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Genetic basis of familial dilated cardiomyopathy patients undergoing heart transplantation
Sofia Cuenca1, Maria J Ruiz-Cano2, Juan Ramón Gimeno-Blanes3
1Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain.
Insights
Genetic testing using next-generation sequencing (NGS) identified the cause of dilated cardiomyopathy (DCM) in most heart transplant (HTx) patients. Familial studies were crucial for confirming genetic mutations in dilated cardiomyopathy (DCM) cases undergoing heart transplantation (HTx).
Area of Science:
- Cardiovascular Genetics
- Genomic Medicine
- Transplantation Science
Background:
- Dilated cardiomyopathy (DCM) is a leading indication for heart transplantation (HTx).
- The genetic underpinnings of DCM in HTx recipients remain incompletely understood.
- Characterizing the genetic basis of familial DCM in this population is essential.
Purpose of the Study:
- To investigate the genetic etiology of familial DCM in patients undergoing heart transplantation.
- To evaluate the diagnostic yield of next-generation sequencing (NGS) for identifying DCM-causing mutations in this cohort.
Main Methods:
- Fifty-two patients with familial DCM who underwent HTx were analyzed using a 126-gene NGS panel.
- Genetic variants were initially classified as pathogenic or variants of uncertain significance (VUS).
- Familial cosegregation studies were performed to confirm variant pathogenicity.
Main Results:
- Next-generation sequencing (NGS) identified pathogenic mutations in 40% of patients initially.
- Subsequent familial evaluation confirmed causative mutations in 73% of all studied patients.
- Variants of uncertain significance (VUS) were reclassified, highlighting the importance of family studies.
Conclusions:
- The genetic landscape of familial DCM in heart transplant recipients is diverse, involving numerous genes.
- NGS combined with detailed familial studies effectively identifies causative mutations in most familial DCM cases.
- Familial segregation analysis is critical for accurate pathogenicity determination of genetic variants.
Background:
Dilated cardiomyopathy (DCM) is the most frequent cause of heart transplantation (HTx). The genetic basis of DCM among patients undergoing HTx has been poorly characterized. We sought to determine the genetic basis of familial DCM HTx and to establish the yield of modern next generation sequencing (NGS) technologies in this setting.
Methods:
Fifty-two heart-transplanted patients due to familial DCM underwent NGS genetic evaluation with a panel of 126 genes related to cardiac conditions (59 associated with DCM). Genetic variants were initially classified as pathogenic mutations or as variants of uncertain significance (VUS). Final pathogenicity status was determined by familial cosegregation studies.
Results:
Initially, 24 pathogenic mutations were found in 21 patients (40%); 25 patients (48%) carried 19 VUS and 6 (12%) did not show any genetic variant. Familial evaluation of 220 relatives from 36 of the 46 families with genetic variants confirmed pathogenicity in 14 patients and allowed reclassification of VUS as pathogenic in 17 patients, and as non-pathogenic in 3 cases. At the end of the study, the DCM-causing mutation was identified in 38 patients (73%) and 5 patients (10%) harbored only VUS. No genetic variants were identified in 9 cases (17%).
Conclusions:
The genetic spectrum of familial DCM patients undergoing HTx is heterogeneous and involves multiple genes. NGS technology plus detailed familial studies allow identification of causative mutations in the vast majority of familial DCM cases. Detailed familial studies remain critical to determine the pathogenicity of underlying genetic defects in a substantial number of cases.
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