Evidence map›Paper›PMID 38418263›Full record

ArticleEBioMedicine2024

Genome-wide enhancer-associated tandem repeats are expanded in cardiomyopathy.

Aleksandra Mitina, Mahreen Khan, Robert Lesurf, Yue Yin, Worrawat Engchuan, Omar Hamdan, Giovanna Pellecchia, Brett Trost, Ian Backstrom, Keyi Guo and 22 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in EBioMedicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.

0numbers the graph read from it
0cells of the map it votes in
7citing papers in PubMed
4.8field-weighted citation impact, top 4% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

7 citing papers in PubMed, 12 citations in OpenAlex.

  1. Article
  2. No Evidence for an Association Between DIP2B Repeat Expansion and Neurological Disease.Movement disorders : official journal of the Movement Disorder Society · 2026
    Article
  3. Article
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

32 authors at 13 institutions in 2 countries.

Aleksandra MitinaGenetics and Genome Biology, The Hospital for Sick Children; Toronto, Ontario, Canada.
Mahreen KhanGenetics and Genome Biology, The Hospital for Sick Children; Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto; Toronto, Ontario, Canada.
Robert LesurfGenetics and Genome Biology, The Hospital for Sick Children; Toronto, Ontario, Canada.
Yue YinGenetics and Genome Biology, The Hospital for Sick Children; Toronto, Ontario, Canada.
Worrawat EngchuanGenetics and Genome Biology, The Hospital for Sick Children; Toronto, Ontario, Canada; The Centre for Applied Genomics, The Hospital for Sick Children; Toronto, Ontario, Canada.
Omar HamdanGenetics and Genome Biology, The Hospital for Sick Children; Toronto, Ontario, Canada; The Centre for Applied Genomics, The Hospital for Sick Children; Toronto, Ontario, Canada.
Giovanna PellecchiaGenetics and Genome Biology, The Hospital for Sick Children; Toronto, Ontario, Canada; The Centre for Applied Genomics, The Hospital for Sick Children; Toronto, Ontario, Canada.
Brett TrostGenetics and Genome Biology, The Hospital for Sick Children; Toronto, Ontario, Canada; The Centre for Applied Genomics, The Hospital for Sick Children; Toronto, Ontario, Canada.
Ian BackstromGenetics and Genome Biology, The Hospital for Sick Children; Toronto, Ontario, Canada.
Keyi GuoGenetics and Genome Biology, The Hospital for Sick Children; Toronto, Ontario, Canada.
Linda M PallottoGenetics and Genome Biology, The Hospital for Sick Children; Toronto, Ontario, Canada.
Phoenix Hoi Lam DoongGenetics and Genome Biology, The Hospital for Sick Children; Toronto, Ontario, Canada.
Zhuozhi WangGenetics and Genome Biology, The Hospital for Sick Children; Toronto, Ontario, Canada; The Centre for Applied Genomics, The Hospital for Sick Children; Toronto, Ontario, Canada.
Thomas NalpathamkalamGenetics and Genome Biology, The Hospital for Sick Children; Toronto, Ontario, Canada; The Centre for Applied Genomics, The Hospital for Sick Children; Toronto, Ontario, Canada.
Bhooma ThiruvahindrapuramGenetics and Genome Biology, The Hospital for Sick Children; Toronto, Ontario, Canada; The Centre for Applied Genomics, The Hospital for Sick Children; Toronto, Ontario, Canada.
Tanya PapazTed Rogers Centre for Heart Research; Toronto, Ontario, Canada; Division of Cardiology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto; Toronto, Ontario, Canada.
Christopher E PearsonGenetics and Genome Biology, The Hospital for Sick Children; Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto; Toronto, Ontario, Canada.
Jiannis RagoussisMcGill Genome Centre, Victor Phillip Dahdaleh Institute of Genomic Medicine, McGill University, Montreal, Quebec, Canada.
Padmaja SubbaraoDepartment of Paediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Program in Translation Medicine & Division of Respiratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
Meghan B AzadDepartment of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada.
Stuart E TurveyDepartment of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
Piushkumar MandhaneDepartment of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
Theo J MoraesDepartment of Paediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Program in Translation Medicine & Division of Respiratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
Elinor SimonsDepartment of Pediatrics and Child Health, Section of Allergy and Clinical Immunology, University of Manitoba, Winnipeg, Manitoba, Canada; Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba, Canada.
Stephen W SchererGenetics and Genome Biology, The Hospital for Sick Children; Toronto, Ontario, Canada; The Centre for Applied Genomics, The Hospital for Sick Children; Toronto, Ontario, Canada; Department of Molecular Genetics and McLaughlin Centre, University of Toronto, Toronto, Ontario, Canada.
Jane LougheedDivision of Cardiology, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
Tapas MondalDivision of Cardiology, Department of Pediatrics, McMaster Children's Hospital, Hamilton, Ontario, Canada.
John SmytheDivision of Cardiology, Department of Pediatrics, Kingston General Hospital, Kingston, Ontario, Canada.
Luis Altamirano-DiazDivision of Cardiology, Department of Pediatrics, London Health Sciences Centre, London, Ontario, Canada.
Erwin OechslinDivision of Cardiology, Toronto Adult Congenital Heart Disease Program at Peter Munk Cardiac Centre, Department of Medicine, University Health Network, and University of Toronto, Toronto, Ontario, Canada.
Seema MitalGenetics and Genome Biology, The Hospital for Sick Children; Toronto, Ontario, Canada; Ted Rogers Centre for Heart Research; Toronto, Ontario, Canada; Division of Cardiology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto; Toronto, Ontario, Canada. Electronic address: seema.mital@sickkids.ca.
Ryan K C YuenGenetics and Genome Biology, The Hospital for Sick Children; Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto; Toronto, Ontario, Canada; The Centre for Applied Genomics, The Hospital for Sick Children; Toronto, Ontario, Canada. Electronic address: ryan.yuen@sickkids.ca.
University of Toronto · CAGreat Ormond Street Hospital · GBHospital for Sick Children · CAChildren's Hospital of Eastern Ontario · CAChildren's Hospital Research Institute of Manitoba · CAKingston General Hospital · CALondon Health Sciences Centre · CAMcGill Genome Centre · CAMcMaster Children's Hospital · CAUniversity Health Network · CAUniversity of Alberta · CAUniversity of British Columbia · CAUniversity of Manitoba · CA

