Identifying novel genetic factors predisposing to inherited cardiac disorders
Principal Investigator
Name
Connie Bezzina
Degrees
Ph.D.
Institution
Amsterdam Universitair Medisch Centrum
Position Title
Professor
Email
About this CDAS Project
Study
PLCO
(Learn more about this study)
Project ID
PLCO-1507
Initial CDAS Request Approval
Mar 25, 2024
Title
Identifying novel genetic factors predisposing to inherited cardiac disorders
Summary
Introduction
Inherited cardiac disorders are a group of heart conditions that can be passed from generation to
generation due to specific gene variants. They encompass a range of conditions including
hypertrophic cardiomyopathy (HCM) and Long QT Syndrome (LQTS).
HCM is a condition characterized by the thickening of the heart muscle, especially the ventricles,
which can disrupt normal cardiac function and lead to serious complications such as arrhythmia,
heart failure, or sudden cardiac death.
On the other hand, LQTS is an arrhythmic disorder which may trigger a sudden fainting spell, seizure,
or in severe cases, sudden death. The name 'Long QT' refers to an abnormality seen on an
electrocardiogram (ECG), which is a representation of the electrical activity of the heart. In patients
with LQTS, the QT interval, which represents the time it takes for the heart muscle to contract and
then recover, is longer than usual.
Aim of the project
In the last 20 years, the Mendelian inheritance paradigm led to the discovery of several genes that
can underlie inherited cardiac disorders. Despite these discoveries, however, an important issue still
hinders the implementation of genetic testing in clinical care: Large phenotypic variability often
exists among individuals harbouring the same Mendelian genetic defect. We hypothesize that the
inheritance of additional genetic variants (i.e., inheritance of ‘modifier genes’ alongside the
Mendelian defect) underlies phenotypic variability in these patients.
To further investigate this, we are performing Genome Wide Association Studies (GWAS) to search
for disease susceptibility and severity genes in inherited cardiac disorders. We have already gathered
case samples from multiple European countries. However, to ensure the reliability and validity of our
study, we also need control samples matched by the country they are from.
We are looking for control samples that are done on the GSA (Global Screening Array) chip, as all our
cases are as well. This array is a broad-coverage genotyping tool that has been widely used in
population-scale genomic studies. Additionally, we would require basic demographics (i.e. sex and
age) as well to correct for in our analysis.
In conclusion, while significant strides have been made in understanding the genetics of inherited
cardiac disorders, GWAS may improve our understanding of these conditions and ultimately help
those affected by them. International collaboration is needed to reach the numbers (cases and
controls) necessary for such studies to obtain reliable results
Inherited cardiac disorders are a group of heart conditions that can be passed from generation to
generation due to specific gene variants. They encompass a range of conditions including
hypertrophic cardiomyopathy (HCM) and Long QT Syndrome (LQTS).
HCM is a condition characterized by the thickening of the heart muscle, especially the ventricles,
which can disrupt normal cardiac function and lead to serious complications such as arrhythmia,
heart failure, or sudden cardiac death.
On the other hand, LQTS is an arrhythmic disorder which may trigger a sudden fainting spell, seizure,
or in severe cases, sudden death. The name 'Long QT' refers to an abnormality seen on an
electrocardiogram (ECG), which is a representation of the electrical activity of the heart. In patients
with LQTS, the QT interval, which represents the time it takes for the heart muscle to contract and
then recover, is longer than usual.
Aim of the project
In the last 20 years, the Mendelian inheritance paradigm led to the discovery of several genes that
can underlie inherited cardiac disorders. Despite these discoveries, however, an important issue still
hinders the implementation of genetic testing in clinical care: Large phenotypic variability often
exists among individuals harbouring the same Mendelian genetic defect. We hypothesize that the
inheritance of additional genetic variants (i.e., inheritance of ‘modifier genes’ alongside the
Mendelian defect) underlies phenotypic variability in these patients.
To further investigate this, we are performing Genome Wide Association Studies (GWAS) to search
for disease susceptibility and severity genes in inherited cardiac disorders. We have already gathered
case samples from multiple European countries. However, to ensure the reliability and validity of our
study, we also need control samples matched by the country they are from.
We are looking for control samples that are done on the GSA (Global Screening Array) chip, as all our
cases are as well. This array is a broad-coverage genotyping tool that has been widely used in
population-scale genomic studies. Additionally, we would require basic demographics (i.e. sex and
age) as well to correct for in our analysis.
In conclusion, while significant strides have been made in understanding the genetics of inherited
cardiac disorders, GWAS may improve our understanding of these conditions and ultimately help
those affected by them. International collaboration is needed to reach the numbers (cases and
controls) necessary for such studies to obtain reliable results
Aims
- To find disease susceptibility and disease modifying common genetic variants through Genome Wide Association Studies
- To find novel clinical parameters to discrimitate symptomatic from asymptomatic patients
- To find rare genetic variants involved in disease susceptibility or as disease modifiers though WHole Genome Sequencing or Whole Exome Sequencing
Collaborators
Christian Krijger Juárez - Amsterdam UMC
Najim Lahrouchi - Amsterdam UMC
Roddy Walsh - Amsterdam UMC
Sean Jurgens - Amsterdam UMC