Whole genome sequencing delineates regulatory, copy number, and cryptic splice variants in early onset cardiomyopathy

Lesurf, Robert; Said, Abdelrahman; Akinrinade, Oyediran; Breckpot, Jeroen; Delfosse, Kathleen; Liu, Ting; Yao, Roderick; Persad, Gabrielle; McKenna, Fintan; Noche, Ramil R.; Oliveros, Winona; Mattioli, Kaia; Shah, Shreya; Miron, Anastasia; Yang, Qian; Meng, Guoliang; Yue, Michelle Chan Seng; Sung, Wilson W L; Thiruvahindrapuram, Bhooma; Lougheed, Jane; Oechslin, Erwin; Mondal, Tapas; Bergin, Lynn; Smythe, John; Jayappa, Shashank; Rao, Vinay J.; Shenthar, Jayaprakash; Dhandapany, Perundurai S.; Semsarian, C.; Weintraub, Robert G.; Bagnall, Richard D.; Ingles, Jodie; Ambrose, J. C.; Arumugam, Prabhu; Baple, Emma L.; Bleda, Marta; Boardman-Pretty, F.; Boissière, Julien; Boustred, C. R.; Brittain, Helen; Caulfield, Mark J.; Chan, G. C.; Craig, Clare; Daugherty, Louise C.; Burca, Anna de; Devereau, A.; Elgar, Greg; Foulger, Rebecca E.; Fowler, Tom; Furió-Tarí, P.; Giess, Adam; Hackett, J.M.; Halai, Dina; Hamblin, Angela; Henderson, Shirley; Holman, John E.; Hubbard, Tim; Ibáñez, Kristina; Jackson, R.; Jones, Louise; Kasperavičiūtė, Dalia; Kayikci, Melis; Kousathanas, Athanasios; Lahnstein, L.; Lawson, Katy L.; Leigh, Sarah; Leong, I. U. S.; Lopez, Fabrice; Maleady‐Crowe, F.; Mason, Joanne; McDonagh, Ellen M.; Moutsianas, Loukas; Mueller, Michael; Murugaesu, Nirupa; Need, Anna C.; Odhams, Christopher A.; Orioli, Andrea; Patch, Christine; Perez-Gil, D.; Pereira, Mariana Buongermino; Polychronopoulos, Dimitris; Pullinger, J.; Rahim, T.; Rendon, Augusto; Riesgo-Ferreiro, P.; Rogers, T.; Ryten, Mina; Savage, K.; Sawant, K.; Scott, Richard; Siddiq, Afshan; Sieghart, A.; Smedley, Damian; Ks, Smith; Smith, Samuel C.; Sosinsky, Alona; Will, Stefan; Stevens, Hallam; Stuckey, A.; Mohammad, Razia Sultana; Tanguy, M.; Thomas, Ellen; Thompson, S. R.; Tregidgo, Carolyn; Tucci, Arianna; Walsh, E.; Watters, Scott; Welland, M. J.; Williams, Eleanor; Witkowska, K.; Wood, S. M.; Zarowiecki, Magdalena; Melé, Marta; Maass, Philipp G.; Ellis, James; Scherer, Stephen W.; Mital, Seema

doi:10.1038/s41525-022-00288-y

Cited by 21 publications

(15 citation statements)

References 108 publications

(124 reference statements)

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“… 52 ) HCM, LV/ECG traits HCM and DCM features BAG5 Co-chaperone of proteostasis regulation DCM 2 (refs. 60 , 61 ) 5 6 PTV Exome (3 trio, 2 proband) – LV dilation and arrhythmogenicity CAP2 Thin filament protein (actin regulation) DCM 3 (refs. 62 – 64 ) 3 4 PTV Exome (2 trio, 1 proband).…”

Section: Resultsmentioning

confidence: 99%

Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies

Lipov,

Jurgens,

Mazzarotto

et al. 2023

Nat Cardiovasc Res

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Discrete categorization of Mendelian disease genes into dominant and recessive models often oversimplifies their underlying genetic architecture. Cardiomyopathies (CMs) are genetic diseases with complex etiologies for which an increasing number of recessive associations have recently been proposed. Here, we comprehensively analyze all published evidence pertaining to biallelic variation associated with CM phenotypes to identify high-confidence recessive genes and explore the spectrum of monoallelic and biallelic variant effects in established recessive and dominant disease genes. We classify 18 genes with robust recessive association with CMs, largely characterized by dilated phenotypes, early disease onset and severe outcomes. Several of these genes have monoallelic association with disease outcomes and cardiac traits in the UK Biobank, including LMOD2 and ALPK3 with dilated and hypertrophic CM, respectively. Our data provide insights into the complex spectrum of dominance and recessiveness in genetic heart disease and demonstrate how such approaches enable the discovery of unexplored genetic associations.

