NGS for Diagnosing Inherited Bleeding, Thrombotic and Platelet Disorders: Points to Consider by Reporting Results—Primum Non Nocere, Secundum Cavere, Tertium Sanare

Introduction Inherited bleeding, thrombotic, and platelet disorders (IBTPD) are a heterogeneous group of rare disorders caused by DNA variants in a large number of loci. To date there are close to 100 diagnostic genes associated with coagulation, thrombotic, and platelet disorders. A substantial proportion of patients cannot be diagnosed, and in some cases, the pathogenic mechanisms of certain variants cannot be confirmed. NGS refers to various types of sequencing platforms that can sequence millions of fragments of DNA in parallel. NGS offers opportunities to advance medical diagnostics and treatments, but also raises complicated ethical questions.

Areas Considered (1) Approaches for reporting variants with uncertain significance (VUS), a major challenge, especially in the case of novel variants and VUS, whose role in diseases cannot be ruled out. Attempts to interpret VUS may require affected patients to be informed, which may cause them unnecessary anxiety. (2) Approaches for reporting incidental or secondary findings, taking into account ethical and clinical circumstances. (3) Ethical challenges particular in three main ethical areas: privacy, informed consent, and return to results. A fundamental question is to what extent information generated by NGS testing should be communicated to patients. Patients should be informed about findings of high clinical importance that are at least partially correctable, thus balancing risks and benefits. (4) Reporting results of children.

Conclusion NGS is a promising tool for the diagnosis of IBTPD but poses ethical, legal, and social questions. It has unrestricted potential to find incidental genomic findings for which interpretation is still challenging and requires careful evaluation in order to avoid either a false-positive or a false-negative result.

Publication History

Article published online:
13 November 2020