Evidence map›Paper›PMID 40468825›Full record

ArticleAnnals of neurology2025

HCN2-Associated Neurodevelopmental Disorders: Data from Patients and Xenopus Cell Models.

Clara Houdayer, A Marie Phillips, Marie Chabbert, Jennifer Bourreau, Reza Maroofian, Henry Houlden, Kay Richards, Nebal Waill Saadi, Eliška Dad'ová, Patrick Van Bogaert and 43 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Annals of neurology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
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

3 citing papers in PubMed.

  1. Article
  2. Review
  3. 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

53 authors.

Clara Houdayer *Department of Medical Genetics, Angers University Hospital, Angers, France.
A Marie Phillips *Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia.
Marie ChabbertUniversity of Angers, INSERM, CNRS, MITOVASC, Equipe CarMe, SFR ICAT, Angers, France.
Jennifer BourreauUniversity of Angers, INSERM, CNRS, MITOVASC, Equipe CarMe, SFR ICAT, Angers, France.ORCID 0009-0007-7239-6373
Reza MaroofianDepartment of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, University College London, London, UK.
Henry HouldenDepartment of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, University College London, London, UK.
Kay RichardsFlorey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia.
Nebal Waill SaadiCollege of Medicine, University of Baghdad, Baghdad, Iraq.
Eliška Dad'ováUniversity of Angers, INSERM, CNRS, MITOVASC, Equipe CarMe, SFR ICAT, Angers, France.
Patrick Van BogaertDepartment of Pediatric Neurology, Angers University Hospital, Angers, France.
Mailys RupinDepartment of Pediatric Neurology, Angers University Hospital, Angers, France.
Boris KerenDepartment of Genetics, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne University, Paris, France.
Perrine CharlesDepartment of Genetics, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne University, Paris, France.
Thomas SmolUniversity of Lille, CHU Lille, ULR7364 - RADEME, Institute of Medical Genetics, Lille, France.
Audrey RiquetDepartment of Pediatric Neurology, Saint Vincent de Paul Hospital, GHICL, Lille, France.
Lynn PaisProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Anne O'Donnell-LuriaProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Grace E VanNoyProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Allan BayatDepartment for Genetics and Personalized Medicine, Danish Epilepsy Centre, Dianalund, Denmark.
Rikke S MøllerDepartment for Genetics and Personalized Medicine, Danish Epilepsy Centre, Dianalund, Denmark.ORCID 0000-0002-9664-1448
Kern OlofssonDepartment of Paediatrics, Danish Epilepsy Centre Filadelfia, Dianalund, Denmark.
Rami Abou JamraInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
Steffen SyrbeDivision of Paediatric Epileptology, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
Majed DasoukiDepartment of Medical Genetics, Genomics and Personalized Health at AdventHealth-Orlando, Orlando, FL, USA.
Laurie H SeaverDivision of Medical Genetics, Corewell Health Helen DeVos Children's Hospital, Grand Rapids, MI, USA.
Jennifer A SullivanDepartment of Pediatrics - Medical Genetics, Duke University, Durham, NC, USA.
Vandana ShashiDepartment of Pediatrics - Medical Genetics, Duke University, Durham, NC, USA.
Fowzan S AlkurayaDepartment of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.ORCID 0000-0003-4158-341X
Alexis F PossPediatrics-Clinical Genetics and Metabolism, School of Medicine, University of Colorado-Anschutz Medical Campus, Aurora, CO, USA.
J Edward SpencePediatrics-Clinical Genetics and Metabolism, School of Medicine, University of Colorado-Anschutz Medical Campus, Aurora, CO, USA.
Rhonda E SchnurGeneDx, Gaithersburg, MD, USA.
Ian C ForsterFlorey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia.
Chaseley E MckenzieFlorey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia.
Cas SimonsMurdoch Children's Research Institute, Melbourne, Victoria, Australia.
Min WangMurdoch Children's Research Institute, Melbourne, Victoria, Australia.
Penny SnellMurdoch Children's Research Institute, Melbourne, Victoria, Australia.
Kavitha KothurDepartment of Neuropediatrics, The Children's Hospital at Westmead, Sydney Children's Hospital Network, Sydney, New South Wales, Australia.
Michael BuckleyNew South Wales Health Pathology Randwick Genomics Laboratory, Sydney, New South Wales, Australia.
Tony RoscioliNew South Wales Health Pathology Randwick Genomics Laboratory, Sydney, New South Wales, Australia.
Noha ElserafyNew South Wales Health Pathology Randwick Genomics Laboratory, Sydney, New South Wales, Australia.
Benjamin DauriatDepartment of Medical Genetics and Cytogenetics, Limoges University Hospital, Limoges, France.
Vincent ProcaccioDepartment of Medical Genetics, Angers University Hospital, Angers, France.
Daniel HenrionUniversity of Angers, INSERM, CNRS, MITOVASC, Equipe CarMe, SFR ICAT, Angers, France.
Guy LenaersDepartment of Medical Genetics, Angers University Hospital, Angers, France.
Estelle ColinDepartment of Medical Genetics, Angers University Hospital, Angers, France.
Nienke E VerbeekDepartment of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Koen L Van GassenDepartment of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Claire LegendreUniversity of Angers, INSERM, CNRS, MITOVASC, Equipe CarMe, SFR ICAT, Angers, France.
Dominique BonneauDepartment of Medical Genetics, Angers University Hospital, Angers, France.
Christopher A ReidFlorey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia.
Katherine B HowellMurdoch Children's Research Institute, Melbourne, Victoria, Australia.ORCID 0000-0002-5469-8411
Alban Ziegler *Department of Medical Genetics, Angers University Hospital, Angers, France.
Christian Legros *University of Angers, INSERM, CNRS, MITOVASC, Equipe CarMe, SFR ICAT, Angers, France.ORCID 0000-0002-3346-7059

