JACC: ADVANCES
2, 2024
ª 2024 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN
COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER
THE CC BY LICENSE (http://creativecommons.org/licenses/by/4.0/).
EDITORIAL COMMENT
Ensuring Equity, Diversity, and
Inclusiveness in Genetic Analysis
Will Empower the Future of
Precision Medicine*
Keith R. Brunt, PHD,a,b,c,y Victoria Northrup, PHDa,b,y
C ardiovascular disease is a spectrum of heri-
table and acquired exposures driving com-
plex disease presentations.
disparity is a collective effort we should all embrace
Reducing
to achieve clinical precision. Genetic testing is a
powerful clinical tool. It can reconcile heritable traits
with cardiovascular diseases, like cardiomyopathies,
as part of standard medical management.1-4 There is
a persisting risk of variant misclassification as vali-
dated pathogenicity is informed iteratively by new in-
formation.5 Inaccurate variant classification can
result in false alarm/reassurance. Prior studies
showed 5 hypertrophic cardiomyopathy-associated
variants with higher minor allele frequency (MAF) in
Black Americans compared to White Americans
resulting in downgraded pathogenicity.5 Golbus
6
et al established a wide variation of allele fre-
quencies in 3 cardiomyopathy-associated genes in Af-
rican, American, Asian, and European ancestries.
Ancestry has a significant impact on allele fre-
quencies and classification. Genetic studies elevate
our understanding of pathogenic variants and their
*Editorials published in JACC: Advances reflect the views of the authors
and do not necessarily represent the views of JACC: Advances or the
American College of Cardiology.
Fom the aDepartment of Pharmacology, Dalhousie University, Halifax,
Nova Scotia, Canada; bDalhousie Medicine New Brunswick, Saint John,
New Brunswick, Canada; and the cDepartments of Cardiology & Cardiac
Surgery, New Brunswick Heart Center, Saint John Regional Hospital,
Saint John, New Brunswick, Canada. yDrs Brunt and Northrup are part of
the IMPART Investigator Team Canada (https://impart.team/).
The authors attest they are in compliance with human studies commit-
tees and animal welfare regulations of the authors’ institutions and Food
and Drug Administration guidelines, including patient consent where
appropriate. For more information, visit the Author Center.
ISSN 2772-963X
VOL. 3, NO.
associated molecular pathways and present new
therapeutic targets. Despite a substantial increase in
genomic studies, the heavy bias toward European
ancestry hinders clinical utility and reliability. This
ancestry accounts for 80% to 90% of genomic
studies,5,7-9 whereas European descent is only w15%
of the world’s population (Figure 1A).10 Even in
countries with diverse urban populations, genomic
studies remain heavily biased toward European
ancestry. Multiple factors contribute to this.
Large-scale genomic studies are sophisticated and
costly—capacity abundant in Europe and North
America (colonized foremost by Europeans). Under-
represented or marginalized populations experienced
historical injustices, coercion, or deception, driving
negative experiences and distrust.7 Low visible rep-
resentation and unconscious bias of who is
approaching and who is approached for study
enrollment. Low genomic diversity leads to inaccu-
rate allele frequency estimates, as European allele
frequencies dominate risk assignment and are un-
linked to evolutionary events such as human migra-
tion, ecological assimilation, or diversification that
are physiological.
As genetic tests are to be considered in an ancestry
context, this can perpetuate healthcare disparities,
especially when pathogenicity is conflated with race
or ethnicity. 11 Social constructs are ill-suited for
pathogenetic diagnosis or differentials, and negative
outcomes associated with racial context are more
likely caused by racist actions, social determinants, or
systemic racism perpetrating harm to patients.12 It is
important to distinguish biologically determined
pathogenetic variation, sex determinism, and epige-
netics into reference data or annotations that inform
https://doi.org/10.1016/j.jacadv.2023.100769
2 Brunt and Northrup
Diversity Empowers Precision Medicine
F I G U R E 1 Diversity of Genomic Studies Improves Precision Medicine
(A) World population projections compared to genome-wide association studies (GWAS). (B) State-of-the-art known human variation (outer circle) is fragmented into
what is needed (inner circle, gray) for precision medicine.
