CMT-SYT2

SYT2 | 2014

What Is CMT-SYT2?

CMT-SYT2 is a type of CMT caused by autosomal dominant mutations in the SYT2 gene. This gene provides instructions for making synaptotagmin-2, a protein that helps regulate the release of neurotransmitters at the connections between nerves and muscles. Mutations in the SYT2 gene disrupt this function, leading to impaired nerve signal transmission.

CMT-SYT2 is autosomal dominant, meaning that just one of the gene’s two copies needs a mutation to cause this subtype.

Clinical Features

The age of symptom onset in CMT-SYT2 is variable, ranging from childhood to adulthood. Symptoms typically begin in the lower extremities and progress over time to involve the upper limbs. Nerve conduction studies usually show somewhat slowed conduction velocities and reduced amplitudes, consistent with an axonal form of CMT.

CMT-SYT2 symptoms may include:

  • Weakness in the feet and lower legs
  • Muscle atrophy
  • Foot drop
  • Reduced or absent reflexes
  • Reduced sensation
  • A steppage-style walking pattern
  • Foot deformities, including high arches, and hammertoes (clawed toes)
  • Progressive involvement of the hands and forearms
  • Difficulty with fine motor skills and manual dexterity
  • Additional symptoms not listed here

Disease Course

CMT-SYT2 shows wide variability in severity and progression. Some individuals are mildly affected, while others develop a more severe disease. Disease progression is generally slow, and life expectancy is not reduced.

Clinical Basics

Subtype
CMT-SYT2

Classification
Unclassified Subtypes

Neuropathy Type
Axonal

Inheritance Pattern
autosomal dominant

Genetic Context

HGNC-Approved Gene Symbol
SYT2

Gene Full Name
Synaptotagmin 2

Chromosome
1q32.1

Zygosity of Responsible Variant
Heterozygous

Variant Mechanism

Dominant-Negative

Details

Mechanistic basis:
Dominant-negative

Confidence:
High

Prediction:
The literature predicts a dominant-negative mechanism for CMT-SYT2: heterozygous C2B-domain missense variants in SYT2 (for example p.Pro308Leu, p.Asp307Ala) produce a mutant synaptotagmin-2 that incorporates into the release machinery and interferes with calcium-triggered synaptic vesicle exocytosis, impairing presynaptic neurotransmission. Because the mutant sensor is built into the release machinery, added wild-type protein is not predicted to rescue. Biallelic null alleles instead cause a separate recessive presynaptic myasthenic syndrome, a loss-of-function phenotype distinct from this dominant missense mechanism.

Rationale:
Mutant synaptotagmin-2 from the heterozygous C2B-domain missense variants incorporates into the release machinery and disrupts calcium-triggered vesicle exocytosis, which points to a dominant-negative effect rather than loss of function. That biallelic nulls instead cause a separate recessive presynaptic myasthenic syndrome supports the distinction, and because the mutant sensor is built into the release apparatus, wild-type add-back is not predicted to rescue.

ClinVar Pathogenic Variants

View CMT-SYT2 ClinVar Variants

ClinGen Curation

View SYT2 ClinGen Curation

SYT2 OMIM Entry

SYT2 OMIM

More Info

CMT-SYT2 Research Opportunity

CMT Natural History Study

Original Discovery Publication

Publication Title

Synaptotagmin 2 Mutations Cause an Autosomal-Dominant Form of Lambert-Eaton Myasthenic Syndrome and Nonprogressive Motor Neuropathy

Authors

Herrmann, D. N., Horvath, R., Sowden, J. E., Gonzalez, M., Sanchez-Mejias, A., Guan, Z., Whittaker, R. G., Almodovar, J. L., Lane, M., Bansagi, B., Pyle, A., Boczonadi, V., Lochmüller, H., Griffin, H., Chinnery, P. F., Lloyd, T. E., Littleton, J. T., & Züchner, S.

Publication Date
September 4, 2014

DOI
10.10CHCHD1016/j.ajhg.2014.08.007

Updated: July 18, 2026 | By: K. Raymond

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