Whole Sequencing of Most Prevalent Dilated Cardiomyopathy-Causing Genes as a Molecular Strategy to Improve Molecular
Louis Januel1, Valérie Chanavat1,2, Pierre-Antoine Rollat-Farnier3
1Laboratoire de Cardiogénétique Moléculaire, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, Lyon, France.
Insights
Deep intronic variants in BAG3, DSP, FLNC, and LMNA genes are not a common cause of dilated cardiomyopathy (DCM). This study found that whole gene sequencing of these genes does not significantly improve DCM molecular diagnosis rates.
Area of Science:
- Genetics
- Cardiology
- Molecular Biology
Background:
- Dilated cardiomyopathy (DCM) is a primary cause of heart failure, frequently linked to genetic factors.
- Truncating variants in TTN, BAG3, DSP, FLNC, and LMNA are established DCM causes.
- The role of deep intronic variants in these genes remains less understood.
Purpose of the Study:
- To investigate the prevalence of deep intronic pathogenic variants in BAG3, DSP, FLNC, and LMNA in DCM patients.
- To assess if whole intronic sequencing of these genes enhances molecular diagnosis in DCM.
Main Methods:
- Next-generation sequencing (NGS) was used for whole gene sequencing of BAG3, DSP, FLNC, and LMNA.
- The study included 95 DCM patients negative for causative point mutations after a 48-gene panel NGS.
- Intronic regions were analyzed for splice-defect-causing variants.
Main Results:
- The implemented NGS workflow did not alter the molecular diagnosis for any patient in the cohort.
- Deep intronic variants in the studied genes did not account for a significant proportion of unexplained DCM cases.
- Whole intronic sequencing of BAG3, DSP, FLNC, and LMNA did not improve diagnostic yield for DCM.
Conclusions:
- Deep intronic variants in BAG3, DSP, FLNC, and LMNA are unlikely to be a major genetic cause of DCM.
- Current diagnostic strategies for DCM do not need to routinely include whole intronic sequencing of these specific genes.
- Focusing on exonic regions and known pathogenic variants remains the most efficient approach for DCM molecular diagnosis.
Abstract:
Dilated cardiomyopathy (DCM) is the most common form of cardiomyopathy and one of the most common causes of heart failure. TTN-truncating variants represent the most common cause of DCM. Similarly, among other prevalent DCM-causing genes, truncating variants were also frequently detected in BAG3, DSP, FLNC, and LMNA. For these four genes, the current study aims to determine the prevalence of deep intronic pathogenic variants that could lead to splice defects. A next-generation sequencing (NGS) workflow based on whole gene sequencing of BAG3, DSP, FLNC, and LMNA of a cohort of 95 DCM patients, for whom no putatively causative point mutations were identified after NGS of a panel of 48 cardiomyopathy-causing genes, was thus performed. Our approach did not lead us to reconsider the molecular diagnosis of any patient of the cohort. This study suggests that deep splice mutations do not account for a significant proportion of DCM cases. In contrast with MYBPC3 in hypertrophic cardiomyopathy cases, NGS of BAG3, DSP, FLNC, and LMNA whole intronic sequences would not significantly improve the efficiency of molecular diagnosis of DCM probands.
