Worm Study: Modifier Genes in Sudden Cardiac Death

Study Overview
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Brief Summary
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Quest for modifier genes associated with ventricular arrhythmias in presence of a cardiac sodium channel gene (SCN5A-delPhe1617) mutation.

Detailed Description
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In a large Dutch SCN5A founder population with malignant ventricular arrhythmias, the investigators aim to identify genetic modifiers by means of whole-exome sequencing and to establish a comprehensive genotype-phenotype correlation, focussing on clinical and cellular electrophysiological characteristics and neurocardiac modulation.

Official Title
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Worm Study: Identification of Modifier Genes in a Unique Founder Population With Sudden Cardiac Death

Conditions
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Brugada Syndrome, Long QT Syndrome 3

Intervention / Treatment
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* Procedure: Dermal biopsy
* Behavioral: Gastro-intestinal questionnaire
* Genetic: Whole-exome sequencing


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (mutation carrier group): Age ≥ 18 years. Heterozygous or homozygous carriership of SCN5A-delPhe1617. Confirmed kinship to the founder population by haplotype analysis using predefined microsatellite markers. Written informed consent. Inclusion Criteria (non-mutation carrier group): Age ≥ 18 years. Non SCN5A-delPhe1617 genotype. Confirmed kinship to the Founder Group by haplotype analysis using predefined microsatellite marker. Written informed consent. Inclusion criteria Spouse Group Age ≥ 18 years. Biological parent of SCN5A-delPhe1617 positive subject participating to the Worm Study, and not belonging to study group 1 or 2. Written informed consent. Exclusion Criteria: Age ≥ 18 years. Biological parent of SCN5A-delPhe1617 positive subject participating to the Worm Study, and not belonging to study group 1 or 2. Written informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Mutation Carriers<br>Whole-exome sequencing (WES) Dermal biopsy Gastro-intestinal questionnaire | Procedure: Dermal biopsy<br>* Skin biopsy<br>Behavioral: Gastro-intestinal questionnaire<br>* Pagi-Sym, Bristol Stool Chart, gastrointestinal symptom rating scale (GSRS)<br>Genetic: Whole-exome sequencing<br>* Whole-exome sequencing (WES)<br>|
| Placebo Comparator: Non-Mutation Carriers<br>Whole-exome sequencing (WES) Gastro-intestinal questionnaire | Behavioral: Gastro-intestinal questionnaire<br>* Pagi-Sym, Bristol Stool Chart, gastrointestinal symptom rating scale (GSRS)<br>Genetic: Whole-exome sequencing<br>* Whole-exome sequencing (WES)<br>|
| Other: Spouse<br>Whole-exome sequencing (WES) 12-Lead ECG | Genetic: Whole-exome sequencing<br>* Whole-exome sequencing (WES)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in genetic profile (e.g. modifier genes) between mutation carriers expressing different phenotypes and non-mutation carriers. |  | two years |