PROBLEMS OF UNKNOWN SIGNIFICANCE:
COUNSELING IN THE ERA
OF NEXT GENERATION SEQUENCING
Fahrioğlu U
*Corresponding Author: Assistant Professor Umut Fahrioğlu, Department of Medical Biology, Faculty of Medicine, Near
East University, Near East Boulevard, Nicosia, Cyprus. Tel: +90-392-675-1000, Ext: 3019. Fax: +90-392-675-1090. E-mail:
umutfahrioglu@gmail.com or umut.fahrioglu@neu.edu.tr
page: 73
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Abstract
Dear Editor,
Next generation sequencing (NGS) has changed the
way we approach the diagnosis, prognosis and treatment
of genetic disorders. It gave us base pair (bp) precision,
multi-gene approach that can be executed in a timely and
cost-effective manner. Despite some minor technical issues
in NGS, it comes with great advantages. However,
the clinical, and especially, genetic counseling profession
will need to rise to the challenge to face some of the new
issues, dilemmas and problems this new technology is
bringing to the table. Some of the counseling guidelines
predate the NGS era and will urgently need to be brought
up to par with the technology.
Keywords: Cancer; Challenges; Genetic counseling;
Next generation sequencing (NGS); New guidelines.
Conditions such as cystic fibrosis are caused by a
single gene, therefore, counseling and testing for this condition
is relatively straight forward with well established
guidelines to guide the genetic counselor and other health
professionals [1]. However, many genetic disorders can
be heterogenous in both their genetic and clinical presentation,
as demonstrated very clearly with neurological
conditions such as glutaric aciduria type I (GA1), Canavan
Disease, cancer and neuromuscular disorders [2-8]. Next
generation sequencing (NGS) has been changing the way
we approach the diagnosis, prognosis and treatment of
these complex genetic disorders. It provided us with the
ability to investigate the genomes and variations with the
precision of base pair (bp) resolution, decreasing cost and
making the whole process more effective and informative
[2,9].
In today’s clinical environment, a timely and cost-effective
diagnostic approach to genetic disease would surely
include NGS, on top of a gold standard clinical assessment.
We are now able to sequence multiple genes at the same
time instead of a sequential testing approach traditionally
recommended, thus saving precious time and money. Additionally,
the new testing approaches are aiming to reduce
the uncertainty associated with sequential testing. Despite
the advantages of NGS approaches, such as whole exome
sequencing (WES) and whole genome sequencing (WGS),
they both still do have their technical shortcomings, such
as triplet repeat resolution, exome capture, higher falsepositive
rates compared to the Sanger method and higher
incidence of variants with unknown significance [2,7-14].
The sequencing results have reinforced some of the pathological
findings that are already in the common molecular
knowledge but some of the genetic consequence contributing
to neurological disease might still be able to elude
even the best of genome sequencing [9].
With advances in the laboratory coming in leaps and
bounds, the clinical and counseling part will also need
to keep up. Burden is starting to fall more commonly on
the interpretation of the NGS results, requiring a multidisciplinary
team, which must include a well-trained genetic
counselor. This need becomes more pronounced if
the results are ambiguous [2,14]. We are already seeing
some issues with NGS being raised for genetic counseling
in cancer genetics, nephropathies and arrhythmias. Genetic
counselors have always been in the forefront in adopting
and integrating new technology into their practice. The
new technology would mean that genetic counselors need
to cover increasingly more clinically relevant information
in their session. The genes that will be tested in the panel,
or what it means to analyze a whole genome or exome
sequence, the turnaround time, variants of unknown significance
and the quality of the test results are just some of the difficult topics that need to be covered [2,8,15-17]. This
would hold true not just for counseling in cancer genetics
but for many specialized areas of counseling including
pharmacogenomics population screening, presymptomatic
testing and research [18]. The rules and guidelines
and regulations for genetic counseling have been established
for a long time, and with the technology pushing
the laboratory very far, very fast, counseling guidelines
and guidance will need to catch up. The latest guidelines
and recommendations regarding the impact and use of
NGS in areas such as cancer susceptibility could be found
on various human genetics society websites. However,
the most recent of these documents date back to 2014
[19,20]. There is very limited literature on this issue but
genetic counseling in the era of NGS is an urgent topic to
be addressed, especially in fields such as cancer biology,
pediatric disorders such as neuromuscular disorders and
multifactorial disease. Many of these fields have guidelines
that deal with counseling and informed consent in single
gene or sequential gene testing situations. The current
guidelines are not designed to deal with multiplex testing
situations, where multiple genes are tested simultaneously,
and therefore compromise both the counseling and the
informed consent process [8,17]. According to some of
the recommendations, the reason for the lack of practice
guidelines is the absence of enough data on the topic [8].
As evidenced by the term “genomic tsunami” the challenge
for this type of counseling would be the vastness of the
task, not the information that needs to be covered [18].
One of the biggest challenges that accompany the
NGS technology is the greater risk of discovering variants
of unknown clinical significance [17]. The large number
of genes being tested may lead to a number of unwanted
findings, such as risk factors for other diseases, or to unclassified
variants [18]. Very specialized experts such as
molecular pathologists and clinical geneticists are required
to determine the pathogenicity of the variants identified
and tease out the pathogenic ones from the benign ones
[9-11]. Some great questions have already been asked
regarding the clinical and patient follow-up implications
of NGS and genetically overlapping disease [9]. As the
term coined by Ackerman [21] so bluntly puts it, “genetic
purgatory” is something to be aware of when we
face uncertain results or discover a “variant of unknown
significance (VUS)”. The uncertainty and the ambiguous
results are very difficult for families to deal with. These
families and individuals are already dealing with a difficult
psychology related to their difficult situation. We add onto
it the stress of a genetic test and ambiguous results. The
European Society of Human Genetics has put together a
comprehensive “guide” for patients regarding NGS [22].
However, even with this information, multiplex testing and
the VUS create a situation that is challenging for counselors
and other medical professions, let alone patients with
limited understanding of genetics [14].
It is of utmost importance for everyone to clearly
spell out the benefits and limitations of a testing procedure.
Many steps, such as functional assays, will need to be
undertaken to discover the molecular implications of the
VUS, but at the end of the day, the clinical implications of
these findings will remain unclear for the patient in front
of us [11,17]. Moreover, such approaches take a lot of time
to reach a result and the patients and families just do not
have the time to wait as they are desperate for a diagnosis
or reproductive decisions and there is an urgency attached
to all these decisions.
As mentioned earlier, a great effort is already underway
to revise counseling guidelines, especially in the
field of cancer susceptibility. The lessons and observations
from this field would be valuable in setting up new genetic
counseling practice guidelines in various fields that are
using NGS. The current guidelines are very good at providing
the process a great structure. Phenotype-genotype
relationships of the one gene being tested is an easy task.
However, the task becomes immensely harder when tens,
hundreds and sometimes thousands of genes are tested at
the same time. Without solid data to guide us it is not possible
to tease out exactly what the new guidelines should
be. However, these tests are being offered at the moment
without some of the comforts of conventional testing
procedures. Clear and structured research is required to
understand the specific needs of the patients, the counselor
and the process itself with the NGS testing on the table.
Only then can we try to begin to shape the guidelines.
The new guidelines should address the new issues that
come hand in hand with NGS such as the vast amount of
information produced, some of which could be unsolicited,
and the strain this information would put on the pre- and
post-test counseling, informed consent, the counselor, and
of course, the patient. Some of these issues and challenges
have been summarized in Table 1.
Declaration of Interest. The authors report no conflicts
of interest. The authors alone are responsible for the
content and writing of this article.
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