Biallelic loss of function variants in <scp><i>SYT2</i></scp> cause a treatable congenital onset presynaptic myasthenic syndrome

Donkervoort, Sandra; Mohassel, Payam; Laugwitz, Lucia; Zaki, Maha S.; Kamsteeg, Erik Jan; Maroofian, Reza; Chao, Katherine R.; Verschuuren‐Bemelmans, Corien C.; Horber, Veronka; Fock, Annemarie; McCarty, Riley M.; Jain, Minal; Biancavilla, Victoria; McMacken, Grace; Nalls, Matthew; Voermans, Nicol C.; Elbendary, Hasnaa M; Snyder, Molly; Cai, Chunyu; Lehky, Tanya; Stanley, Valentina; Iannaccone, Susan T.; Foley, A. Reghan; Lochmüller, Hanns; Gleeson, Joseph G.; Houlden, Henry; Haack, Tobias B.; Horvath, Rita; Bönnemann, Carsten G.

doi:10.1002/ajmg.a.61765

Cited by 21 publications

(25 citation statements)

References 33 publications

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“…In contrast, the very recently identified homozygous synaptotagmin‐2 variants include nonsense, frameshift and deletion mutations (Exon 3–9 deletion, V243Gfs*13, E269*, Y309*, R397Sfs*37)(Donkervoort et al., 2020; Maselli et al., 2020). These loss‐of‐function mutations are not deleterious in the heterozygous state, as carrier parents are unaffected.…”

Section: Ca2+ Sensors: Synaptotagminsmentioning

confidence: 99%

Disorders of synaptic vesicle fusion machinery

Melland

Carr

Gordon

2020

Journal of Neurochemistry

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Neuronal communication relies on the tightly controlled fusion of synaptic vesicles at nerve terminals, which results in the release of neurotransmitters with strict temporal and quantal precision. At rest, synaptic vesicle fusion is inhibited (Brunger et al., 2018). Action potential-mediated opening of voltage-gated Ca 2+ channels results in Ca 2+ influx into the nerve terminal, creating a Ca 2+ nanodomain that triggers the fusion of vesicles that are docked and primed at the plasma membrane, thereby evoking fast synchronous neurotransmitter release (Chanaday & Kavalali, 2018;Sudhof, 2013).Vesicles can additionally fuse asynchronously following evoked synchronous release and some spontaneous fusion of vesicles also occurs, though this is clamped (Chanaday & Kavalali, 2018).These processes are under exquisite regulatory control, preventing excessive neurotransmitter release and ensuring high-fidelity neuronal communication (Brunger et al., 2019;Rizo, 2018;; perturbation of this regulation can lead to a breakdown in neurotransmission.A range of presynaptic proteins are required to orchestrate these precision events. The SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complex, composed of the vesicular SNARE protein (v-SNARE) synaptobrevin and the target membrane SNARE proteins (t-SNAREs) syntaxin-1 and SNAP-25 (synaptosomal-associated protein-25), is the core fusion machinery that provides the energy required for fusion of synaptic vesicles with the plasma membrane (Weber et al., 1998). Several other key components regulate synaptic vesicle exocytosis in physiological environments (Brunger et al., 2019;Sudhof, 2014). SNARE complex assembly is orchestrated by Munc13 and Munc18, and further

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Section: Ca2+ Sensors: Synaptotagminsmentioning

confidence: 99%

Disorders of synaptic vesicle fusion machinery

Melland

Carr

Gordon

2020

Journal of Neurochemistry

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“…5 Biallelic recessive mutations, leading to SYT2 loss of function, are associated with a more severe phenotype, with features of severe motor axonal damage and NMJ dysfunction. 6,7 Heterozygous mutations in the SYT2 gene have been recently reported in patients presenting as a motor neuropathy from three unrelated families with a dominant pattern of inheritance 4,8,9 and from a case of de novo mutation without electrophysiological alterations. 10 The first reported variants were two missense mutations affecting consecutive residues within the calcium-binding pocket of the C2B domain of SYT2 protein, p.Asp307Ala, and p.Pro308Leu.…”

Section: Discussionmentioning

confidence: 99%

A new de novo SYT2 mutation presenting as distal weakness. Neuropathy or neuromuscular junction dysfunction?

Fionda

Turón-Sans

Fuentes‐Prior

et al. 2020

J Peripheral Nervous Sys

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We report the case of a patient with a clinical phenotype characterized by distal lower limb weakness and pes cavus. The electrophysiological study showed slightly reduced or normal amplitude of motor potentials, a decremental response to repetitive nerve stimulation and post-exercise facilitation. Muscle biopsy showed only mild neurogenic features. Genetic analysis included a clinical exome sequencing, followed by Sanger analysis. Three-dimensional (3D) models were generated with a

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“…To assess the accuracy of our ClinVar 90% sensitivity threshold and evaluate whether StrVCTVRE performs well on clinical data, we evaluated our method on a set of SVs identified by researchers at the Broad Institute Center for Mendelian Genomics (CMG). These SVs were recently identified through exome sequencing of patient cohorts with undiagnosed neuromuscular or retinal degeneration disorders(35–39). Clinical researchers determined these rare SVs were disease-causing or likely disease-causing.…”

Section: Resultsmentioning

confidence: 99%

StrVCTVRE: A supervised learning method to predict the pathogenicity of human genome structural variants

Sharo

Brenner

2020

Preprint

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Whole genome sequencing resolves clinical cases where standard diagnostic methods have failed. However, preliminary studies show that at least half of these cases still remain unresolved, even after whole genome sequencing. Structural variants (genomic variants larger than 50 base pairs) of uncertain significance may be the genetic cause of a portion of these unresolved cases. Historically, structural variants (SVs) have been difficult to detect with confidence from short-read sequencing. As both detection algorithms and long-read/linked-read sequencing methods become more accessible, clinical researchers will have access to thousands of reliable SVs of unknown disease relevance. We show that filtering these SVs by overlap with cataloged SVs is an imperfect solution. Innovative methods to predict the pathogenicity of these SVs will be needed to realize the full diagnostic potential of long-read sequencing. To address this emerging need, we developed StrVCTVRE (Structural Variant Classifier Trained on Variants Rare and Exonic), a classifier that can be used to distinguish pathogenic SVs from benign SVs that overlap exons. We made use of features that capture gene importance, coding region, conservation, expression, and exon structure in a random forest classifier. We found that some features, such as expression and conservation, are important but are absent from SV classification guidelines. Although databases of SVs reflect size biases from sequencing techniques, we leveraged multiple databases to construct a sizematched training set of rare, putatively benign and pathogenic SVs. In independent test sets, we found our method performs accurately across a wide SV size range, which will allow clinical researchers to eliminate nearly 60% of SVs from consideration at an elevated sensitivity of 90%.However, our method and its assessment are still constrained by a small training dataset and acquisition bias in databases of pathogenic variants. StrVCTVRE fills an empty niche in the clinical evaluation of SVs of unknown significance. We anticipate researchers will use it to

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

Cited by 21 publications

References 33 publications

Disorders of synaptic vesicle fusion machinery

Disorders of synaptic vesicle fusion machinery

A new de novo SYT2 mutation presenting as distal weakness. Neuropathy or neuromuscular junction dysfunction?

StrVCTVRE: A supervised learning method to predict the pathogenicity of human genome structural variants

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