Patient Decisions for Disclosure of Secondary Findings Identified from Clinical
Diagnostic Exome Sequencing
Gonzalez
1
K,
Shahmirzadi
1
L,
Palmaer
1
E,
Parra
1
M,
Chao
1
E
1) Ambry Genetics, Aliso Viejo, CA
Background
Methods
 Exome sequencing of a single individual for a clinical indication results in the identification of hundreds of variants unrelated to the
disease of interest. 1 These variants are often referred to as “incidental” or “secondary findings”.1 While the vast majority of these
variants are likely benign polymorphisms or within clinically novel genes of which the function remains largely obscure, a small
number (between roughly 1-5) of well-described disease-association mutations are detected (data in preparation).
 Retrospective review of patient responses to Ambry’s Exome
Sequencing Consent Form received from cohort of 200 individuals
undergoing whole exome sequencing.
 Although secondary to the reason for testing, these variants may also have important clinical and medical significance for the patient
including cancer risks, carrier status for recessive conditions, early and late onset diseases.
 Data collected included age and preference for secondary results ,
categories A-D. Patients <18yo were automatically blinded to
categories A-C [Table 1].
 Currently, several professional groups provide recommendations for the return of these findings, however there is no standard
accepted method for reporting. 2,3,4,5
 Given the recent availability of testing, there is limited knowledge regarding the preferences of secondary findings of actual patients
undergoing whole exome sequencing (WES) and the impact of disclosing these findings.6
 Herein, we provide empirical evidence of preference for secondary findings results disclosure based on the first 200 families referred to
Ambry Genetics for WES. Reportable secondary alterations were defined as being HGMD or OMIM defined, well-established disease
causing genes, and categorized as a mutation (variants of uncertain significance are not reported).
TABLE 1 : Secondary Findings Categories
CATEGORY
AVAILABLE TO:
A) Recessive disease carrier status Adults
B) Cancer predisposition
Adults
Late onset disease
C)
predisposition
Adults
D) Early-onset disease
38
Children
(<18)*
Adults
Adults and Children
2
 Among the first 200 cases to arrive in the laboratory, there was a total
of 162 children (<18yo) and 38 adults (>18yo) [Figure 1].
 187/200 (93.5%) patients chose to receive secondary results for one
or more available categories. Of the children, 155/162 children
(95.6%) opted to receive results for category D-early onset disease.
36/38 (94.7%) adults chose to receive category A,C and D results, and
35/38 (92.1%) adults chose to receive category B results [Figure 2].
Figure 1: Total Patients
1
Results
162
 A total of 13 patients (6.5%) chose to have one or more secondary
finding blinded. 7 children chose to blind childhood-onset disease
alterations. 6 adults chose to blind one or more secondary finding. Of
the adults who chose to blind these findings, preferences were evenly
scattered between categories A-D, with most (3 patients) choosing to
blind category B-cancer predisposition [Figure 3].
1
Adults = >18 years old
2
Children = <18 years old
Figure 3: Adult Patient’s Results Blinding Preferences
Figure 2: Patient Decisions for Secondary Findings Disclosure by Category
100%
90%
%
80%
O
p
t
e
d
70%
I
n
Don’t blind:~93.5%
60%
50%
Adults
Children
40%
Blind A- Recessive disease (2/6)
Blind B-Cancer predisposition (3/6)
Blind C-Late onset disease (2/6)
Blind D-Early onset disease (2/6)
Take-Home Points
30%
 Secondary findings from whole exome sequencing may have important
medical implications.
20%
10%
0%
A) Recessive carrier
B) Cancer Predisposition
C) Late-onset disease
D) Early-onset disease
References
1)
2)
3)
4)
5)
6)
Blind: ~6.5%
Johnston JJ, et al. (2012) Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. AJHG, 91:97-108.
Green et al. (2012) Exploring concordance and discordance for return of incidental findings from clinical sequencing. Genet Med, 4(4):405–410.
Berg JS et al. (2012) An Informatics Approach to Analyzing the Incidentalopme. Genetics in Medicine, DOI:10.1038/gim.2012.112
Wolf et al., (2012). Managing incidental findings and research results in genomic research involving biobanks and archived data sets. Genetics in Medicine, 14(4): 361-384
Fabsitz, R.R. et al. (2010). Ethical and practical guidelines for reporting genetic research results to study participants: updated guidelines from a National Heart, Lung, and Blood Institute working group. Circ Cardiovasc Gene, 3: 574-80.
Murphy J, Scott J, Kaufman D, et al. (2008) Public expectations for return of results from large-cohort genetic research. American Journal of Bioethics, 8(11): 36-43.
 Of the first 200 patients to undergo exome sequencing at Ambry
Genetics, 187 (93.5%) opted to receive one or more category of
available secondary results.
 Interestingly, 24 /162 parents/guardians of patients <18yo marked the
consent form boxes for disclosure of results from categories A-C,
despite our policy to not disclose these categories to minors.
 Based on these findings, future efforts may be needed on a clinical level
for how to best counsel and/or triage patients regarding results from
secondary findings.