Age and Sex Differences in the Genetics of Cardiomyopathy.
Age
Cardiomyopathy
Genetic
Genomic constraints
Sex
Whole genome sequencing
Journal
Journal of cardiovascular translational research
ISSN: 1937-5395
Titre abrégé: J Cardiovasc Transl Res
Pays: United States
ID NLM: 101468585
Informations de publication
Date de publication:
21 Jul 2023
21 Jul 2023
Historique:
received:
12
03
2023
accepted:
04
07
2023
medline:
21
7
2023
pubmed:
21
7
2023
entrez:
21
7
2023
Statut:
aheadofprint
Résumé
Cardiomyopathy has variable penetrance. We analyzed age and sex-related genetic differences in 1,397 cardiomyopathy patients (Ontario, UK) with whole genome sequencing. Pediatric cases (n = 471) harbored more deleterious protein-coding variants in Tier 1 cardiomyopathy genes compared to adults (n = 926) (34.6% vs 25.9% respectively, p = 0.0015), with variant enrichment in constrained coding regions. Pediatric patients had a higher burden of sarcomere and lower burden of channelopathy gene variants compared to adults. Specifically, pediatric patients had more MYH7 and MYL3 variants in hypertrophic cardiomyopathy, and fewer TTN truncating variants in dilated cardiomyopathy. MYH7 variants clustered in the myosin head and neck domains in children. OBSCN was a top mutated gene in adults, enriched for protein-truncating variants. In dilated cardiomyopathy, female patients had a higher burden of z-disc gene variants compared to males. Genetic differences may explain age and sex-related variability in cardiomyopathy penetrance. Genotype-guided predictions of age of onset can inform pre-test genetic counseling. Pediatric cardiomyopathy patients were more likely to be genotype-positive than adults with a higher burden of variants in MYH7, MYL3, TNNT2, VCL. Adults had a higher burden of OBSCN and TTN variants. Females with dilated cardiomyopathy (DCM) had a higher burden of z-disc gene variants compared to males.
Identifiants
pubmed: 37477868
doi: 10.1007/s12265-023-10411-8
pii: 10.1007/s12265-023-10411-8
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : CIHR
ID : PJT 175034
Pays : Canada
Investigateurs
J C Ambrose
(JC)
P Arumugam
(P)
M Bleda
(M)
F Boardman-Pretty
(F)
C R Boustred
(CR)
H Brittain
(H)
M J Caulfield
(MJ)
G C Chan
(GC)
T Fowler
(T)
A Giess
(A)
A Hamblin
(A)
S Henderson
(S)
T J P Hubbard
(TJP)
R Jackson
(R)
L J Jones
(LJ)
D Kasperaviciute
(D)
M Kayikci
(M)
A Kousathanas
(A)
L Lahnstein
(L)
S E A Leigh
(SEA)
I U S Leong
(IUS)
F J Lopez
(FJ)
F Maleady-Crowe
(F)
L Moutsianas
(L)
M Mueller
(M)
N Murugaesu
(N)
A C Need
(AC)
P O'Donovan
(P)
C A Odhams
(CA)
C Patch
(C)
D Perez-Gil
(D)
M B Pereira
(MB)
J Pullinger
(J)
T Rahim
(T)
A Rendon
(A)
T Rogers
(T)
K Savage
(K)
K Sawant
(K)
R H Scott
(RH)
A Siddiq
(A)
A Sieghart
(A)
S C Smith
(SC)
A Sosinsky
(A)
A Stuckey
(A)
M Tanguy
(M)
E R A Thomas
(ERA)
S R Thompson
(SR)
A Tucci
(A)
E Walsh
(E)
M J Welland
(MJ)
E Williams
(E)
K Witkowska
(K)
S M Wood
(SM)
Informations de copyright
© 2023. The Author(s).
