To promote B cell immunity in a rare neurological disorder
HSAN-I is a rare neurological disease. Patients having this disease do not feel pain. As a result, HSAN-I patients usually do not seek immediate medical treatment of small skin injuries. Because of neglecting these minor injuries, HSAN-I patients often have severe infections and ulcerations that may necessitate amputation afterward. Our preliminary study shows that a group of anti-infection immune cells, called “B cells”, have defects in activation and proliferation in HSAN-I patients. We will test a method to correct these defects by giving a chemical compound that is missing in HSAN-I T cells. We believe this novel method will enhance the anti-infection immunity of HSAN-I patients.
Identifying the genetic cause for Actinic Prurigo in Canadian First Nations.
Actinic prurigo (AP) is a rare genetic sun-induced skin condition. It is seen mainly in Aboriginal populations in Canada and the United States as well as Central and South America. The condition is associated with intense itching when the skin is exposed to sunlight. The itching results in compulsive scratching causing deep wounds and a higher risk of skin infections. Sunlight exposure may also cause inflammation of the lips and eyes. The condition starts early in childhood and persists lifelong. AP has a significant impact on the quality of life. Outdoor activities and occupations are severely impacted. This distressing disease is affecting several of our Aboriginal populations yet has been a neglected area of research. The causative genetic mutation is still unknown and no effective treatment is available. In this study, we will investigate the underlying genetic mutation causing AP in First Nations population. This is an essential first step to understand the abnormal response to the sun. This will be done by analyzing the entire genetic code for members of an affected First Nations (Cree) family. If the responsible genetic change is identified, we intend to investigate how such a mutation produces this condition. Understanding this mechanism will help us to explore possible treatment options. We aim to identify the genetic cause and identify treatment options and hope to improve the quality of life for the affected families.
Assessing impact of novel POLG mutations on mitochondrial DNA copy number and mitochondrial function
Mitochondria are the energy power plants of our cells, and their normal function relies on genes encoded on small circles of mitochondrial DNA (mtDNA) that are found in almost all mitochondria. Mutations in the gene for the protein that makes mitochondrial DNA, POLG, are linked to several mitochondrial diseases including Alper’s syndrome and chronic external ophthalmoplegia (CPEO). A review of charts in our neurogenetic clinic revealed that several undiagnosed patients, with symptoms suggesting they might have mitochondrial disease, have genetic variants in the POLG gene. Whether these variants affect POLG function, and, in turn, cause these patient’s health problems, is not yet known. We plan to introduce these POLG variants into cultured cells to test if they affect the number of copies of mitochondrial DNA that POLG makes per cell or the number of mistakes that POLG makes when copying mitochondrial DNA. The blood vessels of patients with disease-causing POLG variants have a problem relaxing and or are unusually stiff, causing hypertension, and even directly impairing blood flow. This circulatory problem can be treated, particularly when diagnosed earlier in life. So knowing who really has the disease is critically important in preventing strokes and organ damage. Our work figuring out which genetic variants in POLG cause disease will help patients with the same variants around the world.
Molecular pathogenesis and targeting of FANCJ in Fanconi Anemia
Fanconi anemia (FA) is a rare genetic disorder characterized by congenital abnormalities, progressive bone marrow failure and cancer predisposition. FA occurs in 1 in 100 000 live births. Mutations in at least 21 genes (FANCA to FANCV) can cause FA. Proteins produced from these genes are involved in a cell process known as the FA pathway. The FA pathway is particularly responsive to a certain type of DNA damage known as interstrand cross-links (ICLs). ICLs occur when two DNA building blocks (nucleotides) on opposite strands of DNA are abnormally attached or linked together, which stops DNA replication that is vital for cells’ survival. FANCJ is one of the FA proteins that participate in this DNA repair process. Some inherited mutations in the FANCJ have been found to lead to FA. However, the mechanism whereby these mutations cause FA remains unknown. Through using biochemical and cellular approaches, the objective of this study is to understand how mutations of FANCJ lead to FA syndrome, and search for potential small molecules to kill FANCJ-related tumor cells while sparing healthy cells. We propose to examine whether these mutations affect FANCJ’s enzymatic activity and/or impair its other biological functions. We will identify small molecules that modulate FANCJ’s function, with the aim of finding novel chemotherapeutic drugs to selectively kill FANCJ-mutated tumor cells. The results obtained from this study will both advance fundamental knowledge of FANCJ pathogenesis and potentially lead to therapeutic strategies by targeting FANCJ for Fanconi anemia patients.
