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Purpose: To describe our process for returning genetic results to participants in the Colorado Center for Personalized Medicine biobank. Methods: Enrollment in the biobank is open to all adult UCHealth patients. Participants who provided a sample that was genotyped and signed the proper consent were eligible to receive results. Genetic data were generated using a custom genotyping array and confirmed via Sanger sequencing. We used 2 models for returning results and conducted interviews with participants to assess satisfaction with our process, follow-up care, and family communication. Results: As of July 2022, 73,313 participants had provided a sample and proper consent. Of these, 10,489 samples were genotyped, 137 (1.3%) had initial results, and 62 were confirmed and eligible for return. We returned results to 51 participants, 33% for cardiac risk, 31% cancer, 15% familial hypercholesterolemia, and 21% for other conditions (11 participants refused or did not respond). Less than half of participants had a relevant family history. The majority of participants were glad to receive results and satisfied with our process. Conclusion: Although array-based genotyping has known limitations that reduce its accuracy, we were able to identify persons with underlying genetic risk who were previously unaware. It is important to establish a process for returning results that follows clinical guidelines, protects participant autonomy, and is amenable to all participants.

Barth syndrome is an X-linked genetic condition featuring neutropenia, skeletal myopathy, and dilated cardiomyopathy in boys due to tafazzin (TAZ) mutations. Pure dilated cardiomyopathy without other features of Barth syndrome may also result from TAZ mutations and survival into adulthood has been described. Although TAZ testing is routinely included in dilated cardiomyopathy panels in adults, the prevalence of TAZ mutations in the adult population, including women who may be at risk to develop later onset disease due to TAZ mutations, has not been measured. We screened 292 families with dilated cardiomyopathy (209 male and 83 female probands) for TAZ mutations using denaturing high-performance liquid chromatography and sequence analysis. Putative mutations were evaluated based on standard criteria including screening available relatives and healthy controls and for effects on splicing efficiency in the case of one intronic variant. Two variants suspicious for being pathogenic were found in two unrelated families (c.387T>C, Phe128Ser and c.507C>T, Leu169Leu). The Phe128Ser variant had been previously reported as a pathogenic mutation; however we determined that this variant is instead a rare polymorphism restricted to African Americans. The Leu169Leu variant was detected in a male patient and altered RNA processing in our minigene assay supporting a pathogenic role. No mutations in female subjects were detected. Tafazzin mutations were rare in our population of adults with dilated cardiomyopathy and none were found in females. Our findings indicate that genetic testing for tafazzin should not be routinely performed in dilated cardiomyopathy as suggested by current guidelines. Furthermore, the Phe128Ser variant is not pathogenic, but likely represents a benign polymorphism in persons of African American ancestry.