Références
Lee TM, Hsu DT, Kantor P, Towbin JA, Ware SM, Colan SD, Chung WK, Jefferies JL, Rossano JW, Castleberry CD, et al. Pediatric Cardiomyopathies. Circ Res. 2017;121:855–73. https://doi.org/10.1161/circresaha.116.309386 .
doi: 10.1161/circresaha.116.309386
pubmed: 28912187
pmcid: 5657298
Lipshultz SE, Law YM, Asante-Korang A, Austin ED, Dipchand AI, Everitt MD, Hsu DT, Lin KY, Price JF, Wilkinson JD, et al. Cardiomyopathy in Children: Classification and Diagnosis: A Scientific Statement From the American Heart Association. Circulation. 2019;140:e9–68. https://doi.org/10.1161/cir.0000000000000682 .
doi: 10.1161/cir.0000000000000682
pubmed: 31132865
Musunuru K, Hershberger RE, Day SM, Klinedinst NJ, Landstrom AP, Parikh VN, Prakash S, Semsarian C, Sturm AC. Genetic Testing for Inherited Cardiovascular Diseases: A Scientific Statement From the American Heart Association. Circ Genom Precis Med. 2020;13:e000067. https://doi.org/10.1161/hcg.0000000000000067 .
doi: 10.1161/hcg.0000000000000067
pubmed: 32698598
Tayal U, Ware JS, Lakdawala NK, Heymans S, Prasad SK. Understanding the genetics of adult-onset dilated cardiomyopathy: what a clinician needs to know. Eur Heart J. 2021;42:2384–96. https://doi.org/10.1093/eurheartj/ehab286 .
doi: 10.1093/eurheartj/ehab286
pubmed: 34153989
pmcid: 8216730
Ware SM, Wilkinson JD, Tariq M, Schubert JA, Sridhar A, Colan SD, Shi L, Canter CE, Hsu DT, Webber SA, et al. Genetic Causes of Cardiomyopathy in Children: First Results From the Pediatric Cardiomyopathy Genes Study. J Am Heart Assoc. 2021;10:e017731. https://doi.org/10.1161/jaha.120.017731 .
doi: 10.1161/jaha.120.017731
pubmed: 33906374
pmcid: 8200745
Burke MA, Cook SA, Seidman JG, Seidman CE. Clinical and Mechanistic Insights Into the Genetics of Cardiomyopathy. J Am Coll Cardiol. 2016;68:2871–86. https://doi.org/10.1016/j.jacc.2016.08.079 .
doi: 10.1016/j.jacc.2016.08.079
pubmed: 28007147
pmcid: 5843375
Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, Moss AJ, Seidman CE, Young JB. Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation. 2006;113:1807–16. https://doi.org/10.1161/circulationaha.106.174287 .
doi: 10.1161/circulationaha.106.174287
pubmed: 16567565
Ho CY, Day SM, Ashley EA, Michels M, Pereira AC, Jacoby D, Cirino AL, Fox JC, Lakdawala NK, Ware JS, et al. Genotype and Lifetime Burden of Disease in Hypertrophic Cardiomyopathy: Insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). Circulation. 2018;138:1387–98. https://doi.org/10.1161/circulationaha.117.033200 .
doi: 10.1161/circulationaha.117.033200
pubmed: 30297972
pmcid: 6170149
Marston NA, Han L, Olivotto I, Day SM, Ashley EA, Michels M, Pereira AC, Ingles J, Semsarian C, Jacoby D, et al. Clinical characteristics and outcomes in childhood-onset hypertrophic cardiomyopathy. Eur Heart J. 2021;42:1988–96. https://doi.org/10.1093/eurheartj/ehab148 .
doi: 10.1093/eurheartj/ehab148
pubmed: 33769460
pmcid: 8139852
Patel MD, Mohan J, Schneider C, Bajpai G, Purevjav E, Canter CE, Towbin J, Bredemeyer A, Lavine KJ. Pediatric and adult dilated cardiomyopathy represent distinct pathological entities. JCI Insight. 2017;2. https://doi.org/10.1172/jci.insight.94382
Wittlieb-Weber CA, Lin KY, Zaoutis TE, O’Connor MJ, Gerald K, Paridon SM, Shaddy RE, Rossano JW. Pediatric versus adult cardiomyopathy and heart failure-related hospitalizations: a value-based analysis. J Cardiac Fail. 2015;21:76–82. https://doi.org/10.1016/j.cardfail.2014.10.011 .