Funding

Joint Center for Mendelian GenomicsUM1HG008900 · NHGRI · BROAD INSTITUTE, INC. · PI O'DONNELL-LURIA, ANNE, REHM, HEIDI L · 2016 to 2020
$16.5M
Broad Institute Mendelian Genomic Research CenterU01HG011755 · NHGRI · BROAD INSTITUTE, INC. · PI Anne O'Donnell-Luria, MICHAEL E TALKOWSKI · 2021 to 2026
$14.6M
A powerful web-based discovery platform for rare disease geneticsR01HG009141 · NHGRI · BROAD INSTITUTE, INC. · PI QUINLAN, AARON R, REHM, HEIDI L · 2017 to 2020
$2.9M
NHGRI NIH HHS R01 HG009141NHGRI NIH HHS U01 HG011755NHGRI NIH HHS UM1 HG008900
6 · The paper itself

Abstract

objectiveWe aimed to characterize the phenotypic spectrum and functional consequences associated with variants in HCN2, encoding for the hyperpolarization-activated cyclic nucleotide (HCN) gated channel 2.

methodsGeneMatcher facilitated the recruitment of 21 individuals with HCN2 variants from 15 unrelated families, carrying HCN2 variants. In vitro functional studies were performed by electrophysiology with Xenopus laevis oocytes and membrane trafficking was investigated in HEK cells by confocal imaging. Structural 3D-analysis of the HCN2 variants was performed.

resultsThe phenotypic spectrum included developmental delay/intellectual disability (DD/ID, 17/21), epilepsy (10/21), language disorders (16/21), movement disorders (12/21), and axial hypotonia (10/21). Thirteen pathogenic variants (12 new and 1 already described) were identified: 11 missense (8 monoallelic and 3 biallelic), 1 recurrent inframe deletion (monoallelic), and 1 frameshift (biallelic). Functional analysis of p.(Arg324His) variant showed a strong increase of HCN2 conductance, whereas p.(Ala363Val) and p.(Met374Leu) exhibited dominant negative effects. The p.(Leu377His), p.(Pro493Leu), and p.(Gly587Asp) variants rendered HCN2 electrophysiologically silent and impaired membrane trafficking. Structural 3D-analysis revealed that, except for p.(Arg324His), all variants altered HCN2 stability.

interpretationOur findings broadened the HCN2 disease clinical spectrum to include DD/ID with or without epilepsy. Functional analysis in cellular models reveal that pathogenic HCN2 variants can cause either loss-of-function or gain-of-function, providing critical information for the development of targeted therapies for HCN2-related disorders. ANN NEUROL 2025;98:573-589.

Indexed as

Hyperpolarization-Activated Cyclic Nucleotide-Gated ChannelsNeurodevelopmental DisordersPotassium ChannelsAdolescentAdultAnimalsChildChild, PreschoolFemaleHEK293 CellsHumansInfantMaleOocytesXenopus laevisYoung AdultHCN2 protein, humanHyperpolarization-Activated Cyclic Nucleotide-Gated ChannelsPotassium Channels

Identifiers

PMID40468825
PMCPMC12226820

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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.