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Prevalence and Clinical Consequences of Multiple Pathogenic Variants in Dilated Cardiomyopathy
Sophie L V M Stroeks1,2, Ida G Lunde3,4, Debby M E I Hellebrekers5
1Cardiovascular Research Institute Maastricht (CARIM); S.L.V.M.S., T.H.M.H., A.G.R., M.A.S., E.A.V.J., S.R.B.H., J.A.J.V.), Maastricht University, Maastricht, Netherlands.
Insights
A small percentage of dilated cardiomyopathy patients have multiple gene variants, but a second variant did not worsen disease in this study. This finding is important for family screening and genetic counseling.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Genetic Disease Modeling
Background:
- Dilated cardiomyopathy (DCM) is increasingly recognized as a genetic disorder potentially influenced by multiple gene variants.
- The prevalence and impact of compound pathogenic variants in DCM remain poorly understood.
- This study addresses knowledge gaps regarding the role of multiple variants in DCM onset and progression.
Purpose of the Study:
- To investigate the prevalence of multiple likely pathogenic/pathogenic (LP/P) variants in a DCM cohort.
- To evaluate the clinical course and disease severity associated with multiple LP/P variants in DCM patients.
- To develop and analyze a mouse model for studying the effects of compound genetic variants in DCM.
Main Methods:
- Cardiac phenotyping and genotyping of 685 consecutive DCM patients.
- Systematic collection of clinical information from the DCM cohort.
- Creation and longitudinal phenotypic analysis of a mouse model with compound heterozygous digenic variants (LMNA/titin deletion A-band).
Main Results:
- 19.1% of genotyped DCM patients carried at least one likely pathogenic/pathogenic (LP/P) variant.
- 2.3% of patients with an LP/P variant also had a second LP/P variant in a different gene.
- Patients with one or two LP/P variants exhibited comparable disease onset, severity, and clinical course; mouse models showed no significant functional differences but indicated cardiac stress.
Conclusions:
- In this cohort, 2.3% of DCM patients with an LP/P variant possessed a second LP/P variant.
- The presence of a second LP/P variant did not appear to influence the disease course in patients or the mouse model.
- Identifying a second LP/P variant holds significance for genetic counseling and screening of relatives.
Background:
Dilated cardiomyopathy (DCM) was considered a monogenetic disease that can be caused by over 60 genes. Evidence suggests that the combination of multiple pathogenic variants leads to greater disease severity and earlier onset. So far, not much is known about the prevalence and disease course of multiple pathogenic variants in patients with DCM. To gain insight into these knowledge gaps, we (1) systematically collected clinical information from a well-characterized DCM cohort and (2) created a mouse model.
Methods:
Complete cardiac phenotyping and genotyping was performed in 685 patients with consecutive DCM. Compound heterozygous digenic (LMNA [lamin]/titin deletion A-band) with monogenic (LMNA/wild-type) and wild-type/wild-type mice were created and phenotypically followed over time.
Results:
One hundred thirty-one likely pathogenic/pathogenic (LP/P) variants in robust DCM-associated genes were found in 685 patients with DCM (19.1%) genotyped for the robust genes. Three of the 131 patients had a second LP/P variant (2.3%). These 3 patients had a comparable disease onset, disease severity, and clinical course to patients with DCM with one LP/P. The LMNA/Titin deletion A-band mice had no functional differences compared with the LMNA/wild-type mice after 40 weeks of follow-up, although RNA-sequencing suggests increased cardiac stress and sarcomere insufficiency in the LMNA/Titin deletion A-band mice.
Conclusions:
In this study population, 2.3% of patients with DCM with one LP/P also have a second LP/P in a different gene. Although the second LP/P does not seem to influence the disease course of DCM in patients and mice, the finding of a second LP/P can be of importance to their relatives.
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