New recessive mutations in SYT2 causing severe presynaptic congenital myasthenic syndromes
Abstract
Objective To report the identification of 2 new homozygous recessive mutations in the synaptotagmin 2 (SYT2) gene as the genetic cause of severe and early presynaptic forms of congenital myasthenic syndromes (CMSs). Methods Next-generation sequencing identified new homozygous intronic and frameshift mutations in the SYT2 gene as a likely cause of presynaptic CMS. We describe the clinical and electromyographic patient phenotypes, perform ex vivo splicing analyses to characterize the effect of the intronic mutation on exon splicing, and analyze the functional impact of this variation at the neuromuscular junction (NMJ). Results The 2 infants presented a similar clinical phenotype evoking first a congenital myopathy characterized by muscle weakness and hypotonia. Next-generation sequencing allowed to the identification of 1 homozygous intronic mutation c.465+1G>A in patient 1 and another homozygous frameshift mutation c.328_331dup in patient 2, located respectively in the 5′ splice donor site of SYT2 intron 4 and in exon 3. Functional studies of the intronic mutation validated the abolition of the splice donor site of exon 4 leading to its skipping. In-frame skipping of exon 4 that encodes part of the C2A calcium-binding domain of SYT2 is associated with a loss-of-function effect resulting in a decrease of neurotransmitter release and severe pre- and postsynaptic NMJ defects. Conclusions This study identifies new homozygous recessive SYT2 mutations as the underlying cause of severe and early presynaptic form of CMS expanding the genetic spectrum of recessive SYT2-related CMS associated with defects in neurotransmitter release.
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BibTeX
@article{bauche2026recessive,
title = {{New recessive mutations in SYT2 causing severe presynaptic congenital myasthenic syndromes}},
author = {Stéphanie Bauché and Alain Sureau and Damien Sternberg and John Rendu and Céline Buon and Julien Messéant and Myriam Boëx and Denis Furling and Julien Fauré and Xénia Latypova and Antoinette Bernabe Gelot and Michèle Mayer and Pierre Mary and Sandra Whalen and Emmanuel Fournier and Isabelle Cloix and Ganaelle Remerand and Fanny Laffargue and Marie-Christine Nougues and Bertrand Fontaine and Bruno Eymard and Arnaud Isapof and Laure Strochlic},
journal = {Neurology Genetics},
year = {2026},
month = oct,
doi = {10.1212/nxg.0000000000000534},
url = {https://hal.science/hal-05788938v1},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - New recessive mutations in SYT2 causing severe presynaptic congenital myasthenic syndromes
AU - Stéphanie Bauché
AU - Alain Sureau
AU - Damien Sternberg
AU - John Rendu
AU - Céline Buon
AU - Julien Messéant
AU - Myriam Boëx
AU - Denis Furling
AU - Julien Fauré
AU - Xénia Latypova
AU - Antoinette Bernabe Gelot
AU - Michèle Mayer
AU - Pierre Mary
AU - Sandra Whalen
AU - Emmanuel Fournier
AU - Isabelle Cloix
AU - Ganaelle Remerand
AU - Fanny Laffargue
AU - Marie-Christine Nougues
AU - Bertrand Fontaine
AU - Bruno Eymard
AU - Arnaud Isapof
AU - Laure Strochlic
PY - 2026
DA - 2026/10/09
JO - Neurology Genetics
DO - 10.1212/nxg.0000000000000534
UR - https://hal.science/hal-05788938v1
AB - Objective To report the identification of 2 new homozygous recessive mutations in the synaptotagmin 2 (SYT2) gene as the genetic cause of severe and early presynaptic forms of congenital myasthenic syndromes (CMSs). Methods Next-generation sequencing identified new homozygous intronic and frameshift mutations in the SYT2 gene as a likely cause of presynaptic CMS. We describe the clinical and electromyographic patient phenotypes, perform ex vivo splicing analyses to characterize the effect of the intronic mutation on exon splicing, and analyze the functional impact of this variation at the neuromuscular junction (NMJ). Results The 2 infants presented a similar clinical phenotype evoking first a congenital myopathy characterized by muscle weakness and hypotonia. Next-generation sequencing allowed to the identification of 1 homozygous intronic mutation c.465+1G>A in patient 1 and another homozygous frameshift mutation c.328_331dup in patient 2, located respectively in the 5′ splice donor site of SYT2 intron 4 and in exon 3. Functional studies of the intronic mutation validated the abolition of the splice donor site of exon 4 leading to its skipping. In-frame skipping of exon 4 that encodes part of the C2A calcium-binding domain of SYT2 is associated with a loss-of-function effect resulting in a decrease of neurotransmitter release and severe pre- and postsynaptic NMJ defects. Conclusions This study identifies new homozygous recessive SYT2 mutations as the underlying cause of severe and early presynaptic form of CMS expanding the genetic spectrum of recessive SYT2-related CMS associated with defects in neurotransmitter release.
SN - 2376-7839
ER -