The demographic characteristics of the research participant community are important factors in fully understanding the challenges and benefits of implementing the return of incidental genetic results in this setting.
Study participants reside in an area of northern South Dakota covering 4,266 square miles, with a population density between 2 and 3 people per square mile. Most Tribal members live in cluster housing near small towns, on farmsteads or in cluster sites far removed from basic services. Beyond Tribal government and Federally supported work in health care and education, ranching and farming provide the bulk of employment. Out of more than 3,000 counties in America, two of the three counties in this community have the 2nd and 24th lowest per capita income,9 with 44% and 37% of residents having incomes below the poverty line.10 More than 15% of adult residents have less than a high school education.10
Although no "opt-out" option related to return of individual results was provided at the time of consent, there were no potential parents or participants that indicated an unwillingness to enroll due to concern over this issue.
The predominant source of medical care for tribal members in this community is the Federally funded Indian Health Service and a tribal health department. The IHS hospital and clinic are typically staffed by 3 or 4 primary care physicians (often including a pediatrician) and an equal number of mid-level providers. The Tribe operates an independent clinic with a couple of physicians and a similar number of mid-level providers. The closest specialty care is at least 90 miles and more commonly 170 miles distant (e.g. cardiac or pulmonary consultation). Although all recognized Tribal members are eligible for care at the IHS facility, in order to be paid for with IHS funding, any non-IHS care must be pre-approved and is often deferred or delayed due to lack of funds or insufficient priority.
Both the community at large and individual participants were provided information on the aggregate results of FIPA. This was accomplished by a newsletter to all participants including reference to a YouTube video created conveying our results, a radio broadcast, presentations to both the Tribal council and local clinic staff, as well as Tribal approval of each scientific publication.
All genetic data was de-identified during quality control and analysis as to protect the identity of study participants. Standard quality control for genome-wide association studies was performed, including the removal of variants with low call rates (< 95%) and deviation from Hardy-Weinberg expectations. We also examined individual samples for unexpected genetic relatedness, low genotype call rates, and unexpected levels of heterozygosity (including heterozygosity of the X chromosome for consistency with reported gender). We then performed an intersection of variant identifiers with pathogenic variants listed by the ACGM, followed by visual confirmation of similar genome build, chromosome number, variant position, variant alleles (including strand), and genotype quality. We also compared overall allele frequency and heterozygosity among all FIPA participants for the identified ACGM pathogenic variants specifically, to provide an extra level of more stringent quality control without an arbitrary threshold. Overall, two individuals were identified as having clinically actionable genetic variants in the present genetic study. The two were siblings, and both lived 40 miles from the IHS facility and research headquarters.
The training and relationship to the community of the authors involved in returning these results is pertinent and briefly described here. The lead author (LGB) is board certified in Family Medicine, but with additional, informal training in both DNA diagnostic lab technique and genetic counseling during a year-long sabbatical at the Manitoba Health Sciences Center in Winnipeg, MB, Canada. His career with the IHS spanned over 20 years at a neighboring Tribal community. In the subsequent 24 years he has served as principal investigator on a number of genetic studies within American Indian communities. Two authors (MO and RO) are Tribal members and/or married to a Tribal member, live in the community and have conducted various research efforts there for decades. The senior author (DGT) is experienced in genetic studies and has collaborated with the lead author (LGB) for close to 10 years. She has visited the community on several occasions to support collaborative research, participate in outreach activities, and provide genomics training.
Guided by the set of genes and variants the ACMG considers clinically actionable and pathogenic,11 query of the MEGA-EX data found only a single MYH7 coding variant, R870H (rs36211715) in two FIPA participants who were both heterozygous for this trait. The National Center for Biotechnology Information (NCBI) ClinVar database accession number (VCV000014120) from 2016 lists this variant "pathogenic" as reviewed by an expert panel according to principles outlined by the "Recognition of Public Human Genetic Variant Databases"12 of the US Food and Drug Administration.
The R870H variant is associated with hypertrophic cardiomyopathy (HCM) and the characterization as pathogenic is based on multiple clinical reports in the literature, from about 1995 as documented in dbSNP citations for rs36211715.13 Since this variant acts in a primarily dominant fashion (with penetrance of ~ 60%),14 evidence of pathogenicity is derived mainly from intra-family linkage15 and is at very low prevalence in the general population (frequency of the pathogenic allele is 2.3 x 10− 5 in TOPMED13). The phenotype is characterized by otherwise unexplained left ventricular hypertrophy and increased risk of asymmetric septal hypertrophy and ventricular arrhythmias, occasionally leading to sudden cardiac death.14–16
Prior to contacting participants, a plan was needed to offer independent, no-cost CLIA certified tests to confirm the presence of ACMG variants, however IHS does not have a mechanism to fund clinical follow-up of incidental genetic findings in a research setting. Therefore, we committed to provide discretionary research funds to obtain the needed clinical confirmation should the participants consent. Following this an attempt was made to contact the individuals by phone. Due to unstable cellular connections at the participants' home and the COVID-19 pandemic, there was considerable difficulty making initial contact. However, one of us (LGB) was able to visit with one of the siblings and their father for about 20 minutes and the preliminary results and their basic implications were explained. During this session, the unconfirmed nature of our original results was emphasized, the general characteristics of the phenotype were outlined and a release of information was obtained to review potentially pertinent medical records related to HCM. The participant, who was > 18 years of age at the time of contact, agreed to proceed with confirmatory testing. The Mayo Clinic was the most convenient reference genetic laboratory and arrangements were made to have a new blood sample collected at a local, private clinic. The original results were subsequently confirmed by the Mayo Clinic and the variant was characterized as "pathogenic".
After confirmatory results were available, a video teleconference was conducted with 3 of the authors to discuss the results and implications of this variant more fully. It was recommended (LGB) that the participant have a cardiology consultation and 24 hour ECG recording. Efforts then began to obtain referral from IHS for these services, the results of which showed no current, anatomic evidence of HCM and no arrhythmogenic concerns. Our final contact with this participant was a written statement reiterating the findings from the cardiology consultation, the offer to provide additional testing for family members, the fact that the phenotype has limited penetrance, and strongly encouraging regular follow-up of blood pressure, repeat echocardiogram every few years and general lifestyle recommendations for cardiovascular health. Contact information was also provided with encouragement to reconnect at any time.
Concurrent with above, multiple efforts to communicate with this participant's sibling were unsuccessful, including efforts on the part of the participant we returned results to. A parent of the siblings was present intermittently during the initial 20 minute phone consultation and did not decline offered testing for themself, but has not attempted to follow-up and make arrangements for sample collection. The communicating participant has limited contact with their other parent and testing was not pursued. The full process, from the time the genetic variant was identified through our last contact with the family, lasted approximately 21 months.