To identify genetic modifiers by means of whole-exome (or targeted-genome) sequencing of members of this founder population. Secondarily, to establish a comprehensive genotype-phenotype correlation, focussing on clinical and cellular…
ID
Source
Brief title
Condition
- Cardiac arrhythmias
- Gastrointestinal motility and defaecation conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Identification of novel, modifier genes relevant for VT/progressive cardiac
conduction disease/SCD.
Secondary outcome
Syncope, documented (non)sustained VT, (aborted) cardiac arrest.
Background summary
Investigating the genetic susceptibility of sudden cardiac death (SCD) has been
challenging due to limited sample sizes, heterogeneity of the arrhythmogenic
substrate, and the difficulty of obtaining phenotypic information after sudden
cardiac arrest. We have identified a large Dutch population carrying a
SCN5A-founder mutation with a very divergent clinical presentation. Individuals
from different family clusters exhibit predominant phenotypes of long-QT type 3
or conduction delay (including Brugada syndrome), suggesting gain- or
loss-of-function of SCN5A respectively. Carriers may remain without symptoms or
suffer ventricular arrhythmias (VA) and SCD. This founder population provides a
unique opportunity to identify common genetic variants or genetic modifiers
responsible for the divergent expression.
Study objective
To identify genetic modifiers by means of whole-exome (or targeted-genome)
sequencing of members of this founder population. Secondarily, to establish a
comprehensive genotype-phenotype correlation, focussing on clinical and
cellular electrophysiological characteristics.
Study design
Prospective, nested-case control design (2 years). Thereafter, prospective
cohort study (10 years).
Intervention
A. Whole-exome (or targeted-genome) sequencing on isolated DNA.
B. Dermal biopsy to harvest fibroblasts in order to generate patient-specific
iPSCs and subsequently iPSC-derived cardiomyocytes (in a subset of individuals).
C. Gastro-intestinal questionnaire.
Study burden and risks
Whole-exome sequencing may lead to the identification of incidental genetic
findings, which can impose psychological burden for the individual and his/her
relatives. A dermal biopsy causes a small scar, but leads to bleeding and
infectious complications in less than 1%. A gastrointestinal questionnaire
might be experienced as an invasion of subject's privacy.
P. Debyelaan 25
Maastricht 6202AZ
NL
P. Debyelaan 25
Maastricht 6202AZ
NL
Listed location countries
Age
Inclusion criteria
Inclusion criteria *SCN5A-delPhe1617 positive group*
In order to be eligible for the study population, a subject must meet all of the following criteria:
- Age >= 18 years.
- Heterozygous or homozygous presence of SCN5A-delPhe1617.
- Confirmed kinship to the Founder Group by haplotype analysis using
predefined microsatellite markers.
- Written informed consent.;Inclusion criteria *SCN5A-delPhe1617 negative group*
In order to be eligible to participate in the SCN5A-delPhe1617 negative group, a control subject must meet all of the following criteria:
- Age >= 18 years.
- Non SCN5A-delPhe1617 genotype.
- Confirmed kinship to the Founder Group by haplotype analysis using
predefined microsatellite markers.
- Written informed consent.;Inclusion criteria *Spouse*
- Age >= 18 years.
- Biological father or mother of SCN5A-delPhe1617 positive subject
participating to the Worm Study.
- Written informed consent.
Exclusion criteria
Exclusion criteria *SCN5A-delPhe1617 positive and negative group*
A potential subject who meets any of the following criteria will be excluded from participation in this study:
- Age < 18 years.
- No kinship to founder population.
- Inability or refusal to give informed consent.;Exclusion criteria *spouse*
A potential subject who meets any of the following criteria will be excluded from participation as spouse:
- Age < 18 years.
- Not a biological parent to an individual linked to the SCN5A-delF1617
founder family.
- Inability or refusal to give informed consent.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| ClinicalTrials.gov | NCT02014961 |
| CCMO | NL51018.068.14 |