doi: 10.1016/j.cardfail.2014.10.011
Cannatà A, Fabris E, Merlo M, Artico J, Gentile P, Pio Loco C, Ballaben A, Ramani F, Barbati G, Sinagra G. Sex Differences in the Long-term Prognosis of Dilated Cardiomyopathy. Can J Cardiol. 2020;36:37–44. https://doi.org/10.1016/j.cjca.2019.05.031 .
doi: 10.1016/j.cjca.2019.05.031
pubmed: 31515085
Olivotto I, Maron MS, Adabag AS, Casey SA, Vargiu D, Link MS, Udelson JE, Cecchi F, Maron BJ. Gender-related differences in the clinical presentation and outcome of hypertrophic cardiomyopathy. J Am Coll Cardiol. 2005;46:480–7. https://doi.org/10.1016/j.jacc.2005.04.043 .
doi: 10.1016/j.jacc.2005.04.043
pubmed: 16053962
Rowin EJ, Maron MS, Wells S, Patel PP, Koethe BC, Maron BJ. Impact of Sex on Clinical Course and Survival in the Contemporary Treatment Era for Hypertrophic Cardiomyopathy. J Am Heart Assoc. 2019;8:e012041. https://doi.org/10.1161/jaha.119.012041 .
doi: 10.1161/jaha.119.012041
pubmed: 31663408
pmcid: 6898820
Siontis KC, Ommen SR, Geske JB. Sex, Survival, and Cardiomyopathy: Differences Between Men and Women With Hypertrophic Cardiomyopathy. J Am Heart Assoc. 2019;8:e014448. https://doi.org/10.1161/jaha.119.014448 .
doi: 10.1161/jaha.119.014448
pubmed: 31663428
pmcid: 6898853
Alimohamed MZ, Johansson LF, Posafalvi A, Boven LG, van Dijk KK, Walters L, Vos YJ, Westers H, Hoedemaekers YM, Sinke RJ, et al. Diagnostic yield of targeted next generation sequencing in 2002 Dutch cardiomyopathy patients. Int J Cardiol. 2021;332:99–104. https://doi.org/10.1016/j.ijcard.2021.02.069 .
doi: 10.1016/j.ijcard.2021.02.069
pubmed: 33662488
Meyer S, van der Meer P, van Tintelen JP, van den Berg MP. Sex differences in cardiomyopathies. Eur J Heart Fail. 2014;16:238–47. https://doi.org/10.1002/ejhf.15 .
doi: 10.1002/ejhf.15
pubmed: 24464619
van Velzen HG, Schinkel AFL, Baart SJ, Huurman R, van Slegtenhorst MA, Kardys I, Michels M. Effect of Gender and Genetic Mutations on Outcomes in Patients With Hypertrophic Cardiomyopathy. Am J Cardiol. 2018;122:1947–54. https://doi.org/10.1016/j.amjcard.2018.08.040 .
doi: 10.1016/j.amjcard.2018.08.040
pubmed: 30292335
Fung A, Manlhiot C, Naik S, Rosenberg H, Smythe J, Lougheed J, Mondal T, Chitayat D, McCrindle BW, Mital S. Impact of prenatal risk factors on congenital heart disease in the current era. J Am Heart Assoc. 2013;2:e000064. https://doi.org/10.1161/jaha.113.000064 .
doi: 10.1161/jaha.113.000064
pubmed: 23727699
pmcid: 3698764
Papaz T, Liston E, Zahavich L, Stavropoulos DJ, Jobling RK, Kim RH, Reuter M, Miron A, Oechslin E, Mondal T, et al. Return of genetic and genomic research findings: experience of a pediatric biorepository. BMC Med Genomics. 2019;12:173. https://doi.org/10.1186/s12920-019-0618-0 .
