CMT-SEPTIN9

SEPTIN9 | 2020

What Is CMT-SEPT9?

CMT-SEPT9 is a type of CMT caused by autosomal dominant mutations in the SEPT9 gene. This gene provides instructions for making septin-9, a protein that contributes to the structural organization and division of peripheral nerve cells. Mutations in the SEPT9 gene disrupt this function, leading to impaired nerve signal transmission.

CMT-SEPT9 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-SEPT9 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 slowed conduction velocities, consistent with a demyelinating form of CMT.

CMT-SEPT9 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-SEPT9 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-SEPTIN9

Classification
Unclassified Subtypes

Neuropathy Type
Demyelinating

Inheritance Pattern
autosomal dominant

Genetic Context

HGNC-Approved Gene Symbol
SEPTIN9

Gene Full Name
Septin 9

Chromosome
17q25.3

Zygosity of Responsible Variant
Heterozygous

Variant Mechanism

Toxic Gain of Function (GoF)

Details

Mechanistic basis:
Dosage

Confidence:
Medium

Prediction:
The literature predicts a gain-of-function (dosage) mechanism for SEPTIN9-associated CMT: intragenic SEPTIN9 duplications increase gene dosage, so disease is driven by an extra normal-sequence copy rather than by loss of one, and added wild-type protein is not predicted to rescue. Clustered N-terminal missense alleles are also reported and could instead disrupt the hetero-oligomeric septin filament, a dominant-negative possibility that holds confidence at medium.

Rationale:
Intragenic SEPTIN9 duplications raise gene dosage, and disease from an extra normal-sequence copy cannot arise through simple loss: added wild-type is not predicted to rescue, which points to a gain-of-function dosage effect over haploinsufficiency. The clustered N-terminal missense alleles could instead disrupt the hetero-oligomeric septin filament, a dominant-negative contribution that leaves the mechanism genuinely unresolved and holds confidence at medium.

ClinVar Pathogenic Variants

View CMT-SEPTIN9 ClinVar Variants

ClinGen Curation

View SEPTIN9 ClinGen Curation

SEPTIN9 OMIM Entry

SEPTIN9 OMIM

More Info

CMT-SEPTIN9 Research Opportunity

CMT Natural History Study

Original Discovery Publication

Publication Title

Identification of a Rare SEPT9 Variant in a Family with Autosomal Dominant Charcot-Marie-Tooth Disease

Authors

Grosse, G. M., Bauer, C., Kopp, B., Schrader, C., & Osmanovic, A.

Publication Date
March 2, 2020

DOI
10.1186/s12881-020-0984-7

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

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