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Rare variants in the LMNA gene encoding nuclear lamin A/C are causal for more than a dozen diverse mendelian disorders. Defining the functional consequences of LMNA variants has been challenging given the pleiotropy of gene functions and potential pathogenic mechanisms. It is essential to develop trustworthy, scalable and rapidly deployable in vitro assays of function to enable timely assessment of missense variants that are being uncovered by high throughout next-generation sequencing.
Genetic variants that influence susceptibility to COVID-19 have recently been identified. In this manuscript, we identify and discuss some of the ethical and practical issues raised by these studies. We first outline the ethical case for providing COVID-19 susceptibility testing to healthcare workers, as well as highlighting risks associated with privacy and discrimination. We then argue that the existence of genetically susceptible individuals has implications for the ethical conduct of COVID-19 human challenge trials. Finally, we discuss the ethical issues that could arise from other COVID-19 host–genome interactions, including the prospect of personalized vaccines.
Greater clarity on the nature of clinical utility is desirable. Of itself it may not bring about greater use of tests, including WGS (whole-genome sequencing), not least because clinical utility studies when performed may not confirm predicted changes in patient outcome. The notion that single “pivotal” clinical utility studies will achieve uptake needs to be questioned and that the evidence base for tests is likely to rely on patchworks of imperfect evidence embraced.
In this work, we explore whether raw genetic data generated during sequencing ought to be returned to a pediatric patient and/or their parents/guardians. We identify the principles used by various professional societies in their guidelines on the return of secondary findings and apply them to this new context. We conclude that since each situation is unique, decisions should be made on a case-by-case basis according to the best interests of the child.
