Study Design with Responsible Return of Results for a Fully Remote Genome Sequencing Study in Individuals with Prader-Willi Syndrome

• Published in: Genetics in Medicine Open p. 103448
• Main Authors: Vrana-Diaz, Caroline J., Bohonowych, Jessica, Richards, Jaimie L., Wilk, Brandon M., Gajapathy, Manavalan, Bar-Peled, Yael, Harris, Anna C., Denton, Jessica J., Brown, Donna, Worthey, Elizabeth A., Strong, Theresa V.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.08.2025
• Subjects: Genetics; genome sequencing; incidental findings; pharmacogenomics; Prader-Willi syndrome; secondary findings; genome sequencing; incidental findings; pharmacogenomics; secondary findings; Prader-Willi syndrome
• ISSN: 2949-7744; 2949-7744
• DOI: 10.1016/j.gimo.2025.103448

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 PWS clinical symptom frequency and severity, with responsible return of results. Fifty participants, or their legally authorized representative (LAR), 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 pharmacogenomic (PGx) analysis. A subset of LARs participated in semi-structured interviews about their GS experience. All fifty participants completed the study and elected to receive their primary findings, and forty-eight of forty-nine participants who consented to receive PGx information returned the buccal swab kit. Forty-seven participants consented to receive secondary findings per current American College of Medical Genetics (ACMG) guidelines; two 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 as individuals with PWS are at 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.