Enter Note Done


Keywords: Exome sequencing; Diagnostics; Ethical, legal and social issues; Hematopoietic system; Nervous system

L.E. Hull 1; S. Advani 1; M.H. Hawley 2; A.M. Oza 2; S. Amr 2; P. Pomianowski 1; J.L. Vassy 1,3,4

1) VA Boston Healthcare System, Boston, Massachusetts.; 2) Laboratory for Molecular Medicine, Partners HealthCare; 3) Department of Medicine, Harvard Medical School; 4) Division of General Internal Medicine and Primary Care, Brigham and Women's Hospital

Although exome sequencing (ES) has demonstrated utility in many diagnostic contexts, the range of secondary results that should be returned from ES is an open question. We are conducting a feasibility study of ES in the VA Boston Healthcare System (VABHS), returning indication-based and secondary results.

In the VetSeq Study, providers refer patients for indication-based ES from a CLIA-certified lab through a research protocol. The report includes indication-related results, secondary pathogenic or likely pathogenic variants in >4600 genes associated with monogenic disease risk, carrier status variants, and pharmacogenomic results. Patients complete surveys and interviews before ES and 3 months after receiving results from their referring providers.

Two patients have completed the study. P1 is a 72-year-old man with decades of sensory neuropathy and myalgias. ES identified a pathogenic p.Arg298Cys variant in LMNA associated with Charcot-Marie-Tooth hereditary neuropathy type 2. Though some LMNA variants are associated with dominantly inherited neuromuscular disease, P1’s variant is typically associated with autosomal recessive inheritance and was thus inconclusive for his presentation. Family testing determined the variant was absent in a daughter and grandson with similar symptoms. In his baseline interview, P1 had hoped ES would identify a diagnosis and possible treatment not for himself but possibly for his family or for other patients. In his follow-up interview, he was uncertain ES met these expectations, given the apparent lack of definitive familial benefits or scientific advancement. P2 is a 33-year-old woman with a history of severe thrombocytopenia in her and 1 of 2 sons. In her baseline interview, she hoped that ES would suggest a treatment to stabilize their platelet counts. ES identified a p.Tyr346Cys variant in ETV6 that was present in her affected son but not her unaffected son. ETV6 has been associated with autosomal dominant thrombocytopenia, but this variant was classified as uncertain significance due to insufficient evidence of pathogenicity. In her follow-up interview, P2 said that although ES did not conclusively identify a cause for the family’s thrombocytopenia, learning she carries a pathogenic HFE variant associated with hereditary hemochromatosis was useful.

It is feasible to introduce ES to VABHS clinical care. Patients might find value in outcomes unrelated to their own diagnosis and treatment.