Kimberly A. Strong

Genomics in Clinical Practice: Lessons from the Front Lines

This Commentary explores the challenges in launching a medical genomics clinic for whole genome sequencing and analysis of patient samples. The price of whole-genome and -exome sequencing has fallen to the point where these methods can be applied to clinical medicine. Here, we outline the lessons we have learned in converting a sequencing laboratory designed for research into a fully functional clinical program.

Views of primary care providers regarding the return of genome sequencing incidental findings

Sequencing of the entire exome or genome is increasingly used in clinical practice. Debate continues, however, regarding which incidental findings (IFs) should be returned and who should be involved in those decisions. Previous empirical research regarding stakeholder attitudes to the return of IFs has primarily involved genetics professionals; non‐genetics health professionals have not been widely surveyed. Given this, a survey regarding return of IFs was administered at the Best Practices in Pediatrics Conference following an educational presentation on genetics terminology and genetic condition examples. A total of 258 participants completed the survey. Of particular note, respondents who were positively disposed to sequencing did not always report wanting to learn about IFs, even if actionable. This is noteworthy given recent American College of Medical Genetics and Genomics guidelines recommending particular actionable IF be returned ‘without reference to patient preference’. This studys findings are important because they provide insight regarding the attitudes to the return of genome sequencing results for an important professional group, primary care providers. Ultimately, as likely gatekeepers to referrals for this technology, their opinions about the test will be key to its successful deployment.

Does lack of "genetic-relative family health history" represent a potentially avoidable health disparity for adoptees?

Many adoptees face a number of challenges relating to separation from biological parents during the adoption process, including issues concerning identity, intimacy, attachment, and trust, as well as (for older adopted children) language and other cultural challenges. One common health challenge faced by adoptees involves lack of access to genetic-relative family health history (GRFHx). Lack of GRFHx represents a disadvantage due to a reduced capacity to identify diseases and recommend appropriate screening for conditions for which the adopted person may be at increased risk. In this article, we draw out common features of traditionally understood “health disparities” in order to identify analogous features in the context of adoptees’ lack of GRFHx.

Can targeted genetic testing offer useful health information to adoptees

In 2004, the US Surgeon General launched the Family History Public Health Initiative to increase awareness and discussions regarding family health history (FHx). FHx reflects the combined influences of shared genetic, behavioral, and environmental factors in families. The collection and use of FHx have already been shown to be useful in risk assessment and preventive intervention for cardiovascular disease, osteoporosis, and cancer surveillance/chemoprevention, to name a few.1–3 Yet many segments of the population lack adequate access to the genetic component of FHx that might inform their health management. Here, we focus on adoptees, whose lack of genetic FHx normally reflects separation from biological parents as an inherent feature of adoption. However, our fundamental point is applicable to anyone who lacks access to genetic FHx information, which can occur for many reasons. Lack of genetic FHx is not inconsequential; for example, a recent Swedish study of adoptees emphasizes the importance of genetic factors over environmental factors for several cancers.4 Current genetic testing capabilities are at a stage where it is legitimate to ask, “Could targeted genetic analysis offer any potential benefit for those individuals who have no or limited access to family history, such as many adoptees?” And might the potential benefits and risks of genetic analysis differ between adoptees and those with access to their family history information? According to US Census data (2000), adoptees account for more than 2.5% of the US population (7.8 million). Worldwide, the United Nations estimates that at least 260,000 children are adopted annually, and the number of children globally who have lost both parents is more than 60 times this number.5 Although some adoptees have access to family history information (for example, through open adoption or biological relative adoption), many do not. One study found that for adoptees in general, family medical information was available for less than half of birth fathers.6 For international adoptees (currently one-quarter of adoptions),7 this problem is exacerbated not only by logistical difficulties but also by well-established problems surrounding the limitations of medical records in many countries from which international adoptions occur. For nearly two-thirds of international adoptees, no written medical records exist, even for basic things such as vaccination status.8,9 Moreover, even adoptees with access to some FHx information often lack ongoing, iterative refinement of this knowledge available to biologically related families who have regular, multi-generational interaction. Clinical actionability of FHx in practice is often seen in situations in which the pattern of disease in the family suggests the presence of a genetic disorder and indicates the need for earlier screening or other interventions. Many adoptees do not have access to this potentially lifesaving information. However, emerging genomic technologies are beginning to offer the possibility of accessing some of this medically actionable genetic information. An important point of similarity between genetic data and family history is that both have the greatest clinical impact on medical care when they serve to indicate an uncommon, but dramatic, risk such as that indicated by a strong family history of early diagnosis of breast cancer, colon cancer, or the like (knowledge of which can lead to recommendations for earlier screening or overtly preventive intervention). It is in several of these areas where the strongest gene–disease associations lie, such as for breast cancers and colorectal cancers. Although genetic analysis is unlikely to provide a replacement for family history when available, if properly targeted and interpreted, such analysis may have the potential to provide useful information regarding health risks when no information currently exists. Given an inability to realize family history–derived health benefits (i.e., a need for earlier screening or interventions) by many adoptees, it is critical to evaluate the potential of carefully considered genetic evaluation in this population.

