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A Long Time Coming: Returning Clinically Relevant Exome Results for Developmental Brain Disorders to Adult Research Participants

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A Long Time Coming: Returning Clinically Relevant Exome Results for

Developmental Brain Disorders to Adult Research Participants

Finucane B, Wain K, Palen E, Kasparson L, Ledbetter DH, and Martin CL

Autism & Developmental Medicine Institute, Geisinger Health System, Lewisburg, PA USA

Developmental brain disorders (DBD)

 •Etiologically-heterogeneous conditions in children, adults

•At least 40% of DBD has an identifiable genomic cause
•Shared pathogenic loss-of-function (pLOF) variants      directly connect clinically different DBD, including:
oautism spectrum disorder
ointellectual disability
obipolar disorder
•Most adults with genomic DBD variants not genetically diagnosed and unaware of underlying etiologies



 •As part of a larger investigation into clinical phenotypes       of DBD-related pLOF variants, we sought to develop a    process for returning clinically relevant whole exome sequencing  (WES) results to adult research participants.

•Data was analyzed from the Geisinger Health System – Regeneron Genetics Center DiscovEHR Project (fig.1):
oWES results linked to electronic health record (EHR) data from patient-participants in Geisinger’s MyCode® Community Health Initiative biorepository
oMyCode® currently has over >130,000 biosamples, predominantly from adults of European ancestry receiving care through Geisinger Health System
oConsented patient-participants agree to future  contact about clinically relevant results, including 79 medically actionable secondary findings


Patient-participants with pLOF Variants


•We evaluated 45 genomic regions previously associated with DBD in 47,859 exomes from the DiscovEHR cohort.
•Recurrent copy number variants (CNVs) in these regions were found in ~4% of DiscovEHR patient-participants.
•~1% of the cohort, representing over 500 individuals, had at least one recurrent pLOF CNV known to be clinically associated with DBD. Fewer than 5% of these individuals had a clinical genetic diagnosis recorded in their EHR. For example:
Of 15 participants with a 22q11.2 deletion, only three had a diagnosed  clinical genetic disorder (VCFS or DiGeorge syndrome). However, all of    these individuals had at least one     ICD-9 code for a phenotypic feature    consistent with the deletion, demonstrating high penetrance.
•We developed a return of results (ROR) process for  DBD-related variants, based on the broader ROR  protocol already in place at Geisinger for medically actionable secondary findings (fig.2)
•Given the potentially sensitive nature of ROR for DBD-related variants, the proposed process underwent careful review by Geisinger’s Ethics Advisory Council, Return of Results Oversight Committee, Genomics Council, and MyCode® Governing Board prior to being implemented.

Returning DBD-related Exome Results


Clinical genetic testing as part of the etiological evaluation of DBD is most often done during childhood, if at all, and a majority of adults with causative DBD variants have never been genetically diagnosed. Instead, many live with symptom-based developmental, psychiatric, and medical diagnoses without ever knowing the underlying etiologies that tie these findings together. When developing our ROR protocol, particular consideration was given to the potential for negative psychological reactions to learning about a genetic DBD cause; implications of inherited pLOF variants for participants’ family members; and the effects of cognitive and psychiatric symptoms on the comprehension of information provided. We balanced these challenges against the potential positive impact on medical management, reproductive genetic counseling, and the perceived value of providing these adult research participants with an etiological explanation for their lived experience with DBD. As we move forward with our ROR process, we plan to carefully evaluate

the psychosocial impact of DBD-related results

disclosure in this adult population.

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