Phenotypic overlap between rare disease patients and variant carriers in a large population cohort informs biological mechanisms

Abstract

The biological mechanisms giving rise to the extreme symptoms exhibited by rare disease patients are complex, heterogenous, and difficult to discern. Understanding these mechanisms is critical for developing treatments that address the underlying causes of diseases rather than merely the presenting symptoms. Moreover, the same dysfunctional biological mechanisms implicated in rare recessive diseases may also lead to milder and potentially preventable symptoms in carriers in the general population. Seizures are a common, extreme phenotype that can result from diverse and often elusive biological pathways in patients with ultrarare or undiagnosed disorders. In this pilot study, we present an approach to understand the biological pathways leading to seizures in patients from the Undiagnosed Diseases Network (UDN) by analyzing aggregated genotype and phenotype data from the UK Biobank (UKB). Specifically, we look for enriched phenotypes across UKB participants who harbor rare variants in the same gene known or suspected to be causally implicated in a UDN patient's recessively manifesting disorder. Analyzing these milder but related associated phenotypes in UKB participants can provide insight into the disease-causing molecular mechanisms at play in the rare disease UDN patient. We present six vignettes of undiagnosed patients experiencing seizures as part of their recessive genetic condition, and we discuss the potential mechanisms underlying the spectrum of symptoms associated with UKB participants to the severe presentations exhibited by UDN patients. We find that in our set of rare disease patients, seizures may result from diverse, multi-step pathways that involve multiple body systems. Analyses of large-scale population cohorts such as the UKB can be a critical tool to further our understanding of rare diseases in general.