On the Ethics of Clinical Whole Genome Sequencing of Children

* Abbreviations: AAP — : American Academy of Pediatrics ACMG — : American College of Medical Genetics and Genomics MCW — : Medical College of Wisconsin WES — : whole exome sequencing WGS — : whole genome sequencing In 2009, scientists here at the Medical College of Wisconsin (MCW) demonstrated the ability to apply whole exome sequencing (WES) to diagnose a pediatric patient with a rare digestive disease. WES enables the evaluation of the known protein coding DNA sequence of an individual. For the MCW patient, WES provided confirmation of an immune disorder,* thereby warranting treatment with a cord blood transplant: a treatment that saved his life but would not have been undertaken without that confirmation.1 This groundbreaking story was prominently featured in a series of Pulitzer Prize–winning stories in the Milwaukee Journal Sentinel , scholarly publications, and a segment of the PBS television program Nova . As predicted by Francis Collins,2 success of WES in cases like this has spurred interest in further application of this diagnostic tool. MCW has now expanded its program to include whole genome sequencing (WGS) and has since received requests from around the world to perform WGS. Additionally, in partnership with Children’s Hospital of Wisconsin, a pilot program of clinical WGS has recently been completed. As with most new technologies, WGS has sparked controversy concerning whether its clinical application should move forward or if this technology should be confined to the research domain until specific clinical policies are established. Here, we articulate reasons to continue moving forward with clinical WGS. Until recently, the consensus approach to genetic testing and screening in general has reflected cautious limitations on the use of genetic testing on children. … Address correspondence to Thomas May, PhD, Ursula Von der Ruhr Professor of Bioethics, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail: tmay{at}mcw.edu

Successful Application of Whole Genome Sequencing in a Medical Genetics Clinic

A pilot program was initiated using whole genome sequencing (WGS) to diagnose suspected genetic disorders in the Genetics Clinic at Childrens Hospital of Wisconsin. Twenty-two patients underwent WGS between 2010 and 2013. Initially, we obtained a 14% (3/22) diagnosis rate over 2 years; with subsequent reanalysis, this increased to 36% (8/22). Disease causing variants were identified in SKIV2L, CECR1, DGKE, PYCR2, RYR1, PDGFRB, EFTUD2, and BCS1L. In 75% (6/8) of diagnosed cases, the diagnosis affected treatment and/or medical surveillance. Additionally, one case demonstrated a homozygous A18V variant in VLDLR that appears to be associated with a previously undescribed phenotype.

