Genetic Risk Factors of the Sneddon Syndrome

A Study and Biobank to Identify Genetic Risk Factors in the Pathogenesis of the Sneddon Syndrome

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.

Study Overview

• Status: Completed
• Conditions: Sneddon Syndrome
• Intervention / Treatment: Genetic: Exome Sequencing and Sanger Sequencing

• Study Type: Observational
• Enrollment (Actual): 40

Contacts and Locations

Study Locations

• Austria
  • St. Pölten, Austria, 3100
    • Karl Landsteiner University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Patients with Sneddon syndrome based on standard diagnosis criteria of Sneddon syndrome

Description

Inclusion Criteria:

• Subjects must be at least 18years old.
• Affected subjects must have been clinically diagnosed with Sneddon Syndrome. When analyzing families with Sneddon syndrome, healthy family members and participants with only symptoms of the skin will be included if consent is obtained.Frau Elli Greisenegger
• Unaffected subjects or subjects with symptoms restricted to the skin must have at least one family member with the clinical diagnosis Sneddon syndrome participating in the study.
• Subjects must be able to communicate well with the investigator, to understand the requirements of the study, as well as to understand and sign thewritten informed consent(= informed consent approved by thelocalethics committee).

Exclusion Criteria:

- Subjects who are unable to communicate well with the investigator, to understand the requirements of the study, as well as to understand and sign the written informed consent, are not eligible for inclusion in this study.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Patients with Sneddon; Whole exome sequencing	Genetic: Exome Sequencing and Sanger Sequencing; Exome Sequencing and Sanger Sequencing

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
potential genetic risk factor for Sneddon Syndrome present	occurence of genetic variants in genes associated with Sneddon Syndrome	18 months

Collaborators and Investigators

• Sponsor: Karl Landsteiner University of Health Sciences
• Collaborators: Medical University of Vienna; University Hospital Tuebingen; Technical University of Munich; Instituto de Investigación Marqués de Valdecilla; Centro Hospitalar e Universitário de Coimbra, E.P.E.; Alfried Krupp Krankenhaus

Study record dates

Study Major Dates

• Study Start (Actual): May 12, 2021
• Primary Completion (Actual): November 8, 2024
• Study Completion (Actual): November 8, 2024

Study Registration Dates

• First Submitted: September 8, 2021
• First Submitted That Met QC Criteria: February 21, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 21, 2025
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Disease; Skin Diseases; Skin Diseases, Vascular; Syndrome; Sneddon Syndrome
• Other Study ID Numbers: 1016/2021

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No