doi: 10.1186/s12920-019-0618-0
pubmed: 31775751
pmcid: 6882371
Papaz T, Safi M, Manickaraj AK, Ogaki C, BreatonKyryliuk J, Burrill L, Dodge C, Chant-Gambacort C, Walter LL, Rosenberg H, et al. Factors influencing participation in a population-based biorepository for childhood heart disease. Pediatrics. 2012;130:e1198-1205. https://doi.org/10.1542/peds.2012-0687 .
doi: 10.1542/peds.2012-0687
pubmed: 23045559
Smedley D, Smith KR, Martin A, Thomas EA, McDonagh EM, Cipriani V, Ellingford JM, Arno G, Tucci A, Vandrovcova J, et al. 100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care - Preliminary Report. N Engl J Med. 2021;385:1868–80. https://doi.org/10.1056/NEJMoa2035790 .
doi: 10.1056/NEJMoa2035790
pubmed: 34758253
Lesurf R, Said A, Akinrinade O, Breckpot J, Delfosse K, Liu T, Yao R, Persad G, McKenna F, Noche RR, et al. Whole genome sequencing delineates regulatory, copy number, and cryptic splice variants in early onset cardiomyopathy. NPJ Genom Med. 2022;7:18. https://doi.org/10.1038/s41525-022-00288-y .
doi: 10.1038/s41525-022-00288-y
pubmed: 35288587
pmcid: 8921194
Ingles J, Goldstein J, Thaxton C, Caleshu C, Corty EW, Crowley SB, Dougherty K, Harrison SM, McGlaughon J, Milko LV, et al. Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes. Circ Genom Precis Med. 2019;12:e002460. https://doi.org/10.1161/circgen.119.002460 .
doi: 10.1161/circgen.119.002460
pubmed: 30681346
pmcid: 6410971
Jordan E, Peterson L, Ai T, Asatryan B, Bronicki L, Brown E, Celeghin R, Edwards M, Fan J, Ingles J, et al. Evidence-Based Assessment of Genes in Dilated Cardiomyopathy. Circulation. 2021;144:7–19. https://doi.org/10.1161/circulationaha.120.053033 .
doi: 10.1161/circulationaha.120.053033
pubmed: 33947203
pmcid: 8247549
Mazzarotto F, Tayal U, Buchan RJ, Midwinter W, Wilk A, Whiffin N, Govind R, Mazaika E, de Marvao A, Dawes TJW, et al. Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy. Circulation. 2020;141:387–98. https://doi.org/10.1161/circulationaha.119.037661 .
doi: 10.1161/circulationaha.119.037661
pubmed: 31983221
pmcid: 7004454
Thomson KL, Ormondroyd E, Harper AR, Dent T, McGuire K, Baksi J, Blair E, Brennan P, Buchan R, Bueser T, et al. Analysis of 51 proposed hypertrophic cardiomyopathy genes from genome sequencing data in sarcomere negative cases has negligible diagnostic yield. Genet Med. 2019;21:1576–84. https://doi.org/10.1038/s41436-018-0375-z .
doi: 10.1038/s41436-018-0375-z
pubmed: 30531895
Walsh R, Buchan R, Wilk A, John S, Felkin LE, Thomson KL, Chiaw TH, Loong CCW, Pua CJ, Raphael C, et al. Defining the genetic architecture of hypertrophic cardiomyopathy: re-evaluating the role of non-sarcomeric genes. Eur Heart J. 2017;38:3461–8. https://doi.org/10.1093/eurheartj/ehw603 .
doi: 10.1093/eurheartj/ehw603
pubmed: 28082330
pmcid: 5837460
Akinrinade O, Alastalo TP, Koskenvuo JW. Relevance of truncating titin mutations in dilated cardiomyopathy. Clin Genet. 2016;90:49–54. https://doi.org/10.1111/cge.12741 .
doi: 10.1111/cge.12741
pubmed: 26777568
Herman DS, Lam L, Taylor MR, Wang L, Teekakirikul P, Christodoulou D, Conner L, DePalma SR, McDonough B, Sparks E, et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012;366:619–28. https://doi.org/10.1056/NEJMoa1110186 .
