Genetic Risk Factors of the Sneddon Syndrome

Summary

Sneddon syndrome (SS) is a rare disorder with an incidence of about 4/million/year that affects mainly young and predominantly female adults. It is characterized by recurrent strokes and livedo reticularis, a purple reticular patterning of the skin. A genetic predisposition to this disease, for which there is still no single therapy, is being discussed. Our group recently identified a homozygous nonsense mutation within epidermal growth factor repeat (EGFr) 19 of NOTCH3 in two siblings of a consanguineous family with Sneddon syndrome and pediatric stroke. In an attempt to find other possible contributing genes in Sneddon syndrome patients with adult-onset stroke, we also searched for loss-of-function variants in genes downstream of NOTCH3. In doing so, we found 2 patients carrying heterozygous loss-of-function variants in the PALLD and ANGPTL4 genes. Our results suggest that a bi-allelic loss-of-function mutation in NOTCH3 is a cause of familial Sneddon syndrome with pediatric stroke and that impaired NOTCH3 signaling is an underlying disease mechanism in general. In addition, we have identified several other promising variants that are either located in genes associated with NOTCH3 signaling or play a role in vascular function and stroke.

Based on these results, we now want to investigate whether these aforementioned variants are detectable in a larger number of patients and additionally analyze whether other genetic variants also play a role in disease pathogenesis. The goal of our project is to identify risk variants for Sneddon syndrome by whole exome sequencing and subsequent conventional sequencing....

The detection of a risk gene would be a helpful tool for the diagnosis of Sneddon syndrome and a possible basis for new therapeutic approaches.

Conditions

• Sneddon Syndrome

Interventions

GENETIC

Exome Sequencing and Sanger Sequencing

Exome Sequencing and Sanger Sequencing

Sponsors & Collaborators

• Medical University of Vienna

  collaborator OTHER

• Unidade Local de Saúde de Coimbra, EPE

  collaborator OTHER

• Instituto de Investigación Marqués de Valdecilla

  collaborator OTHER

• Technical University of Munich

  collaborator OTHER

• Alfried Krupp Krankenhaus

  collaborator OTHER

• University Hospital Tuebingen

  collaborator OTHER

• Karl Landsteiner University of Health Sciences

  lead OTHER

Eligibility

Min Age

18 Years

Max Age

80 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2021-05-12

Primary Completion

2024-11-08

Completion

2024-11-08

Countries

• Austria

Study Locations