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  • Titill er á ensku Discovery and Analyses of Pathogenic Variants in Explanted Hearts from Primary Cardiomyopathy Patients
  • Bakkalár
  • Útdráttur er á ensku

    Introduction: Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are disorders of the myocardium that affect the structure and function of the heart. The primary aim of this study was to discover damaging genetic variants in myocardial tissue from patients with DCM or HCM who underwent heart transplantation.
    Methods: Whole exome sequencing was performed on myocardial tissue from 103 explanted hearts; 80 DCM, 13 HCM and 10 donor hearts that were not implanted. Sanger sequencing was performed to confirm the loss of function variants in genes known to be linked to cardiomyopathy. RNA sequencing was conducted to confirm copy number variation deletions detected in the cohort. Burden analysis was performed by comparing the frequency of variants found in the study cohort to the frequency in the population database gnomAD.
    Results: Loss of function variants, deleterious missense variants, or copy number variation deletions, collectively described as damaging variants, were identified in cardiomyopathy genes in 45 of all 103 samples (43.7%). Damaging variants were identified in 37 of 80 DCM samples (46.3%), 5 of 13 HCM samples (38.4%), and 3 of 10 control samples (30.0%). Analyses of variants detected in control samples showed no definitive pathogenic variants. All the 28 loss of function variants in cardiomyopathy genes found in the cardiomyopathy cases were confirmed by Sanger sequencing. Two copy number variation deletions were detected and confirmed in the cohort, both in TTN. Burden analyses showed that the genes MDK, UBE2I, and MATR3, all highly expressed in the heart but not previously linked to cardiomyopathy, had a higher frequency of variants in the DCM cohort compared to the reference population with genome-wide significance (p  2.5E-06).
    Conclusions: The frequency of damaging variants that are likely pathogenic is higher in DCM cases in this cohort compared to previous studies. This could indicate that patients who develop end-stage DCM are more likely to have a genetic cause for their disease. It is also possible that more variants are found by sequencing DNA extracted from cardiac tissue versus blood. The proportion of pathogenic variants in the HCM group is slightly lower than expected in a HCM cohort which may be explained by the low number of HCM patients in the study cohort.

  • 17.5.2019

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