Q & A - Hencher Lee
Please tell us about your academic background and professional experience working in a public-funded Hong Kong hospital?
I completed medical school in The Chinese University of Hong Kong and started my postgraduate fellowship training in chemical pathology and genetic pathology afterwards. I have obtained fellowship in chemical pathology under The Hong Kong College of Pathologists (HKCPath) and The Royal College of Pathologists of Australasia (RCPA), and fellowship in molecular genetics under The Royal College of Pathologists (RCPath). I have also obtained certifications for International Technologist in Molecular Biology by the American Society for Clinical Pathology (MB(ASCPi)) and European registered Clinical Laboratory Geneticist (ErCLG) (affiliated). My part-time studies have earned me a Master of Science in Analytical Chemistry from Hong Kong Baptist University, a Master of Arts in Health Care Ethics and Law from University of Manchester, and a Master of Science in Molecular Pathology and Genomics from Queen Mary University of London.
“..we regard our experience valuable and would always like to document these in the medical literature for the reference of other medical professionals.”
Working in a clinical diagnostic laboratory means that we handle specimens sent to the laboratory from real patients. We oversee the day-to-day laboratory operations and issue interpretative reports for sophisticated tests like genetic tests and toxicology tests. We develop new diagnostic tests when the clinical need arises. Often, we do not have dedicated funding for research and we lack resources for analyses beyond our scope of diagnostic tests. But definitely, we regard our experience valuable and would always like to document these in the medical literature for the reference of other medical professionals.
How did you discover the source of the unknown myopathy you observed in Hong Kong Patients?
In 2008 our neurologist introduced the first patient to our team. The gentleman had weakness in his 50s but he was alarmed by the strong family history that his father and paternal relatives also had a similar problem which started in the 50s and caused deaths in the 60s. So obviously this worried him. His muscle biopsy findings were somehow not typical of the pathology so we did not have any clue, until we gathered the slides of muscle biopsies from all his affected family members and our histopathologist decided it looked like a certain type of myopathy (myofibrillar myopathy) – yet still the condition is heterogeneous and a lot of genes could be implicated. Back then no large-scale sequencing technology was available and the genes were tested one after the other, and as a result we reached the genetic diagnosis after a few years. At that time we already had another family approached us for a similar clinical problem, which were also very quickly proven another group of affected patients. Cases kept coming in and very soon we understood that this is a frequent genetic variant limited to ethnic Chinese patients in our locality.
So far, we have confirmed the pathogenic variant in 34 patients in nine families. In our journal article published in Clinical Genetics in May 2020 we studied the clinical characteristics of our cohort of cases and demonstrated that the pathogenic variant is a founder variant, i.e. it was probably inherited from one single ancestor of these patients.
Is this disease unique to Hong Kong populations? If so, why do you think this is?
We very soon realized this FLNC variant is a common pathogenic variant in Hong Kong Chinese patients when a large majority of patients with adult-onset proximal muscle weakness as well as a strong family history would harbor this pathogenic variant.
The local prevalence is significant and we believe the allele frequency of this variant is not low locally. Interestingly, it is never described in patients in other parts of the world, and it is absent in multiple datasets of normal populations so far. From these, we postulate that this is a founder variant limited to Hong Kong Chinese. A similar FLNC variant is also known to exist in Germany, leading to a higher prevalence of disease in their population as well.
Could your research ease the fears that the disease is a ‘family curse’?
Our patients are often concerned about the strong family history which has been known to them for a few decades. They saw that their affected family members became crippled due to the devastating nature of the disease, one after another, and died of it.
The psychological impact is understandably strong and they have a deep-rooted fear for the condition, with no way to know if they themselves would develop it or not. The molecular diagnosis definitely ends the diagnostic odyssey and gives a scientific basis for the disease.
Proper genetic counselling enables them to make their own choices of whether to test themselves and have better planning, and they now know preimplantation genetic diagnosis is technically feasible and they could end the “curse” at their generation if they opt to. In this era the genetic information also allows them to search online by themselves for relevant information including latest research on potential therapies. This could be a kind of patient empowerment which is achieved via making the correct genetic diagnosis.
How can others support you to raise awareness of the origins of the disease and help to find treatments?
So far the awareness for this particular condition is not high among medical professionals as well as in the public in Hong Kong, and we believe this particular condition is still underdiagnosed.
For instance, our patients told us that some distant relatives of theirs would regard this as escalated aging and refuse to seek medical advice at all.
We hope the local clinicians could be aware of the prevalence of the condition in this locality and refer the suspected patients for appropriate genetic counselling and testing.
When we have a certain number of patients, we also hope that pharmaceutical companies might be made aware of the condition and might consider development of treatments.