Expanding Access to Genome Sequencing: Higher Diagnostic Yield in Self-Referred Participants From the CincyKidsSeq Study and Implications for Hybrid Models of Genetic Service Delivery.

Genome sequencing (GS) has emerged as the gold standard for diagnosing patients with rare diseases. As with many emerging technologies, equitable access remains a concern. To evaluate the feasibility and diagnostic impact of expanding access to GS, we report our experience implementing CincyKidsSeq, a prospective study offering GS as a "proband-first" test. Participants of all ages with at least one symptom were referred by genetics or non-genetics healthcare providers, or alternatively, were self-referred from February 2024 to February 2025. This diverse referral structure was evaluated for diagnostic yield while maintaining clinical oversight through a hybrid model in which reportable variants are delivered through genetic providers. The overall diagnostic yield of GS on 313 participants was 22% in the unstratified cohort. Self-referred patients had a higher diagnostic yield (11/33; 33%), compared with patients referred by a non-genetics provider (27/98; 27%), or genetics provider (32/182; 18%). Self-referred individuals were older, more likely to be female, frequently test-naïve, and utilized fewer human phenotype ontology (HPO) terms (p value = 0.0016). Self-referral may serve as an effective and complementary pathway for improving access to GS. Empowering families to initiate GS may be a reasonable pathway for an alternative model for genetic service delivery.