Genome Screening, Reporting and Counseling for Healthy
Populations
Selina Casalino1,2, Erika
Frangione1,2, Monica Chung1,2,
Georgia MacDonald1,2, Sunakshi
Chowdhary1,2, Chloe Mighton1,2,3,4,
Hanna Faghfoury5, Yvonne Bombard3,4,
Lisa Strug6, Trevor J. Pugh5,7,
Jared Simpson7, Elena Greenfeld1,3,
Limin Hao8, Matthew Lebo8,9, William
Lane9, Abdul Noor1,3, Jennifer
Taher1,3, Jordan Lerner-Ellis1,2,3,
GENCOV Study Workgroup
- Mount Sinai Hospital, Sinai Health
- Lunenfeld-Tanenbaum Research Institute, Sinai Health
- University of Toronto
- Unity Health Toronto
- University Health Network
- The Hospital for Sick Children
- Ontario Institute for Cancer Research
- Laboratory for Molecular Medicine, Partners Personalized Medicine
- Harvard Medical School & Brigham and Women’s Hospital
Corresponding author : Jordan Lerner-Ellis, Pathology &
Laboratory Medicine, Mount Sinai Hospital, Sinai Health System, 600
University Ave, Toronto, ON, Canada, M5G 1X8; T: (416) 586-4800 ext.
6115; E: Jordan.Lerner-Ellis@sinaihealth.ca
Key words: Genome sequencing, genomic data, reporting, genetic
counseling, secondary findings, healthy population
ABSTRACT
Word count: 191 (max. 200)
Introduction : Rapid advancements of genome sequencing (GS)
technologies have enhanced our understanding of the relationship between
genes and human disease. In order to incorporate genomic information
into the practice of medicine, new processes for the analysis, reporting
and communication of GS data are needed.
Methods : blood samples were collected from adults with a
PCR-confirmed SARS-CoV-2 (COVID-19) diagnosis (target N=1500). GS was
performed. Data was filtered and analyzed using custom pipelines and
gene panels. We developed unique patient-facing materials, including an
online intake survey, group counseling presentation, and consultation
letters in addition to a comprehensive GS report.
Results : The final report includes results generated from GS
data: 1) Monogenic disease risks; 2) Carrier status; 3) Pharmacogenomic
variants; 4) Polygenic risk scores for common conditions; 5) HLA
genotype; 6) Genetic ancestry; 7) Blood group; and, 8) COVID-19 viral
lineage. Participants complete pre-test genetic counseling and confirm
preferences for secondary findings before receiving results. Counseling
and referrals are initiated for clinically significant findings.
Conclusion : We developed a genetic counseling, reporting, and
return of results framework that integrates GS information across
multiple areas of human health, presenting possibilities for the
clinical application of comprehensive GS data in healthy individuals.
INTRODUCTION
Rapid advancements in the field of genomic medicine have prompted
discussions about the integration of technologies, such as genome
sequencing (GS), into clinical and personalized medicine (Prokop et al.,
2018). In the clinical context, GS can increase diagnostic rates and
alter medical management in previously undiagnosed pediatric and adult
patients (Wise et al., 2019). GS may also be used opportunistically to
identify hereditary predisposition to several conditions for the
purposes of preventative screening and management (de Wert et al.,
2021). GS may reveal primary findings that explain an aspect of a
patient’s medical or family history, or secondary findings (SF)
unrelated to patient history. Currently, The American College of Medical
Genetics and Genomics (ACMG) recommends the return of SF related to risk
for medically actionable conditions (Miller et al., 2021). However, as
genomic knowledge continues to grow, so do the possibilities for the use
of GS data outside of current recommendations and standards of care. In
addition, the cost of GS and analysis continue to decline (Weymann et
al., 2017), presenting the possibility for it to be used more broadly.
Finally, relevant stakeholders support the return of SF from GS.
Systematic reviews of studies focusing on return of SF show that the
majority of patients, research participants and society at large wish to
learn all types of SF from genetic investigations, including findings
considered to be actionable and non-actionable (Delanne et al., 2019).
Motivations for learning GS results range from establishing a diagnosis
or explanation for symptoms in patients to understanding future disease
risks for currently healthy individuals and their families (East et al.,
2019). Healthcare professionals exhibit similar support for the return
of actionable SF, but take a more cautious approach to the disclosure of
non-actionable SF (Delanne et al., 2019). Professional societies and
organizations acknowledge the need for stringent protocols and informed
consent surrounding the return of SF through research (Lewis et al.,
2021), as well as careful consideration of the risks (i.e. psychological
harm, disparities in accessibility) and benefits (i.e. prevention of
serious genetic disease) of opportunistic GS in the general population
(de Wert et al., 2021).
To date, more comprehensive approaches to GS, analysis, and reporting
have been applied in the research context. In addition to clinically
significant SF related to personal disease risks and carrier status for
genetic disorders, research participants have the opportunity to learn
about pharmacogenomic variants that alter drug metabolism and impact
medications (Cochran et al., 2021; Vassy et al., 2015). Information on
blood type, platelets, and red blood cell antigens has also been
reported to research participants undergoing GS (Vassy et al., 2015).
Advancements in genome-wide associations studies (GWAS) have allowed for
calculations of polygenic risk scores (PRS) pertaining to risk for
multifactorial conditions like coronary artery disease and type 2
diabetes. Studies have taken different approaches to communicating PRS
to research participants. PRS for common conditions have been presented
as both absolute and relative risks, descriptively and visually, through
physical reports as well as interactive web portals (Marjonen et al.,
2021; Linderman et al., 2016; Brockman et al., 2021). Direct-to-consumer
(DTC) companies, such as 23andMe
(https://www.23andme.com/),
promise to provide information about patients’ future health by
presenting results related to PRS and risk for monogenic conditions such
as hereditary cancers and cardiomyopathies. Reports may also include
information on genetic ancestry and traits such as taste, ear wax type
and athletic ability, all for a cost of approximately $200 USD
(Bellcoss et al., 2021). However, DTC testing is often based on SNP-chip
genotyping and rarely involves pre- or post-test genetic counseling,
increasing the risk of misdiagnosis, false diagnosis and failure to
receive appropriate medical care because of misinterpretation of results
by users (Horton et al., 2019). To our knowledge, there is no process
published to date encompassing the return of all of these elements from
GS data to participants in a single report.
The GENCOV study presents a unique opportunity to explore a process for
the return of comprehensive GS results in a large cohort of ostensibly
healthy individuals. We describe our framework for genetic counseling,
reporting, and return of research GS results beyond the scope of current
clinical recommendations and discuss opportunities to explore the
clinical utility and impact on health outcomes in the future.
MATERIALS AND METHODS
A cohort of ostensibly healthy individuals ≥18 years of age from the
GENCOV study (target N=1500) provided blood samples at baseline
(hospitalized inpatients only), 1, 6, and 12 months after PCR-positive
SARS-CoV-2 (COVID-19) diagnosis. GS was performed. An intake survey was
administered at baseline (before pre-test counseling) to collect
pertinent medical history information. A detailed protocol describing
participant recruitment and study design is published elsewhere (Taher
et al., 2021).