homburger, et al. Proc Natl Acad Sci U S A. 2016;113:6701–6 |
3 | HCM | 1 patient also carried MIB1 c.2530_2532delTCTinsC variant | Van Velzen, et al. Am J Cardiol. 2016;118:881–887 |
1 | HCM | 36-year-old male; myecotomy; MWT 17 mm | Helms, et al. Circulation. 2016;134:1738–48 |
16 | HCM | Variant found in 16/6112 HCM patients | Walsh, et al. Genet Med. 2017;19:192–203 |
1 | HCM | Patient possibly already described in Gruner, et al. Circ Cardiovasc Genet. 2011;4:288–95 | Weissler-Snir, et al. Circ Cardiovasc Imaging. 2017;10(2). pii: e005311 |
3 | HCM | Patients also reported in our cohort | Van Lint, et al. Neth Heart J. 2019;27:304–9 |
1 | HCM | 82-year-old Spanish female | Mademont-Soler, et al. PLoS One. 2017;12:e0181465 |
1 | HCM | Also carried MIB1 c.2530_2532delTCTinsC; patient probably already reported in Van Velzen, et al. Am J Cardiol. 2016;118:881–7 and Van Velzen et al. Am J Cardiol. 2018 Sep 8 | Van Velzen, et al. Circ Cardiovasc Genet. 2017;10:e001660 |
35 | HCM | 17 published probands and 18 private (= laboratory internal data) probands | Kelly, et al. Genet Med. 2018;20:351–9 |
1 | HCM | None | Mak, et al. Sci Rep. 2018;8:10846 |
2 | HCM | 2 male patients: 1 also carried MIB1 c.2530_2532delTCTinsC, another also carried MYH7 variant c.3100-2A > C; both were probably already reported in Van Velzen, et al. Am J Cardiol. 2016;118:881–7 | Van Velzen, et al. Am J Cardiol. 2018;122:1947–54 |
1 | HCM | 43-year-old Vietnamese patient; chest pain, eccentric LV hypertrophy, maximal LV thickness 27 mm | Tran Vu, et al. Circ J. 2019;83:1908–16 |
≥ 1 | HCM | None; patient(s) already reported? | Thomson, et al. Genet Med. 2019;21:1576–84 |
1 | HCM | 32-year-old male | Cao, et al. Stem Cell Res. 2021;55:102455 |