Genomic Medicine Group
Polygenic risk in hereditary cardiopathies
Many genetic mutations have variable clinical, phenotypic expression among carrier individuals. This is often evident in families where various relatives with the same mutation may have significantly variable clinical courses. Occasionally, a relative may be completely asymptomatic (non-penetrance). Hereditary cardiac phenotypes, e.g., hypertrophic cardiomyopathies (HCM), illustrate this concept.
Our group studies the correlation of common genetic variants (polygenic score) and rare, coding, disease-causing variants (mutations in cardiac sarcomeric genes, considered to cause monogenic HCM) with clinical expression of the cardiac phenotype. We study patients (probands) and tios (probands and both parents) by exome sequencing and SNP-ome genotyping, or by whole genome sequencing, and compare genetic burdens of common variants between symptomatic and asymptomatic relatives.
Our research aims at characterizing common variants that modify clinical severity in hereditary cardiac disease. It also aims at characterizing the continuum between hereditary and non-hereditary cardiac phenotypes. Indeed, polygenic risk plays an important role in non-hereditary cardiac phenotypes. In both hereditary and non-hereditary cases, our strategy has the potential to delineate genetic subgroups depending on different sub-burdens of common variants, ie, genetic heterogeneity.
Collaborators:
Personalized therapies for ultra-rare disorders of brain development with severe epilepsy
Gene therapy is making rapid progress in treating not-too-rare genetic disorders like hemophilia or sickle cell disease, using industry-developed gene delivery systems, e.g., viral vectors, validated by double-blind randomized controlled trials (RCTs). By contrast, ultra-rare genetic disorders affecting <1/50’000 individuals, and nano-rare disorders affecting < 1/1’000’000 are not amenable to RCTs because patients are so few, and are therefore not interesting to the pharma industry for the same reason. The parallel progress in RNA therapeutics using small molecules like antisense oligonucleotides (ASO) ; in understanding cellular mechanisms of mutations and their chromosomal environment; and in the legal frame of medical research in very small cohorts (N=1) make a novel strategy possible for customized therapies in individual patients.
Developmental and Epileptic Encephalopathy (DEE) is a group of ultra- and nano-rare genetic disorders with early onset, progressive brain damage, no efficient therapy, and devastating clinical outcomes.
Our group aims at treating a pilot cohort of patients with ultra-rare DEE using existing mutation-targeting ASOs already produced and (partially) validated clinically in the USA by the n-lorem foundation, in the HUG in collaboration with the Pedi Neurology team, with the support of the espeRare foundation and HUG resources. In addition, we are developing novel ASOs in collaboration with ETH-Zurich. We will document and study the clinical course of our patients after iterative ASO treatments. In parallel to this translational research, we will derive induced pluripotent stem cells (iPSC) and design them into brain tissue in order to better characterize the molecular pathways involved in the pathophysiology of given DEEs and their responses to ASOs, in collaboration the Human Cellular Neuroscience Platform (the Ribierre Lab, Campus Biotech, Geneva).