Challenges to clinical utilization of hereditary cancer gene panel testing: perspectives from the front lines

AbstractNext generation sequencing (NGS) technology is rapidly being implemented into clinical practice. Qualitative research was performed to gain an improved understanding of the landscape surrounding the use of NGS in cancer genetics. A focus group was conducted at the Wisconsin Cancer Risk Programs Network biannual meeting. Free flowing discussion with occasional open-ended questions provided insights into the use of NGS. 19 genetic counselors and medical professionals participated. Three major themes were identified with respect to NGS and its use in cancer genetics: knowledge gaps, the evolving clinician role, and uncertain utility. Several corresponding subthemes were identified. With respect to knowledge gaps, participants expressed concern regarding unexpected results and variants of unknown significance, lack of data about NGS findings, absence of standardization regarding use of NGS and guidelines for interpretation, and discomfort with new technology. Regarding the evolving clinician role, necessary changes to the roles of genetic counselors and physicians were noted, as was the resultant impact on care received by patients and their families. Finally, the clinical and economic utility of NGS was questioned. While a shift from traditional Sanger sequencing to NGS is occurring in molecular genetic testing for disease susceptibility, there are several obstacles that need to be overcome before widespread adoption of this technology can occur. Furthermore, key aspects of NGS and it utility remain unexplored. Continued investigation into these subjects is necessary before this technology will consistently be of benefit to patients and their families.

Choices of incidental findings of individuals undergoing genome wide sequencing, a single center's experience.

Genome wide sequencing is an emerging clinical tool that may provide information on genetic variants that are not directly related to the patients primary disorder. These incidental findings (IFs) may include information about conditions that can be treated and may also indicate conditions for which treatments are not currently available. Data is currently limited regarding what IFs an individual would want to disclose. This study reports on 305 individual choices for return of IFs that were completed at the Medical College of Wisconsins clinical sequencing laboratory. Individuals were given access to five categories of IFs to select from: no incidental findings, untreatable childhood disorders, treatable adulthood disorders, untreatable adulthood disorders, and carrier of a disorder. Retrospective chart review was conducted and individual choices were recorded and analyzed. The majority of individuals (76.1%) selected every IF to be reported, 14.4% wanted a subset of the options, and 9.5% did not want any IFs reported. This study contributes to the limited data that demonstrates what an individual would actually choose when undergoing genetic sequencing. Furthermore, this data supports the opinion that individuals want and utilize the ability to choose the findings reported.

The Limits of Traditional Approaches to Informed Consent for Genomic Medicine

This paper argues that it will be important for new genomic technologies to recognize the limits of traditional approaches to informed consent, so that other-regarding implications of genomic information can be properly contextualized and individual rights respected. Respect for individual autonomy will increasingly require dynamic consideration of the interrelated dimensions of individual and broader community interests, so that the interests of one do not undermine fundamental interests of the other. In this, protection of individual rights will be a complex interplay between individual and community concerns.

Adult adoptees’ attitudes regarding the potential use of genetic information to fill the gap in their family health history:

Genetic testing can provide useful information related to a person’s health history. Adoptees who lack access to family health history due to inherent separation from their birth family are among those likely to benefit from this. Understanding their attitudes, including their hopes and concerns, will allow for better informed and more appropriate applications of genetic testing within this population and will help guide genetic counselling for adult adoptees. This qualitative study, involving four focus groups totalling 17 participants, examined adult adoptees’ attitudes that might influence decision-making around genetic testing. Using the NVivo 10 data analysis method, transcripts were content and thematically coded for: motivations for positive interest in genetic testing/genome sequencing; reasons for lack of interest or uncertainty about genetic testing/genome sequencing; and mixed feelings or overlapping positive and negative comments by the same individual in the same train of thought. Other studies have examined adoptive parents’ attitudes towards genetic testing, but this is the first to give voice to adoptees themselves. The results indicate that while adult adoptees’ attitudes about genetic testing appear to be similar to that of other laypeople, they reported unique concerns and perspectives regarding its potential use and their motivations and deterrents for pursuing it.