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Transformative Care Through Genome Sequencing: Insights from the First 100 Patients in the CincyKidsSeq Study

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Genomic Medicine
  • Secondary Categories:
    • Genomic Medicine
Introduction:
Introduction: Genome sequencing (GS) has rapidly become the gold standard for diagnosing patients with clinical indications suggestive of an underlying genetic etiology. However, access to this test remains limited without research grant funding, institutional support, or specific insurance coverage, making it challenging for many patients and the broader population to obtain. Supported by an ARC grant, the CincyKidsSeq initiative provides high quality research GS with clinical confirmation.  In our initial cohort, we have already observed transformative outcomes, including overcoming insurance barriers, ending diagnostic odysseys, management changes, and improved access to therapies and clinical trials.

 

Methods:
Methods: The CincyKidsSeq study, initiated with ARC grant funding from Cincinnati Children’s Hospital Medical Center (CCHMC), aims to establish a comprehensive pipeline for the collection of  broad phenotypic and genotypic data. This 3-year genome project is designed to provide a diverse patient population with access to cutting edge genomic services while fostering liaisons across pediatric healthcare divisions.  Patients aged 0-99 who have symptoms that may be associated with a genetic condition are invited to participate in the study through the Division of Human Genetics, collaborative providers, and self-referral. Patients are enrolled through an Institutional Review Board (IRB)-approved consent and protocol to participate in proband-first GS. Deep phenotyping for abstracting of human phenotype ontology (HPO) terms is performed by manual chart review certified by a clinical research coordinator and a genetic counselor.  Results are reviewed by a multidisciplinary team, including board-certified laboratory and medical geneticists, before being released to the referring provider and disclosed by either the referring provider or the CincyKidsSeq study team.

 




Results:
Results: In the first 9 months of the CincyKidsSeq initiative, a total of 921 patients were referred: 575 by a medical provider and 324 through self-referral. The cohort was evenly split by reported sex. Of the individuals who initiated enrollment, 657 (71.3%) were categorized as affected. Enrollment was completed for 504 patients, with 457 (91%) co-enrolling in the Discover Together Biobank, a biorepository of samples and data at CCHMC. Participants were given the option of receiving ACMG secondary findings, of which 95.6% opted in. GS has been completed on an initial cohort of 100 patients. Overall, a previously unknown reportable molecular diagnosis was made in 16/100 participants (16%) and each diagnosis was orthogonally confirmed. 52 patients received a negative GS result. Of the remaining 48 individuals with a potentially actionable finding, additional evaluations included Sanger confirmation, parental segregation studies, X-inactivation studies, RNA-Seq analysis, methylation studies with an EpiSign panel, analyte testing, serum enzyme testing and metabolomics, depending on the clinical situation. Through these additional strategies, a clinical diagnosis was confirmed for 16 patients. Three additional unique cases were identified to have actionable ACMG secondary findings (BTD, MSH6, and HMBS genes). Through follow-up of these patients, we observed an immediate change in patient management for 12/16 patients with a positive finding. This preliminary data suggests a clinical utility of at least 75%.

 

Conclusion:
Conclusion:

Genome sequencing is a groundbreaking technology with clear medical benefits, yet access remains a significant challenge. Through grant funding, CCHMC has successfully implemented a GS testing strategy that is accessible for patients and healthy individuals. The diagnostic yield for an unstratified affected population is currently 16%. Notably, the majority of new clinical diagnoses have been medically actionable, leading to significant improvements in patient care. Key outcomes include overcoming insurance barriers, resolving long-standing diagnostic odysseys, optimizing therapeutic management, and facilitating clinical trial enrollment in the first cohort of individuals tested.

 

Agenda

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