Targeted gene sequencing using large panels has become an increasingly important strategy for evaluating disease risk for many inherited diseases. Expanded gene panels are more sensitive than single gene testing and often more cost effective than sequential testing, leading to additional diagnostic and prevention opportunities. However, these panels also identify rare variants of uncertain clinical significance (VUS) in many patients. VUS typically have some characteristics or associated data indicating the variant may be deleterious, but not enough information to definitively classify them as disease causing. It is estimated that hundreds of thousands of such variants are present at low frequencies in the population. The finding of a VUS is problematic for patients and clinicians. Family segregation studies have the potential to yield powerful data to classify variants, but research resources are inadequate to enroll all the families affected by the exploding number of VUS identified in clinical testing. A potential solution to this quandary is to engage patients and their families in performing meaningful segregation analysis to evaluate their own VUS using available online genealogy and social networking tools facilitate identifying and contacting relatives likely to have the same VUS. In this project we will interview patients who have received clinical reports of VUS to explore patient understanding of their VUS, motivation and interest in classification, opinions of barriers and facilitators to talking with family members about VUS, and initial thoughts about potential for providing samples to classify their VUS. We will use input from 15-25 study participants to evaluate and improve an online patient-driven VUS classification toolkit that teaches individuals to better understand their VUS, use available genealogy and networking resources trace how their own variants segregate in their extended family, and potentially participate meaningfully with clinical experts in the classification of their own VUS. We will work with participants to obtain and test DNA from family members, and a molecular genetic pathologist will perform final variant classification. We will interview participants to determine if goals were met and if the toolkit enhanced participant and family understanding of genetic disease risk. We will also interview family members to understand family members perspectives related to privacy, communication, and provision of data or samples for variant classification. The innovative tools to classify VUS that will be developed in this project will meet a growing clinical need. When made broadly available these tools may demonstrate a way to characterize human variants in clinical settings at an unprecedented pace and at a fraction of the current research cost. The data gathered from this initial R21 project will lay the groundwork for additional development of a systematic, family-based method to help patients understand and classify variants of uncertain significance.
Clinical genetic testing panels often identify rare variants of uncertain clinical significance (VUS) in many patients, which is problematic for patients and clinicians because these findings are confusing and not clinically actionable. We seek to evaluate and improve a patient-driven VUS classification toolkit that teaches individuals to better understand their VUS, use available genealogy and networking resources trace how their own variants segregate in their extended family, and potentially participate meaningfully with clinical experts in the classification of their own VUS. This project will build understanding of the ethical, social, and family issues surrounding a way to characterize human variants in clinical settings at an unprecedented pace and at a fraction of the current research cost. Attachment 1: 1 R21 HG008513-01 Itemized Responses to Human Subjects Concerns We have already addressed the specific human subjects concerns identified by reviewers about the variant classification protocol as part of our IRB approval process for the Damon Runyon Cancer Research Foundation grant, which uses the same family-based online variant classification toolkit, and recently received approval-in-principal (pending web site launch) from the Fred Hutchison Cancer Research Center IRB (IR9396). We will be using a similar protocol for family-based variant classification aspects of this study. We will submit an additional IRB application for the work proposed, which will add collecting feedback from participants and relatives regarding toolkit usability and interviews to learn about patient and family member perspectives related to privacy, communication, and provision of data or samples. We have itemized our responses to human subjects concerns regarding patient centered family studies below. It needs to be clarified that contact and disclosure of genetic results would be limited to family members who have consented and participated in the underlying study and not any broader than that. Study genetic counselors will contact probands and family members who have consented to genetic testing when VUS classification changes. Study staff will contact the probands' or family members' genetic counselors or genetics providers to discuss the variant at those participants request. If requested the study will create a written report that describes individual genetic testing results and variant classification results for individuals share with their medical providers. Study staff will not re- contact family members who have not consented to genetic testing about genetic results. All participants will be able to contact study staff at any time throughout the study. Nothing is said in the application about the disposition of excess DNA from samples provided by family members and what is said in the consent form about that disposition. The consent form will give participants options to opt in to Dr. Shirts' IRB approved Genetic Repository and Registry study (UW Human Subjects #49520) or to have excess DNA disposed of at the end of the study. Clarify whether researchers can contact a family member for recruitment if proband says it is appropriate. Once a proband participant has identified and contacted family members who are genetically informative and interested in being tested for the variant, the proband participant will provide study contact information for the family member to initiate interest in joining the study. Participants will not be required to explain genetic principles or study design to family members, as study genetic counselors will describe this as part of the consent process. In cases where the participant receives specific instructions from the family member, the study staff will initiate contact with the family member in the manner requested by the family member (phone, email, etc.). Upon initial contact, study staff will verify family member interest and desire to join the study. What will be done with information of family member if they ultimately refuse to participate? Study staff will keep family member information confidential unless family members give explicit consent for study staff to share this information with others. When family members refuse participation, no additional information will be included the study databases; however, pedigree structure and information critical for co-segregation analysis that has been obtained from probands or participating family members will not be expunged. Family history information for medical or research purposes usually includes identifiable information on multiple family members. Family members' potential concerns about this information is an interesting issue that will be explored further in this study. It is unclear whether or how spouses will be involved. Family members who are genetically related provide information that is most useful to classify VUS, thus this proposal did not envision spouses being directly involved in project activities. If individuals with VUS are not capable of performing activities necessary to classify VUS themselves, they will not be eligible. Future studies may examine indirect spousal involvement.
