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Published on: February 29, 2020
Spontaneous spinal CSF leaks: a rare variant exome sequencing study and functional analysis.
Cassie A Parks1, Mukti Singh2, Elizabeth Wohler1
1Department of Genetics, Johns Hopkins Medicine, Baltimore, MD, USA.
The Lancet. Neurology
|June 17, 2026
Summary
Rare FBN2 gene variants may cause spontaneous spinal cerebrospinal fluid (CSF) leaks. This finding supports FBN2 genetic testing for patients with these leaks and aids in developing new treatments.
Area of Science:
- Genetics
- Neurosurgery
- Connective Tissue Diseases
Background:
- Spontaneous spinal cerebrospinal fluid (CSF) leaks are linked to connective tissue diseases like Marfan and Loeys-Dietz syndromes, often caused by extracellular matrix gene mutations.
- Patients with spontaneous spinal CSF leaks may exhibit subtle connective tissue abnormalities, suggesting a broader genetic contribution beyond diagnosed syndromes.
- Investigating extracellular matrix protein genes is crucial for understanding the pathophysiology of spontaneous spinal CSF leaks.
Purpose of the Study:
- To elucidate the genetic basis of spontaneous spinal cerebrospinal fluid (CSF) leaks using whole-exome sequencing.
- To identify potential causative genes in individuals diagnosed with type 1b spontaneous spinal CSF leaks.
- To explore the role of extracellular matrix gene variants in the development of spontaneous spinal CSF leaks.
Main Methods:
- Retrospective review identified 42 individuals with type 1b spontaneous spinal CSF leaks.
- Whole-exome sequencing was performed on patients and compared with three independent control cohorts.
- In silico analysis predicted variant locations, in vitro assays tested protein binding, and CRISPR-Cas9 generated mouse models to assess dural integrity and CSF leak properties.
Main Results:
- Whole-exome sequencing revealed rare functional variants in the FBN2 gene in 21% of individuals with type 1b spontaneous spinal CSF leaks.
- A significant enrichment of rare functional FBN2 variants was observed in the patient cohort compared to control groups (p<0.0003).
- FBN2 variants were concentrated in specific domains, reduced cell adhesion in vitro, and mouse models with equivalent variants showed dural rupture predisposition.
Conclusions:
- Rare deleterious variants in the FBN2 gene are implicated as a potential cause of type 1b spontaneous spinal CSF leaks.
- Genetic testing for FBN2 variants should be considered in clinical practice for diagnosing spontaneous spinal CSF leaks.
- Understanding the disruption of cell adhesion to extracellular matrix proteins is key to the pathophysiology and potential therapeutic strategies for spontaneous spinal CSF leaks.
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