EP486: Demonstrating the utility of consumer initiated genetic testing: The identification of a family with vascular Ehlers-Danlos syndrome

Abstract

Vascular Ehlers-Danlos syndrome (vEDS), a potentially life-threatening connective tissue disorder, is caused by pathogenic variants within the COL3A1 gene. Such variants disrupt the integrity of type 3 collagen, a protein found in hollow body structures such as blood vessels, the uterus, and the intestines. As such, vEDS is characterized by aneurysm, dissection, and rupture of arteries; rupture of the intestines; and rupture of the uterus, along with other features common to connective tissue disorders including hypermobility, easy bruisability, and translucent skin. In 70% of adults with a COL3A1 disease-causing variant, the initial presentation of the condition is an organ or blood vessel rupture. Median life expectancy for vEDS is 40-50 years of age. Consumer-initiated genetic testing (CIGT) is an alternative testing model wherein a patient orders a genetic health analysis through an online retailer. That test order receives oversight by a board-certified genetic counselor and physician to ensure test appropriateness, efficacy, and informed consent. In addition, the patient has access to telehealth genetic counseling services and support. CIGT panels that are marketed to the general adult population with an absence of pertinent personal or family histories are termed “healthy adult” panels. A 59 year old male, motivated by curiosity and without significant medical history, ordered a healthy adult CIGT panel. The analysis included next-generation sequencing (NGS) performed by a CLIA-certified laboratory. His result returned a likely-pathogenic variant in COL3A1 (NM_000090.4(COL3A1):c.944G>C, p.Gly315Ala; GRCh37). This variant has been previously reported in an individual with a presentation consistent with vEDS and is classified in a public variant archive as both pathogenic and likely pathogenic. Following outreach regarding his high-risk result, a genetic counseling appointment was declined. This same individual then ordered a second CIGT test which also included testing of the COL3A1 gene via NGS at a separate CLIA-certified laboratory. Outreach to determine his expectation for the second CIGT test resulted in a genetic counseling appointment. The patient reported having ordered a second CIGT because the wait time to confirm his first CIGT result in a traditional genetics clinic was too great. No history of vEDS was known in his family. One first-degree relative died in their sleep at age 52. A second first-degree relative had a cardiac event at age 40 and died of a stroke at age 62. The second CIGT returned the same likely-pathogenic variant in COL3A1 using the same reference sequence. Following the confirmation of the variant by the second test, the patient followed up with a vEDS specialist and cascade testing of his family members was initiated. Three additional first-degree relatives have been identified to have the likely pathogenic variant and have initiated follow-up for this result. Consumer-initiated genetic testing, performed by a CLIA-certified laboratory and with oversight by board-certified genetic counselors, provides alternative, and possibly more timely, access to clinical-grade genetic testing. CIGT marketed to the general adult population has the ability to identify disease-causing variants in individuals whose family histories may not be known or which lack features striking for hereditary disease. The downstream effect of CIGT, in the form of readily accessible cascade testing, is largely impactful. In addition, by identifying disease-causing variants in individuals who seek testing due to health curiosity, it aids in defining the phenotypic spectrum. Additional work should be done to determine outreach practices which increase uptake of CIGT genetic counseling services, further elevating the benefit of this testing modality.