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Title: Genetic, genotype and imaging studies of hypertrophic cardiomyopathy
Author: Walsh, Roddy
ISNI:       0000 0004 7223 5503
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2018
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Hypertrophic cardiomyopathy (HCM) is an inherited disorder of cardiac muscle whose genetic basis has been investigated for over 25 years. However, considerable uncertainty remains about the genetic aetiology of HCM, including the validity of implicated genes, the effective analysis of variants detected in patients and the interpretation and follow-up of genetic testing results. Here, genetic data from large cardiomyopathy cohorts and 60,706 individuals of the Exome Aggregation Consortium (ExAC) was used to reassess the role of genes implicated in HCM and other cardiomyopathies. A significant excess of rare variation in cases over ExAC, along with supporting genetic evidence, was observed for only three non-sarcomeric genes, causative in < 2% of cases, with moderate evidence of association for five other non-sarcomeric genes. This data suggests HCM genetic testing should be limited to 16 valid genes, including the eight core sarcomeric genes. Variant analysis in sarcomeric genes has struggled to balance accuracy and sensitivity, with clinical genetics guidelines overly conservative in assigning pathogenicity. Here, by utilising stringent frequency thresholds and case-control analyses, classes of variants with high prior probabilities of pathogenicity (≥95%) were identified in five sarcomeric genes. By adapting current variant interpretation guidelines, the yield of pathogenic variants in HCM cases was increased by 14%, corresponding to 4% of all tested HCM patients. Building on this enhanced understanding of HCM genetics, genotype-phenotype analyses demonstrated that cases without causative variants follow a distinct clinical course, with later presentation, less pronounced fibrosis and markedly different hypertrophy patterns - lesser maximum wall thickness (19.85mm vs 18.51mm, p=0.006) but greater overall left ventricular mass (101.2g/m2 vs 88.6g/m2, p < 0.001). These results posit an informative interpretation of negative tests, indicating a benign prognosis and low likelihood of familial transmission. Taken together, these data redefine the genetic architecture of cardiomyopathy and significantly enhance the interpretability of HCM genetic testing.
Supervisor: Cook, Stuart ; Barton, Paul Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral