Fall 2021 (Volume 31, Number 3)
Learning to Find Needles in Haystacks:
Fellowship for Advanced Genomics in
Rare Diseases
By Jason W. An, MD, MSc, FRCPC
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Fifty. That’s the number of new autoinflammatory
diseases discovered in
the past decade. The invention of and
rapid developments in genomic sequencing
technologies have revolutionized our ability
to make molecular diagnoses and ushered
in an unprecedented era of precision
medicine in rheumatology.
With the introduction of the Genome-wide
Sequencing Ontario (GSO) program
in April 2021, genetic testing that was
previously sent out internationally can
now be performed locally in the
province. As more genetic studies
are performed, we as rheumatologists
will have to be prepared
to address complex questions.
Referring colleagues may inquire on “What is the significance
of this heterozygous variant of uncertain significance
in the MEFV gene, in my patient with unexplained
fevers?” Similarly, our patients may ask “Does this TNFRSF1A
pathogenic variant mean I have tumor necrosis factor
receptor-associated periodic syndrome (TRAPS), and what
are the risks of my children developing inflammatory disease?”
We will need to read genetic reports that describe
a variant’s population frequencies, conservation, and in
silico prediction scores — and interpret them to manage
patients. How are we to make sense of all this information,
which we were never taught in medical school or residency?
How do we keep up with these rapid advancements in
immunology and genetics?
In 2019, the Department of Clinical and Metabolic Genetics
at The Hospital for Sick Children launched the Fellowship
for Advanced Genomics in Rare Diseases. Funded
by the Canadian Gene Cure Advanced Therapies for Rare
Disease (Can-GARD), the fellowship had two aims: First, to
promote education and literacy in genetics across all fields
of medicine; and second, to equip newly graduated specialists
to proficiently manage patients with rare genetic
conditions within their own specialty.
As a rheumatologist with an interest in genetically driven
inflammatory conditions, I was fortunate to graduate from
this unique program in rare diseases. By attending pediatric
and adult clinics in genetics, metabolomics, autoinflammation
and immunology, I learned approaches
to investigating complex genetic conditions.
Training in the molecular laboratory taught
me the intricacies of analyzing genomic
data. Just as it is important to know whether
anti-nuclear antibodies were assayed with
immunofluorescence or ELISA, it is important
to understand the different genetic sequencing
technologies with their strengths
and limitations in order to interpret
the results, counsel patients, and inform
management. Indeed, finding needles in
haystacks is the essence of rare
disease medicine.
The Rare Diseases Fellowship was
eye opening and highlighted the discrepancy
between the importance
of genetic literacy in our future practices and the lack of
genetics education in our current residency programs. As
genetic testing continues to develop at a rapid pace and
becomes increasingly integrated into rheumatology practice,
we will need to place greater emphasis on genetics
education at all levels, from medical school to subspecialty
fellowship training.
The skills I learned in this fellowship will indeed be
important as a new staff rheumatologist at St. Michael’s
Hospital in Toronto. With the continued mentorship of
Dr. Ron Laxer and collaborations with the rheumatology-genetics
research team at SickKids, we aim to establish a
clinic for the investigation and management of adult patients
with recurrent fevers and undifferentiated systemic
inflammation.
Gone are the days when every recurrent fever syndrome
was labelled as Familial Mediterranean Fever (FMF) or
“atypical FMF.” As we find more needles in the haystack,
the 50 monogenic diseases discovered in the past decade
may prove to be just the tip of the iceberg.
Jason W. An, MD, MSc, FRCPC
Staff Rheumatologist,
St. Michael’s Hospital
Toronto, Ontario
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