Evidence map›Paper›PMID 38311799›Full record

ArticleAnnals of clinical and translational neurology2024

Recurring homozygous ACTN2 variant (p.Arg506Gly) causes a recessive myopathy.

Sandra Donkervoort, Payam Mohassel, Melanie O'Leary, Devon E Bonner, Taila Hartley, Nicole Acquaye, Astrid Brull, Tahseen Mozaffar, Mario A Saporta, David A Dyment and 14 more

Registry-linked trialOpen access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Annals of clinical and translational neurology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02450851 (Clinical and Genetic Evaluation of Patients With Undiagnosed Disorders Through the Undiagnosed Diseases Network), which is not on this map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
1.2field-weighted citation impact, top 21% 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.

NCT02450851 recruitingnot on this map

Clinical and Genetic Evaluation of Patients With Undiagnosed Disorders Through the Undiagnosed Diseases Network

TypeobservationalSponsorNational Human Genome Research Institute (NHGRI)Ran2015 to 2028Enrolled20,000ConditionsGenetic Disease
3 · Its place in the literature

Who cites it

2 citing papers in PubMed, 3 citations in OpenAlex.

  1. Review
  2. 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

24 authors at 8 institutions in 3 countries.

Sandra DonkervoortNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.ORCID 0000-0001-6399-1444
Payam MohasselNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
Melanie O'LearyProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Devon E BonnerStanford Center for Undiagnosed Diseases, Stanford University, Stanford, California, USA.
Taila HartleyChildren's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Nicole AcquayeNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
Astrid BrullNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
Tahseen MozaffarDepartment of Neurology, University of California, Irvine, California, USA.
Mario A SaportaDepartment of Neurology, University of Miami Miller School of Medicine, Miami, Florida, USA.ORCID 0000-0002-7142-9993
David A DymentChildren's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.ORCID 0000-0001-9085-3602
Jacinda B SampsonStanford Center for Undiagnosed Diseases, Stanford University, Stanford, California, USA.
Sander PajusaluProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.ORCID 0000-0002-5435-0781
Christina Austin-TseProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Kyle HurthDepartment of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Julie S CohenDepartment of Neurology and Developmental Medicine, Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, Maryland, USA.
Kirsty McWalterGeneDx, Gaithersburg, Maryland, USA.
Jodi Warman-ChardonDepartment of Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada.
Amy CrunkGeneDx, Gaithersburg, Maryland, USA.
A Reghan FoleyNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.ORCID 0000-0003-2168-1119
Undiagnosed Diseases Network *
Andrew L MammenDepartment of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Matthew T WheelerStanford Center for Undiagnosed Diseases, Stanford University, Stanford, California, USA.
Anne O'Donnell-LuriaProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Carsten G BönnemannNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.ORCID 0000-0002-5930-2324
National Institutes of Health · USBroad Institute · USUniversity of Ottawa · CAStanford University · USKennedy Krieger Institute · USUniversity of California, Irvine · USUniversity of Miami · USUniversity of Southern California · US

Funding

Molecular and Clinical Manifestations of Matrix and Aggregate MyopathiesZIANS003129 · NINDS · NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE · PI BÖNNEMANN, CARSTEN · 2011 to 2025
$52.8M
Joint Center for Mendelian GenomicsUM1HG008900 · NHGRI · BROAD INSTITUTE, INC. · PI O'DONNELL-LURIA, ANNE, REHM, HEIDI L · 2016 to 2020
$16.5M
What comes next? Engaging stakeholders in governance of participant data and relationships during the sunset of large genomic medicine research initiativesU01HG010218 · NHGRI · STANFORD UNIVERSITY · PI ASHLEY, EUAN A, BERNSTEIN, JONATHAN ADAM · 2018 to 2022
$6.3M
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
UCLA clinical site for the investigation of undiagnosed disordersU01NS134356 · NINDS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI MARTINEZ-AGOSTO, JULIAN, NELSON, STANLEY F. · 2023 to 2023
$936k
The role of TGF beta pathway dysregulation in pathogenesis of collagen VI-related muscular dystrophyK22NS104135 · NINDS · JOHNS HOPKINS UNIVERSITY · PI MOHASSEL, PAYAM · 2022 to 2024
$666k
NHGRI NIH HHS R01 HG009141NHGRI NIH HHS U01 HG010218NHGRI NIH HHS UM1 HG008900NINDS NIH HHS K22 NS104135NINDS NIH HHS U01 NS134356
6 · The paper itself

Abstract

objectiveACTN2, encoding alpha-actinin-2, is essential for cardiac and skeletal muscle sarcomeric function. ACTN2 variants are a known cause of cardiomyopathy without skeletal muscle involvement. Recently, specific dominant monoallelic variants were reported as a rare cause of core myopathy of variable clinical onset, although the pathomechanism remains to be elucidated. The possibility of a recessively inherited ACTN2-myopathy has also been proposed in a single series.

methodsWe provide clinical, imaging, and histological characterization of a series of patients with a novel biallelic ACTN2 variant.

resultsWe report seven patients from five families with a recurring biallelic variant in ACTN2: c.1516A>G (p.Arg506Gly), all manifesting with a consistent phenotype of asymmetric, progressive, proximal, and distal lower extremity predominant muscle weakness. None of the patients have cardiomyopathy or respiratory insufficiency. Notably, all patients report Palestinian ethnicity, suggesting a possible founder ACTN2 variant, which was confirmed through haplotype analysis in two families. Muscle biopsies reveal an underlying myopathic process with disruption of the intermyofibrillar architecture, Type I fiber predominance and atrophy. MRI of the lower extremities demonstrate a distinct pattern of asymmetric muscle involvement with selective involvement of the hamstrings and adductors in the thigh, and anterior tibial group and soleus in the lower leg. Using an in vitro splicing assay, we show that c.1516A>G ACTN2 does not impair normal splicing.

interpretationThis series further establishes ACTN2 as a muscle disease gene, now also including variants with a recessive inheritance mode, and expands the clinical spectrum of actinopathies to adult-onset progressive muscle disease.

Indexed as

CardiomyopathiesMuscular DiseasesActininAdultHumansMuscle, SkeletalPhenotypeActininACTN2 protein, human

Identifiers

PMID38311799
PMCPMC10963296
OpenAlexW4391537253

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Registered trials

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.