Funding

Wellcome Trust
6 · The paper itself

Abstract

backgroundCardiomyopathy is a clinically and genetically heterogeneous heart condition that can lead to heart failure and sudden cardiac death in childhood. While it has a strong genetic basis, the genetic aetiology for over 50% of cardiomyopathy cases remains unknown.

methodsIn this study, we analyse the characteristics of tandem repeats from genome sequence data of unrelated individuals diagnosed with cardiomyopathy from Canada and the United Kingdom (n = 1216) and compare them to those found in the general population. We perform burden analysis to identify genomic and epigenomic features that are impacted by rare tandem repeat expansions (TREs), and enrichment analysis to identify functional pathways that are involved in the TRE-associated genes in cardiomyopathy. We use Oxford Nanopore targeted long-read sequencing to validate repeat size and methylation status of one of the most recurrent TREs. We also compare the TRE-associated genes to those that are dysregulated in the heart tissues of individuals with cardiomyopathy.

findingsWe demonstrate that tandem repeats that are rarely expanded in the general population are predominantly expanded in cardiomyopathy. We find that rare TREs are disproportionately present in constrained genes near transcriptional start sites, have high GC content, and frequently overlap active enhancer H3K27ac marks, where expansion-related DNA methylation may reduce gene expression. We demonstrate the gene silencing effect of expanded CGG tandem repeats in DIP2B through promoter hypermethylation. We show that the enhancer-associated loci are found in genes that are highly expressed in human cardiomyocytes and are differentially expressed in the left ventricle of the heart in individuals with cardiomyopathy.

interpretationOur findings highlight the underrecognized contribution of rare tandem repeat expansions to the risk of cardiomyopathy and suggest that rare TREs contribute to ∼4% of cardiomyopathy risk.

fundingGovernment of Ontario (RKCY), The Canadian Institutes of Health Research PJT 175329 (RKCY), The Azrieli Foundation (RKCY), SickKids Catalyst Scholar in Genetics (RKCY), The University of Toronto McLaughlin Centre (RKCY, SM), Ted Rogers Centre for Heart Research (SM), Data Sciences Institute at the University of Toronto (SM), The Canadian Institutes of Health Research PJT 175034 (SM), The Canadian Institutes of Health Research ENP 161429 under the frame of ERA PerMed (SM, RL), Heart and Stroke Foundation of Ontario & Robert M Freedom Chair in Cardiovascular Science (SM), Bitove Family Professorship of Adult Congenital Heart Disease (EO), Canada Foundation for Innovation (SWS, JR), Canada Research Chair (PS), Genome Canada (PS, JR), The Canadian Institutes of Health Research (PS).

Indexed as

CardiomyopathiesHeart Defects, CongenitalAdultDNA MethylationHumansNerve Tissue ProteinsOntarioTandem Repeat SequencesDIP2B protein, humanNerve Tissue ProteinsCardiomyopathy (CMP)Long-read sequencingTandem repeat expansions (TREs)Transcription regulation

Identifiers

PMID38418263
PMCPMC10944212
OpenAlexW4392204233

What Socratic holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.