Investigation of inherited cardiovascular disorders in the Anabaptist communities
Muggenthaler, M. M. A. (2019). Investigation of inherited cardiovascular disorders in the Anabaptist communities. (Unpublished Doctoral thesis, St. Georges, University of London)
Abstract
The work described in this thesis involves the detailed investigation of two inherited cardiovascular conditions identified amongst the Anabaptist communities of Ohio (USA) as part of a long-running clinical-genetics program, called ‘Windows of Hope’.
The Anabaptist communities in North America form closed founder populations with a homogenous lifestyle, large families and extensive genealogical records enabling the construction of extensive family trees. These and other factors greatly empower the investigation of genetic disorders in the community. The first series of studies relate to a novel autosomal recessive syndrome consistent of cleft lip and palate and cor triatriatum sinister observed in multiple Amish families. The project aims were to clinically characterise the phenotype, to define the genetic basis of the condition, and to investigate the molecular function of the molecule identified. Genomic studies (genome-wide autozygosity mapping and exome sequencing) defined an Amish founder gene variant in the HYAL2 gene, encoding hyaluronidase 2, as the likely cause of this condition. Subsequent functional and mouse model studies confirmed dramatic reductions in HYAL2 protein levels associated with gene mutation and revealed overlapping phenotypical outcomes in Hyal2 knock-out mice which mirror the human condition. These findings highlight the vital role hyaluronidase enzymes play in both human and mouse development and reveal a previously unrecognised pathway involved in the pathogenesis of cor triatriatum sinister and orofacial clefting, which may ultimately be amenable to treatment strategies.
The second disorder investigated is a form of hypertrophic cardiomyopathy (HCM) associated with a splice site variant (resulting in frameshift) in the MYBPC3 gene, encoding myosin binding protein C3. HCM is the most common inherited cardiovascular disease worldwide, and affected individuals show extreme variations in severity of phenotype, even when carrying the same causative genetic variant. The mechanisms underlying the phenotypic variation are unknown, but genetic modifying factors are likely involved impacting on expression of the phenotype. This project comprises the clinical characterisation of the largest cohort of individuals carrying the same HCM pathogenic variant described to date. Detailed molecular studies identified potential genetic modifiers of the phenotype using a combined approach of whole exome sequence analysis, genome wide SNP data analyses, and gene-splicing transcript outcomes. This study provided important insight into the expression of the phenotype, confirmed the significant phenotypic variation amongst individuals harbouring the same HCM causing genetic variant observed in other HCM cohorts, and identified putative genetic modifiers contributing to an improved understanding of the development of the variable phenotype in MYBPC3-associated HCM, which may ultimately enable more accurate prognostication and personalised treatment.
An additional and overarching objective of the project, in keeping with the wider aims of the Windows of Hope studies, was the translation of the beneficial findings of this research into direct clinical benefits to the families and communities involved.
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