Next-Generation DNA Sequencing, Regulation, and the Limits of Paternalism

Abstract

WITH THE ADVENT OF NEXT-GENERATION SEquencing technologies, the ability to quickly and relatively inexpensively learn the sequence of an individual’s entire genome will soon be available to medical practitioners, patients, and consumers. Whole-genome and whole-exome sequencing will routinely uncover both trivial and important medical results, both welcome and unwelcome. This upheaval in sequencing technology presents new challenges to implementation and regulation, forcing physicians to consider what genomics has to offer patients, clinicians, and consumers, ultimately prompting a consideration of the role of paternalism in medicine. Next-generation sequencing has already shown promise as a diagnostic tool for patients with enigmatic disorders and features that suggest a primary genetic etiology, such as a strong family history, developmental anomalies, or unusual presentations of common diseases (eg, cancer at a young age). Moreover, when evaluating disorders that can result from mutations in many different genes, nextgeneration sequencing allows simultaneous assessment of multiple genes. On the other hand, next-generation sequencing is unlikely to substantially contribute to the management of most common diseases because their multifactorial nature places an inherent limit on the utility of pure genetic analysis. In the realm of public health, the proactive identification of individuals carrying mutations that confer high risk of preventable disease could be a logical application of next-generation sequencing. For example, more than 500 000 individuals in the United States carry a Lynch syndrome–associated mutation and are at a substantially increased risk of colorectal cancer. A population approach to sequencing Lynch-associated genes in asymptomatic individuals (or in appropriate patients diagnosed with colorectal cancer with cascade testing of family members) could identify many who are unknowingly at high risk of this preventable disorder. Another emerging application of next-generation sequencing in public health is preconception screening in which prospective parents ascertain their carrier status for autosomal recessive disorders. Although such disorders are individually rare, collectively they represent a major public health issue accounting in aggregate for more than 10% of pediatric deaths. Screening tests are already commercially available for assessing carrier status of more than 100 severe autosomal recessive diseases. The policy implications of such screening are complex given that selective abortion is one way that parents deal with the realities of shared carrier status. But such testing can in principle be used to identify carrier status for any autosomal recessive (or Xlinked) disease and is bound to expand. Beyond the realms of clinical medicine and public health, some consumers (and those who would profit from providing testing) have an interest in applying genomic technology outside the traditional medical establishment. This nascent movement is exemplified by direct-to-consumer genetic testing. With the advent of genomic microarray technologies over the past several years, affordable genomic analysis quickly led to direct-to-consumer genetic testing for risk of a host of common diseases. Just as quickly, controversy ensued. Those supporting unregulated availability of such testing offerings touted the potential utility for consumers, criticizing regulatory efforts as paternalistic. Others, emphasizing unproven utility and substantial inconsistencies in test performance, called for regulation of direct-toconsumer genetic testing. In response, the US Food and Drug Administration (FDA) has clearly expressed its intention to regulate direct-to-consumer genetic testing but has yet to articulate details of envisioned regulation. Although this controversy has attracted considerable attention, it has arguably been, until now, a tempest in a teapot. There is little evidence to suggest widespread uptake of microarray-based direct-to-consumer testing by the public and few data have emerged suggesting that risk