doi: 10.1056/NEJMoa1110186
pubmed: 22335739
pmcid: 3660031
Roberts AM, Ware JS, Herman DS, Schafer S, Baksi J, Bick AG, Buchan RJ, Walsh R, John S, Wilkinson S, et al. Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Sci Transl Med. 2015;7:270ra276. https://doi.org/10.1126/scitranslmed.3010134 .
doi: 10.1126/scitranslmed.3010134
Tadros R, Francis C, Xu X, Vermeer AMC, Harper AR, Huurman R, KeluBisabu K, Walsh R, Hoorntje ET, Te Rijdt WP, et al. Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect. Nat Genet. 2021;53:128–34. https://doi.org/10.1038/s41588-020-00762-2 .
doi: 10.1038/s41588-020-00762-2
pubmed: 33495596
pmcid: 7611259
Homburger JR, Green EM, Caleshu C, Sunitha MS, Taylor RE, Ruppel KM, Metpally RP, Colan SD, Michels M, Day SM, et al. Multidimensional structure-function relationships in human β-cardiac myosin from population-scale genetic variation. Proc Natl Acad Sci USA. 2016;113:6701–6. https://doi.org/10.1073/pnas.1606950113 .
doi: 10.1073/pnas.1606950113
pubmed: 27247418
pmcid: 4914177
Debold EP, Schmitt JP, Patlak JB, Beck SE, Moore JR, Seidman JG, Seidman C, Warshaw DM. Hypertrophic and dilated cardiomyopathy mutations differentially affect the molecular force generation of mouse alpha-cardiac myosin in the laser trap assay. Am J Physiol Heart Circ Physiol. 2007;293:H284-291. https://doi.org/10.1152/ajpheart.00128.2007 .
doi: 10.1152/ajpheart.00128.2007
pubmed: 17351073
Spudich JA, Aksel T, Bartholomew SR, Nag S, Kawana M, Yu EC, Sarkar SS, Sung J, Sommese RF, Sutton S, et al. Effects of hypertrophic and dilated cardiomyopathy mutations on power output by human β-cardiac myosin. J Exp Biol. 2016;219:161–7. https://doi.org/10.1242/jeb.125930 .
doi: 10.1242/jeb.125930
pubmed: 26792326
pmcid: 6514469
Toepfer CN, Garfinkel AC, Venturini G, Wakimoto H, Repetti G, Alamo L, Sharma A, Agarwal R, Ewoldt JF, Cloonan P, et al. Myosin Sequestration Regulates Sarcomere Function, Cardiomyocyte Energetics, and Metabolism, Informing the Pathogenesis of Hypertrophic Cardiomyopathy. Circulation. 2020;141:828–42. https://doi.org/10.1161/circulationaha.119.042339 .
doi: 10.1161/circulationaha.119.042339
pubmed: 31983222
pmcid: 7077965
Pugh TJ, Kelly MA, Gowrisankar S, Hynes E, Seidman MA, Baxter SM, Bowser M, Harrison B, Aaron D, Mahanta LM, et al. The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing. Genet Med. 2014;16:601–8. https://doi.org/10.1038/gim.2013.204 .
doi: 10.1038/gim.2013.204
pubmed: 24503780
Seidel F, Holtgrewe M, Al-Wakeel-Marquard N, Opgen-Rhein B, Dartsch J, Herbst C, Beule D, Pickardt T, Klingel K, Messroghli D, et al. Pathogenic Variants Associated With Dilated Cardiomyopathy Predict Outcome in Pediatric Myocarditis. Circ Genom Precis Med. 2021;14:e003250. https://doi.org/10.1161/CIRCGEN.120.003250 .
