Secondary findings from clinical genomic sequencing: prevalence, patient perspectives, family history assessment, and health-care costs from a multisite study

Abstract

Purpose: Clinical sequencing emerging in healthcare may result in secondary findings (SFs). Methods: Seventy-four of 6,240 (1.2%) participants who underwent genome or exome sequencing through the Clinical Sequencing Exploratory Research (CSER) Consortium received one or more SFs from the original ACMG-recommended 56 gene-condition pair list; we assessed clinical and psychosocial actions. Results: The overall adjusted prevalence of SFs in the ACMG 56 genes across the CSER consortium was 1.7%. Initially 32% of the family histories were positive, and post disclosure, this increased to 48%. The average cost of follow-up medical actions per finding up to a 1-year period was $128 (observed, range: $0-$678) and $421 (recommended, range: $141-$1114). Case reports revealed variability in the frequency of and follow-up on medical recommendations patients received associated with each SF gene-condition pair. Participants did not report adverse psychosocial impact associated with receiving SFs; this was corroborated by 18 participant (or parent) interviews. All interviewed participants shared findings with relatives and reported that relatives did not pursue additional testing or care. Conclusion: Our results suggest that disclosure of SFs shows little to no adverse impact on participants and adds only modestly to near term healthcare costs; additional studies are needed to confirm these findings.

Family History Assessment Significantly Enhances Delivery of Precision Medicine in the Genomics Era

“…It is also possible that the family histories are incomplete and that further relevant family information could be revealed. 8 In contrast, by integrating family history assessment, our findings indicated that selecting participants according to their family history for genomic testing significantly increased the detection of carriers for cancer syndromes. Therefore, the traditional triaging of participants by family risk assessment in our study appears to be a cost-effective alternative in contrast to genome screening unselected populations to increase the detection of clinically actionable variants.…”

“…Some recent cohort studies have suggested that family history is not a useful tool for identifying carriers of monogenic conditions, as at least half of the carriers detected in their unselected populations did not present with a corresponding increased risk family history, nor would have met eligibility criteria for genetic testing. 8,9,11 We also detected carriers of cancer syndromes that did not meet testing guidelines according to their family history (17 participants), half of which had no family history of cancer. Possible explanations include reduced penetrance or a milder phenotype of the disease-causing variant in absence of other environmental or genetic risk factors not present in these families or that the identified variant is de novo.…”

“…Several screening programs are initiating genomic sequencing for healthy or unselected populations, irrespective of health status or family history. [3][4][5][6][7][8][9] Amongst these population screening programs there is consensus to return genomic results which are medically significant however there is less concordance regarding which genes fall into this category.…”

“…6,8,9 There is emerging evidence that in unselected populations, 48%-60% of individuals identified as having a clinically actionable variant have no associated family history. 8,9,11 A case control study observed a similar prevalence of Ashkenazi Jewish BRCA founder variants amongst individuals with and without breast cancer in their family 12 , and a more recent study found the frequency of clinically actionable variants was similar amongst breast cancer patients who met and did not meet clinical criteria for genetic testing. 13 These studies have provided evidence to support that testing could be offered to affected and unaffected individuals, with and without an associated increased risk family history.…”

Critical assessment of secondary findings in genes linked to primary arrhythmia syndromes

“…Overall, there are limited data available on the frequency of SF in the population. A recently published study by Hart et al (2019) reported that 74 of 6,240 (1.2%) participants who underwent genome or exome sequencing through the Clinical Sequencing Exploratory Research (CSER) Consortium received one or more SF from the original ACMG recommended 56 genes (Hart et al, 2019). Additionally, Dorschner and coworkers classified pathogenic variants of 1,000 individuals (Dorschner et al, 2013) in a defined group of actionable genes.…”