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Section: Resultsmentioning

confidence: 99%

Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies

Lipov,

Jurgens,

Mazzarotto

et al. 2023

Nat Cardiovasc Res

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“…Furthermore, thousands of cardiac specific enhancers have been described, and it is hypothesized that enhancers may have critical roles in cardiac diseases (1,14,24). This was also elegantly illustrated in a recent GWAS, where several regulatory variants in the promoter and enhancer regions were linked to cardiomyopathy (33).…”

Section: Cardiomyopathy-associated Genetic Variants In Enhancer and P...mentioning

confidence: 94%

The role of noncoding genetic variants in cardiomyopathy

Htet,

Lei,

Bajpayi

et al. 2023

Front. Cardiovasc. Med.

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Cardiomyopathies remain one of the leading causes of morbidity and mortality worldwide. Environmental risk factors and genetic predisposition account for most cardiomyopathy cases. As with all complex diseases, there are significant challenges in the interpretation of the molecular mechanisms underlying cardiomyopathy-associated genetic variants. Given the technical improvements and reduced costs of DNA sequence technologies, an increasing number of patients are now undergoing genetic testing, resulting in a continuously expanding list of novel mutations. However, many patients carry noncoding genetic variants, and although emerging evidence supports their contribution to cardiac disease, their role in cardiomyopathies remains largely understudied. In this review, we summarize published studies reporting on the association of different types of noncoding variants with various types of cardiomyopathies. We focus on variants within transcriptional enhancers, promoters, intronic sites, and untranslated regions that are likely associated with cardiac disease. Given the broad nature of this topic, we provide an overview of studies that are relatively recent and have sufficient evidence to support a significant degree of causality. We believe that more research with additional validation of noncoding genetic variants will provide further mechanistic insights on the development of cardiac disease, and noncoding variants will be increasingly incorporated in future genetic screening tests.

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“…Cardiac symptoms have been more often reported during the second decade of life, especially in patients with subtypes caused by p.Q358P and p.R179T mutations, who experience DCM with minimal muscle weakness [14]. Our systematic search results in 77 patients with FKTN deficiency and cardiac manifestations, encompassing DCM, VD, DI, SI, AF, PFO, double subaortic ventricular defect, HoLV, PPS, MF and infundibular TGA (with no innominate vein) [14,185,[330][331][332][333][334][335][336][337][338][339][340][341][342][343] (Table 5, Supplementary Tables S2 and S3).…”

Section: Fktn-cdgmentioning

confidence: 99%

Metabolic Cardiomyopathies and Cardiac Defects in Inherited Disorders of Carbohydrate Metabolism: A Systematic Review

Conte,

Sam,

Lefeber

et al. 2023

IJMS

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Heart failure (HF) is a progressive chronic disease that remains a primary cause of death worldwide, affecting over 64 million patients. HF can be caused by cardiomyopathies and congenital cardiac defects with monogenic etiology. The number of genes and monogenic disorders linked to development of cardiac defects is constantly growing and includes inherited metabolic disorders (IMDs). Several IMDs affecting various metabolic pathways have been reported presenting cardiomyopathies and cardiac defects. Considering the pivotal role of sugar metabolism in cardiac tissue, including energy production, nucleic acid synthesis and glycosylation, it is not surprising that an increasing number of IMDs linked to carbohydrate metabolism are described with cardiac manifestations. In this systematic review, we offer a comprehensive overview of IMDs linked to carbohydrate metabolism presenting that present with cardiomyopathies, arrhythmogenic disorders and/or structural cardiac defects. We identified 58 IMDs presenting with cardiac complications: 3 defects of sugar/sugar-linked transporters (GLUT3, GLUT10, THTR1); 2 disorders of the pentose phosphate pathway (G6PDH, TALDO); 9 diseases of glycogen metabolism (GAA, GBE1, GDE, GYG1, GYS1, LAMP2, RBCK1, PRKAG2, G6PT1); 29 congenital disorders of glycosylation (ALG3, ALG6, ALG9, ALG12, ATP6V1A, ATP6V1E1, B3GALTL, B3GAT3, COG1, COG7, DOLK, DPM3, FKRP, FKTN, GMPPB, MPDU1, NPL, PGM1, PIGA, PIGL, PIGN, PIGO, PIGT, PIGV, PMM2, POMT1, POMT2, SRD5A3, XYLT2); 15 carbohydrate-linked lysosomal storage diseases (CTSA, GBA1, GLA, GLB1, HEXB, IDUA, IDS, SGSH, NAGLU, HGSNAT, GNS, GALNS, ARSB, GUSB, ARSK). With this systematic review we aim to raise awareness about the cardiac presentations in carbohydrate-linked IMDs and draw attention to carbohydrate-linked pathogenic mechanisms that may underlie cardiac complications.

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Whole genome sequencing delineates regulatory, copy number, and cryptic splice variants in early onset cardiomyopathy

Cited by 21 publications

References 108 publications

Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies

Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies

The role of noncoding genetic variants in cardiomyopathy

Metabolic Cardiomyopathies and Cardiac Defects in Inherited Disorders of Carbohydrate Metabolism: A Systematic Review

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