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, Riley M. McCarty, Minal S. Jain, Victoria Biancavilla, Grace McMacken, Matthew Nalls, Nicol C. Voermans, Hasnaa M. Elbendary, Molly Snyder, Chunyu Cai, Tanya J. LehkyValentina Stanley, Susan T. Iannaccone, A. Reghan Foley, Hanns Lochmüller, Joseph Gleeson, Henry Houlden, Tobias B. Haack, Rita Horvath, Carsten G. Bönnemann

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)2272-2283
Number of pages12
JournalAmerican Journal of Medical Genetics, Part A
Issue number10
StatePublished - Oct 1 2020


  • SYT2
  • congenital myasthenic syndrome
  • neuromuscular junction
  • presynaptic CMS
  • synaptotagmins

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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