the intersectionality of genetic diagnosis, counseling,
3,13,14
and medical management. Reconciling the pre-
dominance of male/White, first and foremost in clin-
ical trials and research data collections requires
conscientious action to achieve equity. 15
Thankfully, cardiologists and clinical geneticists
are making antiracism progress medically by focusing
attention on expanding ancestral diversity of genetic
reference and variant risk (re)assignment, so as to be
more inclusive of the diverse populations we seek to
serve.12 Rosamilia et al 16 examined the instability of
variant classification in cardiomyopathy-associated
genes including 10 sarcomeric and 6 desmosomal
genes from the ClinVar database between 2011 and
2021. Cardiomyopathy-associated variants in ClinVar
were reevaluated at a higher rate compared to other
variants in ClinVar (2.34 times/10 y in cardiomyopa-
thy vs 2.03 times/10 y average). Importantly, 7.3% of
the cardiomyopathy-associated variants underwent a
clinically significant category change (compared to
4.4% average for all variants). These results suggest
an increased instability in the categorization of
cardiomyopathy-associated variants. A change in
categorization could result in inaccurate diagnosis
and prognostic information for patients. A pathogenic
or likely pathogenic variant can be stressful to an
individual and their family, resulting in additional
testing, radical changes to lifestyle, or medical man-
agement (under-over-treatment).
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Rosamilia et al16 further evaluated the potential
reasons for the lower stability in classification of
these variants and found that variation in MAF be-
tween populations resulted in the downgrading of
29% of the variants that were reevaluated. MAF is
utilized in the categorization of variants as the typi-
cally pathogenic are very low MAF and higher MAFs
are typically considered benign.17 Many of the vari-
ants that decreased in pathogenicity had a MAF
of <0.0001 in European ancestry, suggesting higher
pathogenicity. Yet, the MAF in non-European
ancestry was >0.0001, indicative of benign varia-
tion. Ancestry was even more significant in these
downgrades compared to variant evidence quality.
Given the overrepresentation of European ancestry in
genetic studies, this biases MAF to those of European
populations. Therefore, variants with MAF that are
higher in non-European populations may not be
captured and result in increased pathogenicity clas-
sifications. Taken together, potential harm to patients
of both European and non-European ancestry is
implicated.
Increasing diversity in genomic studies will allow
for improved recognition of natural and evolutionary
genetic diversity. This will result in accurate variant
classification by accounting for diversity in popula-
tion genetics (Figure 1B). One limitation of the Rosa-
mali et al16 study is that they did not examine
temporal variations. During the period of the study,
JACC: ADVANCES, VOL. 3, NO. 2, 2024
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the classification framework was updated in 2015.17
Therefore, it is possible that accuracy is already
improving as awareness of studies of priority pop-
ulations grows. Regardless, continuing to increase
our diversity in genomic studies will lead to better
and more equitable healthcare for all patients. The
variant classification instability shown by Rosamilia
et al 16 also highlights the need for clinical reviews of
patients that have already received genetic testing.
Particularly for patients that showed sarcomeric
variation, a significant number were downgraded
from pathogenic or likely pathogenic to a variant of
unknown significance. Patient reviews could recon-
cile unnecessary medical management (for the pa-
tient or any relatives). A downgrade from a variant of
unknown significance to benign is less likely to
change medical management and therefore will be
16
less significant. Rosamilia et al did not examine how
these changes would affect medical management for
the patient or their relatives. However, this study16
does support the need for patient review as sug-
gested by the American Heart Association.1
As we improve the accuracy of genetic testing with
increased diversity of genetic studies, we should
reflect on the non-European ancestry as a percentage
of the world population compared to genome-wide
association studies completed to date. If we do not
increase diversity in genomic studies, the disparity
will worsen (Figure 1). Just as the issue of bias in ge-
netic studies results from multiple factors, the solu-
tions to improving diversity are also multifaceted.
Fatumo et al 7 and Lemke et al 9 advise steps toward
improving diversity. Briefly, they recommend col-
laborations that focus funding on establishing or
expanding global capacity within various underrep-
resented regions. Building capacity will also improve
engagement with marginalized communities in North
America. In addition to scientific capacity, collabora-
tions should include expertise in ethical, legal, and
social implications of genomic research. This will
improve accountability and allow for appropriate data
sharing and annotations. By engaging with local
communities as patient partners 18,19 and encouraging
collaboration, we can secure diverse representation
globally. This should include connecting meaning-
fully with Indigenous communities
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Brunt and Northrup 3
Diversity Empowers Precision Medicine
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FUNDING SUPPORT AND AUTHOR DISCLOSURES
Dr Brunt was funded by the Natural Sciences and Engineering
Research Council (NSERC) [grant # RGPIN-(2020)-04878]. Dr
Northrup was supported by the NSERC Alexander Graham Bell Can-
ada Graduate Scholarship-Doctoral (CGS D).
ADDRESS FOR CORRESPONDENCE: Dr Keith R. Brunt,
Dalhousie Medicine New Brunswick (DMNB), 100 Tucker
Park Road, Box 5050, Saint John, New Brunswick E2L 4L5,
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KEY WORDS cardiomyopathy, genetic testing,
gene variant classification, race