Kontorovich AR, Patel N, Moscati A, Richter F, Peter I, Purevjav E, Selejan SR, Kindermann I, Towbin JA, Bohm M, et al. Myopathic Cardiac Genotypes Increase Risk for Myocarditis. JACC Basic Transl Sci. 2021;6:584–92. https://doi.org/10.1016/j.jacbts.2021.06.001 .
doi: 10.1016/j.jacbts.2021.06.001
pubmed: 34368507
pmcid: 8326270
Wu G, Liu J, Liu M, Huang Q, Ruan J, Zhang C, Wang D, Sun X, Jiang W, Kang L, et al. Truncating Variants in OBSCN Gene Associated With Disease-Onset and Outcomes of Hypertrophic Cardiomyopathy. Circ Genom Precis Med. 2021;14:e003401. https://doi.org/10.1161/circgen.121.003401 .
doi: 10.1161/circgen.121.003401
pubmed: 34601892
Marston S. Obscurin variants and inherited cardiomyopathies. Biophys Rev. 2017;9:239–43. https://doi.org/10.1007/s12551-017-0264-8 .
doi: 10.1007/s12551-017-0264-8
pubmed: 28510120
pmcid: 5498328
Grogan A, Kontrogianni-Konstantopoulos A. Unraveling obscurins in heart disease. Pflugers Arch. 2019;471:735–743. https://doi.org/10.1007/s00424-018-2191-3
Hu LR, Kontrogianni-Konstantopoulos A. Proteomic Analysis of Myocardia Containing the Obscurin R4344Q Mutation Linked to Hypertrophic Cardiomyopathy. Front Physiol. 2020;11:478. https://doi.org/10.3389/fphys.2020.00478 .
Mayosi BM, Fish M, Shaboodien G, Mastantuono E, Kraus S, Wieland T, Kotta MC, Chin A, Laing N, Ntusi NB, et al. Identification of Cadherin 2 (CDH2) Mutations in Arrhythmogenic Right Ventricular Cardiomyopathy. Circ Cardiovasc Genet. 2017;10. https://doi.org/10.1161/circgenetics.116.001605 .
Sarker M, Lee HT, Mei L, Krokhotin A, de Los Reyes SE, Yen L, Costantini LM, Griffith J, Dokholyan NV, Alushin GM, et al. Cardiomyopathy Mutations in Metavinculin Disrupt Regulation of Vinculin-Induced F-Actin Assemblies. J Mol Biol. 2019;431:1604–18. https://doi.org/10.1016/j.jmb.2019.02.024 .
doi: 10.1016/j.jmb.2019.02.024
pubmed: 30844403
pmcid: 6693633
Zemljic-Harpf AE, Miller JC, Henderson SA, Wright AT, Manso AM, Elsherif L, Dalton ND, Thor AK, Perkins GA, McCulloch AD, et al. Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy. Mol Cell Biol. 2007;27:7522–37. https://doi.org/10.1128/mcb.00728-07 .
doi: 10.1128/mcb.00728-07
pubmed: 17785437
pmcid: 2169049
Hawley MH, Almontashiri N, Biesecker LG, Berger N, Chung WK, Garcia J, Grebe TA, Kelly MA, Lebo MS, Macaya D, et al. An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy. Hum Mutat. 2020;41:1577–87. https://doi.org/10.1002/humu.24061 .
doi: 10.1002/humu.24061
pubmed: 32516855
pmcid: 7714388
Lakdawala NK, Olivotto I, Day SM, Han L, Ashley EA, Michels M, Ingles J, Semsarian C, Jacoby D, Jefferies JL, et al. Associations Between Female Sex, Sarcomere Variants, and Clinical Outcomes in Hypertrophic Cardiomyopathy. Circ Genom Precis Med. 2021;14:e003062. https://doi.org/10.1161/circgen.120.003062 .
doi: 10.1161/circgen.120.003062
pubmed: 33284039
Shi W, Sheng X, Dorr KM, Hutton JE, Emerson JI, Davies HA, Andrade TD, Wasson LK, Greco TM, Hashimoto Y, et al. Cardiac proteomics reveals sex chromosome-dependent differences between males and females that arise prior to gonad formation. Dev Cell. 2021;56:3019-3034.e3017. https://doi.org/10.1016/j.devcel.2021.09.022 .
doi: 10.1016/j.devcel.2021.09.022
pubmed: 34655525
pmcid: 9290207