Clinical Genetics: Medicine, Genomics, and Education, in Action

Dr. Faghfoury, a prominent clinical geneticist at SickKids, shares her expertise on all things medical genomics; including her professional journey, misconceptions, and challenges of genetic testing.

George Guirguis, Yasmeen Kurdi, and Anahita Bahreini-Esfahani

Dr. Hanna Faghfoury is a well-known clinical geneticist currently working at some of the most prominent healthcare facilities in Canada such as Mount Sinai Hospital, The Hospital for Sick Children (Sickkids), and University Health Network. She obtained her MD degree from McGill University in 2004, and pursued her interest in medical genetics by completing her post-graduate studies in Medical Genetics, followed by an additional two years training in Clinical Biochemical Genetics – both at the University of Toronto. She is currently the post-graduate director of the Medical Genetics and Genomics program at University of Toronto, and also holds an associate professor position at the Temerty faculty of Medicine. Photo credit Dr Faghfoury.

Imagine being in medical school after years of hard work and dedication only to find yourself not drawn to any of its disciplines. Most medical disciplines are categorized based on organ groups. Dr. Hanna Faghfoury found herself in this specific situation – not drawn to any particular organ system, she was uncertain whether she would find a suitable specialty. This doubt changed to passion and excitement when she enrolled in a Medical Genetics elective. “After the  first day, I called my parents, and I said I found what I want to do for the rest of my life.” What really stood out to Dr. Faghfoury was that a medical geneticist is not focused on a single organ system, yet was not considered to be a generalist. More importantly, medical geneticists had the ability to follow patients longitudinally – from birth and throughout the patient’s life. After getting accepted into the medical genetics residency at the University of Toronto (UofT), she enrolled in an elective of which she has never heard before in medicine- Metabolics. Having completed an undergraduate degree in biochemistry was helpful – despite the often dry and seemingly irrelevant delivery of biochemical pathways as Dr. Faghfoury highlighted. In light of genetics, metabolic pathways made more sense, as they provided clearly actionable targets of intervention. This intensified Dr. Faghfoury’s passion for medical genetics and she pursued this specialty for her career. Today, Dr. Faghfoury is the post-graduate director of the Medical Genetics and Genomics program at UofT, where she also holds an associate professor position at the Temerty Faculty of Medicine.

The completion of the Human Genome project in 2003 ushered in a new era of modern medicine and led to the advent of sophisticated technologies used to sequence DNA. These advances have since transformed the landscape of clinical diagnostics and management of genetic disorders. Contemporary medical genetics has become an expansive subspecialty of medicine, entailing the use of genetic principles such as inheritance and gene mapping in the diagnosis of management of disease. Previously, a geneticist’s expertise in recognizing dysmorphological features was a pivotal factor in identifying candidates for genetic testing1. Furthermore, genetic testing was widely inaccessible due to the slow turnaround times of lab results processing and the astronomically high cost of sequencing. Fast forward to 2011 when the FDA approved next generation sequencing for application in clinical diagnosis2– this marked a paradigm shift in clinical assessment. As genetic testing became cheaper and more accessible, geneticists increasingly integrated these sequencing technologies into their practice, slowly moving away from strictly assessing clinical presentation, or phenotyping, to identify or rule out disease. Dr. Faghfoury notes that as technological and financial barriers surrounding genetic testing decrease over time, the need for phenotyping will decrease – which is what clinical geneticists have been traditionally trained for. She notes that this gradual shift poses somewhat of a professional identity crisis for clinical geneticists in terms of distinguishing the profession from that of a genetic counselor. That being said, medical geneticists have distinct skills from lab personnel and counselors because they are trained in patient management. One limitation that prevents geneticists from broadening the scope of their practice is constraints in capacity and resources that can be attributed to the current model of care. Addressing these limitations will require a systemic re-imagination of the role and scope of medical geneticists in the rapidly changing era of genomics. Despite these capacity and resource constraints, medical geneticists, like Dr. Faghfoury, maintain an invaluable role in patient care.

