Evidence map›Paper›PMID 31813956›Full record

ArticleHuman molecular genetics2020

Functional genomics and gene-environment interaction highlight the complexity of congenital heart disease caused by Notch pathway variants.

Gavin Chapman, Julie L M Moreau, Eddie I P, Justin O Szot, Kavitha R Iyer, Hongjun Shi, Michelle X Yam, Victoria C O'Reilly, Annabelle Enriquez, Joelene A Greasby and 12 more

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

Article in Human molecular genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
30citing papers in PubMed, 1 pooled it
2.2field-weighted citation impact, top 11% 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

30 citing papers in PubMed, 1 synthesis or guideline pooled it, 50 citations in OpenAlex.

  1. Pooled it
  2. Article
  3. Article
  4. Article
  5. Review
  6. Article
  7. Article
  8. Genetic and Environmental Contributors To Congenital Heart Disease.Current treatment options in cardiovascular medicine · 2025
    Review
  9. Case Report: A novelFrontiers in pediatrics · 2025
    Article
  10. Article
  11. Article
  12. Review
  13. Review
  14. Review
  15. Review
  16. Identification ofDiagnostics (Basel, Switzerland) · 2022
    Article
  17. Molecular genetic mechanisms of congenital heart disease.Current opinion in genetics & development · 2022
    Review
  18. Observational
  19. Article
  20. Article
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

22 authors at 4 institutions in 3 countries.

Gavin ChapmanVictor Chang Cardiac Research Institute, Sydney, NSW, 2010, Australia.
Julie L M MoreauVictor Chang Cardiac Research Institute, Sydney, NSW, 2010, Australia.
Eddie I PVictor Chang Cardiac Research Institute, Sydney, NSW, 2010, Australia.
Justin O SzotVictor Chang Cardiac Research Institute, Sydney, NSW, 2010, Australia.
Kavitha R IyerVictor Chang Cardiac Research Institute, Sydney, NSW, 2010, Australia.
Hongjun ShiVictor Chang Cardiac Research Institute, Sydney, NSW, 2010, Australia.
Michelle X YamVictor Chang Cardiac Research Institute, Sydney, NSW, 2010, Australia.
Victoria C O'ReillyVictor Chang Cardiac Research Institute, Sydney, NSW, 2010, Australia.
Annabelle EnriquezVictor Chang Cardiac Research Institute, Sydney, NSW, 2010, Australia.
Joelene A GreasbyVictor Chang Cardiac Research Institute, Sydney, NSW, 2010, Australia.
Dimuthu AlankarageVictor Chang Cardiac Research Institute, Sydney, NSW, 2010, Australia.
Ella M M A MartinVictor Chang Cardiac Research Institute, Sydney, NSW, 2010, Australia.
Bernadette C HannaHunter Genetics, John Hunter Hospital, Newcastle, NSW, 2298, Australia.
Matthew EdwardsHunter Genetics, John Hunter Hospital, Newcastle, NSW, 2298, Australia.
Steven MongerVictor Chang Cardiac Research Institute, Sydney, NSW, 2010, Australia.
Gillian M BlueVictor Chang Cardiac Research Institute, Sydney, NSW, 2010, Australia.
David S WinlawVictor Chang Cardiac Research Institute, Sydney, NSW, 2010, Australia.
Helen E RitchieSchool of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, 2006, Australia.
Stuart M GrieveSydney Translational Imaging Laboratory, Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia.
Eleni GiannoulatouVictor Chang Cardiac Research Institute, Sydney, NSW, 2010, Australia.
Duncan B SparrowDepartment of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom.
Sally L DunwoodieVictor Chang Cardiac Research Institute, Sydney, NSW, 2010, Australia.
Victor Chang Cardiac Research Institute · AUThe University of Sydney · AUJohn Hunter Hospital · AUUniversity of Oxford · GB

Funding

British Heart Foundation FS/17/55/33100
6 · The paper itself

Abstract

Congenital heart disease (CHD) is the most common birth defect and brings with it significant mortality and morbidity. The application of exome and genome sequencing has greatly improved the rate of genetic diagnosis for CHD but the cause in the majority of cases remains uncertain. It is clear that genetics, as well as environmental influences, play roles in the aetiology of CHD. Here we address both these aspects of causation with respect to the Notch signalling pathway. In our CHD cohort, variants in core Notch pathway genes account for 20% of those that cause disease, a rate that did not increase with the inclusion of genes of the broader Notch pathway and its regulators. This is reinforced by case-control burden analysis where variants in Notch pathway genes are enriched in CHD patients. This enrichment is due to variation in NOTCH1. Functional analysis of some novel missense NOTCH1 and DLL4 variants in cultured cells demonstrate reduced signalling activity, allowing variant reclassification. Although loss-of-function variants in DLL4 are known to cause Adams-Oliver syndrome, this is the first report of a hypomorphic DLL4 allele as a cause of isolated CHD. Finally, we demonstrate a gene-environment interaction in mouse embryos between Notch1 heterozygosity and low oxygen- or anti-arrhythmic drug-induced gestational hypoxia, resulting in an increased incidence of heart defects. This implies that exposure to environmental insults such as hypoxia could explain variable expressivity and penetrance of observed CHD in families carrying Notch pathway variants.

Indexed as

Gene-Environment InteractionGenetic Predisposition to DiseaseMutationAnimalsCase-Control StudiesExome SequencingFemaleGenomicsHeart Defects, CongenitalHumansMaleMiceMice, Inbred C57BLMice, KnockoutReceptor, Notch1Receptor, Notch1

Identifiers

PMID31813956
PMCPMC7068028
OpenAlexW2984297742

What OpenQuestion holds

Textmetadata
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 OpenQuestion graph.