Evidence map›Paper›PMID 32776697›Full record

ArticleAmerican journal of medical genetics. Part A2020

Biallelic loss of function variants in SYT2 cause a treatable congenital onset presynaptic myasthenic syndrome.

Sandra Donkervoort, Payam Mohassel, Lucia Laugwitz, Maha S Zaki, Erik-Jan Kamsteeg, Reza Maroofian, Katherine R Chao, Corien C Verschuuren-Bemelmans, Veronka Horber, Annemarie J M Fock and 19 more

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PubMed Full text at PMC Publisher
In one paragraph

Article in American journal of medical genetics. Part A, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.

0numbers the graph read from it
0cells of the map it votes in
16citing papers in PubMed
2.2field-weighted citation impact, top 13% 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

16 citing papers in PubMed, 27 citations in OpenAlex.

  1. Review
  2. Muscles (Basel, Switzerland) · 2026
    Review
  3. Review
  4. Article
  5. Article
  6. Article
  7. Article
  8. Review
  9. Review
  10. Calcium Sensors of Neurotransmitter Release.Advances in neurobiology · 2023
    Article
  11. Observational
  12. Centers for Mendelian Genomics: A decade of facilitating gene discovery.Genetics in medicine : official journal of the American College of Medical Genetics · 2022
    Review
  13. Article
  14. Review
  15. Function of Drosophila Synaptotagmins in membrane trafficking at synapses.Cellular and molecular life sciences : CMLS · 2021
    Review
  16. 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

29 authors at 15 institutions in 6 countries.

Sandra DonkervoortNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.ORCID https://orcid.org/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.
Lucia LaugwitzInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Maha S ZakiClinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
Erik-Jan KamsteegDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Reza MaroofianDepartment of Neuromuscular Disorders, University College London Institute of Neurology, London, UK.
Katherine R ChaoCenter for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Corien C Verschuuren-BemelmansDepartment of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Veronka HorberDepartment of Paediatric Neurology, University Children's Hospital, Tübingen, Germany.
Annemarie J M FockDepartment of Neurology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Riley M McCartyNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
Minal S JainRehabilitation Medicine Department, Clinical Research Center, National Institutes of Health, Bethesda, Maryland, USA.
Victoria BiancavillaRehabilitation Medicine Department, Clinical Research Center, National Institutes of Health, Bethesda, Maryland, USA.
Grace McMackenDepartment of Neurosciences, Royal Victoria Hospital, Belfast, UK.
Matthew NallsNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
Nicol C VoermansDepartment of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands.
Hasnaa M ElbendaryClinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
Molly SnyderDepartment of Neurology, Children's Health, Dallas, Texas, USA.
Chunyu CaiDepartment of Pathology, UT Southwestern Medical Center, Dallas, Texas, USA.
Tanya J LehkyEMG Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
Valentina StanleyLaboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, University of California, San Diego, California, USA.
Susan T IannacconeDepartment of Pediatrics, UT Southwestern Medical Center, Dallas, Texas, USA.
A Reghan FoleyNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
Hanns LochmüllerDepartment of Neuropediatrics and Muscle Disorders, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany.
Joseph GleesonLaboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, University of California, San Diego, California, USA.
Henry HouldenDepartment of Neuromuscular Disorders, University College London Institute of Neurology, London, UK.
Tobias B HaackInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Rita HorvathDepartment of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
Carsten G BönnemannNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
National Institutes of Health · USChildren’s Institute · USNational Human Genome Research Institute · USNational Institutes of Health Clinical Center · USRadboud University Nijmegen · NLSouthwestern Medical Center · USUniversity Children's Hospital Tübingen · DEUniversity College London · GBUniversity Medical Center Groningen · NLBroad Institute · USMedical City Children's Hospital · USUniversity of Cambridge · GBUniversity of Ottawa · CAUniversity of Tübingen · DEUniversity of Ulster · GB

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
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
Canadian Institutes of Health Research Foundation Grant CIHR FDN-167281European Research Council 309548Intramural NIH HHS ZIA NS003129Medical Research Council G1000848Medical Research Council MR/N010035/1Medical Research Council MR/N025431/1Medical Research Council MR/N025431/2NHGRI NIH HHS R01 HG009141NHGRI NIH HHS UM1 HG008900Wellcome TrustWellcome Trust Investigator 109915/Z/15/ZWellcome Trust Pathfinder Scheme 201064/Z/16/Z
6 · The paper itself

Abstract

Synaptotagmins are integral synaptic vesicle membrane proteins that function as calcium sensors and regulate neurotransmitter release at the presynaptic nerve terminal. Synaptotagmin-2 (SYT2), is the major isoform expressed at the neuromuscular junction. Recently, dominant missense variants in SYT2 have been reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment. These variants are thought to have a dominant-negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated. Here we report seven patients of five families, with biallelic loss of function variants in SYT2, clinically manifesting with a remarkably consistent phenotype of severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings were consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in three patients showed clinical improvement with increased strength and function. This series further establishes SYT2 as a CMS-disease gene and expands its clinical and genetic spectrum to include recessive loss-of-function variants, manifesting as a severe congenital onset presynaptic CMS with potential treatment implications.

Indexed as

Genetic Predisposition to DiseaseAdolescentChildChild, PreschoolFemaleHumansMaleMuscle HypotoniaMuscle WeaknessMutation, MissenseMyasthenic Syndromes, CongenitalPedigreePhenotypeSynaptic TransmissionSynaptotagmin IISynaptotagmin IISYT2 protein, humancongenital myasthenic syndromeneuromuscular junctionpresynaptic CMSsynaptotagminsSYT2

Identifiers

PMID32776697
PMCPMC7959540
OpenAlexW3048669180

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Registered trials

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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.