Dr. Faghfoury’s day-to-day work is dynamic and varied given her multitude of roles. However, a constant part of her work is patient education, where she addresses hesitancies and misconceptions surrounding genetic testing. In pre-test consultations with patients, she emphasizes that “there isn’t a one size fits all for genetic testing”, and that a myriad of tests can offer varied insights that together aid in clinical evaluation. A type of genetic test routinely used in genetic clinics, such as the Fred A Litwin Family Centre in Genetic Medicine where Dr. Faghfoury works as a geneticist, is whole exome sequencing (WES). This technique made its way into clinical diagnostics around the year 2011, and applies next generation sequencing to determine variation in coding regions of genes, also known as exons. About 85% of disease-causing mutations in Mendelian disorders- disorders caused by mutations in only one gene- are contained in exons3. One example of a disease where WES provides a high level of sensitivity and specificity to identify or rule out disease is Wilson’s disease – a genetic disorder that interferes with the body’s ability to remove excess copper. One important limitation of WES is that it only examines one percent of the human genome4. At times, this limitation may render WES ineffective at determining a genetic cause for a patient’s suspected disorder. This is because regulatory regions that modulate expression of genes- essentially turning them on/off- exist outside of exons5. For example, in malformations of cortical development disorders, many patients have no mutations in their genes, but rather in the regulatory regions surrounding them6. For example, intronic repeat expansions have been shown to cause brain disorders such as epilepsy7. The mutations present in these patients are often missed with the use of WES. This is why Dr. Faghfoury educates her patients that a normal WES result does not equate to a negative result, rather it is inconclusive.  “I don’t call a negative result negative, I say ‘it’s inconclusive’ because we just haven’t found the cause of [the] problem”. On the contrary, many patients believe that genetic testing is the be-all-end-all, and that it will always provide answers. “The misconceptions either fall in the category of overvaluing genetic testing or undervaluing it”. Whole genome sequencing (WGS), on the other hand, captures virtually the entire genome, including regulatory regions. Because of this, WGS can provide a more conclusive result. Alongside the advantage of capturing immensely more of the genome, WGS requires extensively more analysis. In addition, WGS is more accurate than WES4.Regrettably, for most Ontario patients, WGS is not currently requestable by physicians. Instead, it is conducted randomly in lieu of WES.

Figure 1: Diagram depicting the whole exome sequencing pipeline. The left side of the figure displays an enrichment of DNA fragments to isolate for protein coding regions (exons). The exons then go through the process of Next-generation sequencing, which involves mapping reads to a reference genome to identify variants including deletions and single nucleotide polymorphisms. Processed reads are then filtered and annotated for associations with disease. (Retrieved from8)

There are many challenges facing the field of clinical genetics, where limited resources represent an especially pertinent challenge. Ideally, a clinical geneticist would diagnose a patient and continually follow-up with them long term. Unfortunately in Canada, there are only seven genetics residency programs in the country that graduate a handful of students each year, creating a high demand for geneticists with a low supply. Because there are not enough clinical geneticists to go around, patients are often followed up by their family physician post diagnosis. This can pose potential issues as clinical genetics is a rapidly evolving specialty and family physicians may not have the specific expertise to follow up with patients diagnosed with genetic disorders. This led to coinage of the term ‘diagnose and adios’ by clinical geneticists, who oftentimes find themselves disengaged from patient management. This is an area in the current medical system that requires more advocacy and change. Not all patients diagnosed with a genetic disorder follow-up with their family physician, however. For certain genetic disorders, there are clinics where clinical geneticists follow-up with their patients, such as the GoodHope clinic (for Ehlers-Dalnos syndrome) and the Genometabolic clinic, where Dr Faghfoury practices. Unfortunately for many patients, this is an equity problem. For example, a patient with a certain genetic disorder will not find a clinic with clinical geneticists to follow-up with, and must do so with their family physician. “Why is it their fault that their mutation happened to be in a gene that didn’t have a subspecialty clinic attached to it? It’s not fair.” This inequity between patients with different genetic disorders is a target for many genetic professionals, whose goal is to ensure that all patients get the best care possible.

