Study design with responsible return of results for a fully remote genome sequencing study in individuals with...

Prader-Willi syndrome (PWS) is a complex neurodevelopmental genetic disorder affecting multiple systems. We describe the design and feasibility of a fully remote, patient group-led, genome sequencing (GS) study that will evaluate the impact of genetic variants on the frequency and severity of PWS clinical symptoms, with responsible return of results.

A total of 50 participants, or their legally authorized representative, provided consent via videoconference discussion and selected which genetic results would be returned. Participants were sent dried blood spot cards for GS and a buccal swab kit for orthogonal pharmacogenomics analysis. A subset of legally authorized representative LARs participated in semistructured interviews about their GS experience.

All 50 participants completed the study and elected to receive their primary findings, and 48 of 49 participants who consented to receive pharmacogenomic information returned the buccal swab kit. Forty-seven participants consented to receive secondary findings per current American College of Medical Genetics guidelines; 2 had actionable results, with online genetic counseling support provided. Three families received medically significant findings related to variants associated with blood clot formation, which is important because individuals with PWS are at an increased risk for thrombotic events. Interview participants expressed a high degree of interest in the findings and emphasized the ease of participating in the study but felt the process was lengthy.

A fully remote GS study is feasible to perform within a rare disease population, and responsibly returning genetic findings that are important to families is achievable.