Evidence map›Paper›PMID 34002542›Full record

ArticleAnnals of clinical and translational neurology2021

Loss-of-function variants in K

Ming S Soh, Richard D Bagnall, Mark F Bennett, Lauren E Bleakley, Erlina S Mohamed Syazwan, A Marie Phillips, Mathew D F Chiam, Chaseley E McKenzie, Michael Hildebrand, Douglas Crompton and 5 more

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

Article in Annals of clinical and translational neurology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.

0numbers the graph read from it
0cells of the map it votes in
9citing papers in PubMed
1.7field-weighted citation impact, top 17% 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

9 citing papers in PubMed, 16 citations in OpenAlex.

  1. Article
  2. Review
  3. Article
  4. Review
  5. Sudden Death-AssociatedbioRxiv : the preprint server for biology · 2025
    Article
  6. Article
  7. KBrain communications · 2025
    Article
  8. Proceedings of the National Academy of Sciences of the United States of America · 2023
    Article
  9. The ERG1 KFrontiers in molecular neuroscience · 2022
    Review
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

15 authors at 3 institutions in 1 country.

Ming S SohThe Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.ORCID 0000-0002-5689-2082
Richard D BagnallAgnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, NSW, Australia.
Mark F BennettPopulation Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.ORCID 0000-0002-3561-6804
Lauren E BleakleyThe Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
Erlina S Mohamed SyazwanThe Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
A Marie PhillipsThe Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
Mathew D F ChiamThe Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
Chaseley E McKenzieThe Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
Michael HildebrandEpilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC, Australia.
Douglas CromptonEpilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC, Australia.
Melanie BahloPopulation Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
Christopher SemsarianAgnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, NSW, Australia.
Ingrid E SchefferThe Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
Samuel F BerkovicEpilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC, Australia.ORCID 0000-0003-4580-841X
Christopher A ReidThe Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
The University of Melbourne · AURoyal Children's Hospital · AUThe University of Sydney · AU

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

objectiveTo compare the frequency and impact on the channel function of KCNH2 variants in SUDEP patients with epilepsy controls comprising patients older than 50 years, a group with low SUDEP risk, and establish loss-of-function KCNH2 variants as predictive biomarkers of SUDEP risk.

methodsWe searched for KCNH2 variants with a minor allele frequency of <5%. Functional analysis in Xenopus laevis oocytes was performed for all KCNH2 variants identified.

resultsKCNH2 variants were found in 11.1% (10/90) of SUDEP individuals compared to 6.0% (20/332) of epilepsy controls (p = 0.11). Loss-of-function KCNH2 variants, defined as causing >20% reduction in maximal amplitude, were observed in 8.9% (8/90) SUDEP patients compared to 3.3% (11/332) epilepsy controls suggesting about threefold enrichment (nominal p = 0.04). KCNH2 variants that did not change channel function occurred at a similar frequency in SUDEP (2.2%; 2/90) and epilepsy control (2.7%; 9/332) cohorts (p > 0.99). Rare KCNH2 variants (<1% allele frequency) associated with greater loss of function and an ~11-fold enrichment in the SUDEP cohort (nominal p = 0.03). In silico tools were unable to predict the impact of a variant on function highlighting the need for electrophysiological analysis.

interpretationThese data show that loss-of-function KCNH2 variants are enriched in SUDEP patients when compared to an epilepsy population older than 50 years, suggesting that cardiac mechanisms contribute to SUDEP risk. We propose that genetic screening in combination with functional analysis can identify loss-of-function KCNH2 variants that could act as biomarkers of an individual's SUDEP risk.

Indexed as

AdolescentAdultAgedAged, 80 and overAnimalsBiomarkersChildCohort StudiesEpilepsyERG1 Potassium ChannelFemaleGenetic VariationHumansInfantMaleMiddle AgedBiomarkersERG1 Potassium ChannelKCNH2 protein, human

Identifiers

PMID34002542
PMCPMC8283159
OpenAlexW3161615466

What OpenQuestion holds

Textmetadata
LicenceCC BY
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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.