The future of the field of clinical genetics looks promising. Recent developments in the field of genetics such as whole-genome sequencing and whole exome sequencing have drastically changed the landscape of managing genetic disorders. An exciting paradigm shift for clinical geneticists mentioned by Dr. Faghfoury is straying away from strictly depending on phenotyping for clinical identification thanks to genetic testing. One example of this shift can be seen with the rapidly expanding field of pharmacogenomics, the study of how genes affect an individual’s response to drugs. Cytochrome P450 2D6 (CYP2D6) is an important gene involved in the metabolism of about 20% of commonly prescribed drugs (Taylor 2020). Interestingly, CYP2D6 is highly variable across different populations, which can directly influence drug metabolism in individuals carrying such variants. To date, 72 different drugs have CYP2D6 clinical guidelines mentioned within their FDA-approved product labels (Taylor 2020). Instead of the trial and error approach typically needed to assess drug efficacy in patients, genetic testing of CYP2D6 can identify individuals that may experience adverse reactions or reduced efficiency, to tailor therapeutic doses accordingly (Taylor 2020). While pharmacogenomics offers exciting potential for personalizing medicine, barriers remain to clinical implementation. Such barriers include the necessary educational and equipment infrastructure to perform and interpret such tests. Moving forward, there will be a greater need for expertise to efficiently integrate genetic testing into commonplace clinical practice. As Dr. Faghfoury puts it,  “right now we need all hands on deck” to effectively usher in this new and rapidly evolving era of healthcare.

References

  1. Tromans, E., Barwell, J. Clinical genetics: past, present and future. Eur J Hum Genet (2022). https://doi.org/10.1038/s41431-022-01041-w
  2. Efthymiou, S., Manole, A., & Houlden, H. Next-generation sequencing in neuromuscular diseases. Current opinion in neurology, 29(5), 527–536. (2016). https://doi.org/10.1097/WCO.0000000000000374
  3. Rabbani, B., Tekin, M. & Mahdieh, N. The promise of whole-exome sequencing in medical genetics. J Hum Genet 59, 5–15 (2014). https://doi.org/10.1038/jhg.2013.114
  4. Belkadi, A., et al. Whole-genome sequencing is more powerful than whole-exome sequencing for detecting exome variants. Proc Natl Acad Sci U S A. 112(17), 5473–5478. (2015). https://doi.org/10.1073/pnas.1418631112
  5. Barrett, L. W., Fletcher, S., & Wilton, S. D. Regulation of eukaryotic gene expression by the untranslated gene regions and other non-coding elements. Cellular and molecular life sciences : CMLS, 69(21), 3613–3634. (2012). https://doi.org/10.1007/s00018-012-0990-9
  6. Perenthaler, E., Yousefi, S., Niggl, E., & Barakat, T. S. Beyond the Exome: The Non-coding Genome and Enhancers in Neurodevelopmental Disorders and Malformations of Cortical Development. Frontiers in cellular neuroscience, 13, 352. (2019). https://doi.org/10.3389/fncel.2019.00352
  7. Scheffer IE. The Key to FAME: Intronic Repeat Expansions Cause Human Epilepsies. Epilepsy Curr. 2018;18(4):238-239. doi:10.5698/1535-7597.18.4.238
  8. Goh, G., Choi, M. Application of Whole Exome Sequencing to identify Disease-Causing Variants in Inherited Human Disease. Genomics Inform. 10(4):214-219. (2014).
  9. Taylor C, Crosby I, Yip V, Maguire P, Pirmohamed M, Turner RM. A Review of the Important Role of CYP2D6 in Pharmacogenomics. Genes (Basel). 2020;11(11):1295. Published 2020 Oct 30. doi:10.3390/genes11111295

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