Assessing the psychosocial impact of surveillance in the pediatric population
Childhood cancer is rare, with 161 out of 1,000,000 children being diagnosed with cancer in Canada per year. An even smaller percentage of these cancers, approximately 10-30%, are hereditary, or cancer that is running in the family. These cancers are due to a genetic predisposition, which puts children and their family members at an increased risk to develop cancers over their lifetime. Children who are identified to have a predisposition to developing cancer are recommended to undergo surveillance imaging, which can consist of MRIs, ultrasounds, colonoscopies and bloodwork to detect early asymptomatic cancers. Challenges of surveillance include anxiety surrounding the tests and awaiting results, further invasive testing to clarify uncertain findings, risks of general anesthesia or sedation, and the multiple trips to specialty centres. While cancer surveillance can improve patient outcomes, the psychosocial impact is unknown in this rare group of children and adolescents. In order for health-care providers to better support patients and their families, it is important to understand the psychosocial impact of undergoing regular cancer surveillance. In this study, we will interview adolescents and parents of children who are undergoing regular cancer surveillance at our hospital. These interviews will explore participants’ understanding about the cancer risks associated with their condition, their experiences with and attitudes towards surveillance, and coping strategies. The findings from this study will inform the future development of surveillance guidelines and allow health care providers to better support their patients. As fears and anxieties regarding surveillance have led to the avoidance of this potentially life-saving intervention, a better understanding of the psychosocial impact on families aims to improve patient outcomes and quality of life.
Results - The findings from this study provide a fundamental understanding of families' experiences with surveillance in the pediatric population. We completed 20 semi-structured interviews of 11 parents and nine adolescents. Four major themes were identified to be shared among the two groups: what contributes to resiliency, perceived personal utility of surveillance, challenges of surveillance and factors influencing surveillance experience. Participants felt that the benefits of surveillance outweighed the perceived challenges and that the worry surrounding surveillance is generally cyclical (i.e., the appointment acts as a reminder of cancer risk but is not a day-to-day worry). Both parents and adolescents expressed difficulties sharing or explaining information related to their condition and surveillance to those outside their immediate family system. This study identifies a need for psychological support embedded within the cancer predisposition surveillance clinic, particularly during the first year following diagnosis, and reinforces the need to develop resources for families to discuss their genetic condition and surveillance strategies with others. The results from this study give health-care providers a better understanding of the families' experiences undergoing cancer screening, which will allow them to anticipate potential challenges and better support their patients.
This work has been presented in poster format at the Genetics Research Day at the Hospital for Sick Children and will be presented at the Canadian Association for Genetic Counsellors Annual Education Day 2019. We are currently working on publishing this project in a peer-reviewed journal.
Resolving the molecular cause in patients with undiagnosed genetic diseases
Whole-genome sequencing (WGS) is the most comprehensive genetic test that is currently available for diagnosing patients with rare genetic disorders. Although WGS offers remarkably higher molecular diagnostic yield compared to conventional genetic tests, more than half of patients who undergo WGS fail to receive a conclusive diagnosis. This can be explained, at least in part, by the inability of current clinical short-read WGS approaches to reliably diagnose certain kinds of disease-causing mutations. Newer sequencing technology like long-read WGS can overcome these limitations and permit the detection of many mutations that are currently being missed, but long-read WGS is too expensive and/or error-prone for routine clinical diagnostic application. Recently, Bionano Genomics, Inc., launched an advanced optical mapping solution to query complex genetic variants that are not being found with current short-read WGS analysis. We will use Bionano optical mapping to screen for the underlying molecular cause in two patients who are strongly suspected to have a genetic disease but were not diagnosed by standard clinical WGS analysis.
Skeletal dysplasia: Establishing metabolic and nutritional requirements to improve healthcare
Lay Summary: Skeletal dysplasia is a rare genetic condition that prevents bones from growing in the usual way (sometimes referred to as “dwarfism”). Most people notice that this results in short arms and legs but are unaware of the many other health problems that limit quality of life (e.g. breathing difficulties, back pain and spine surgeries, joint pain and difficulties moving around in a world designed for taller people). All these problems are made worse if a person is overweight or obese. This is important because people with skeletal dysplasia are more likely than those of average height to gain weight and so are also more at risk of life-threatening diseases like type 2 diabetes and heart disease. Nobody knows why being extremely short causes these problems but our previous pilot work supported by the Rare Disease Foundation has indicated that individuals with skeletal dysplasia may have a disproportionately low metabolic rate, possibly due to low levels of thyroid hormone. We therefore hope to take further blood samples to confirm this finding both to publish the new information and to inform the design of a larger trial to better understand and help this unique group of people.
Targeting malonylation in mitochondrial phosphate carrier deficiency and mitochondrial cardiomyopathy
Mitochondrial diseases are a heterogeneous group of genetic disorders unified by defects in mitochondrial energy metabolism. Mitochondrial diseases are rare, occur with an incidence of ~1 in 5000 births, and impact vital organ systems with high energy demands, such as the heart. Currently, there are no cures and patients are treated for their symptoms with limited long-term efficacy. Thus, therapies that directly address mitochondrial dysfunction are urgently needed. In this study, we are focusing on mitochondrial phosphate carrier deficiency (MPCD), a devastating mitochondrial disease where patients display cardiomyopathy, muscle weakness and early mortality. MPCD is caused by mutations in the mitochondrial phosphate carrier (PiC) which imports inorganic phosphate into the mitochondria. Because inorganic phosphate is required to make energy (ATP), PiC is essential for energy production. Thus, MPCD patients have an impaired capacity to make energy. To understand the molecular mechanisms underlying MPCD cardiomyopathy, we have developed a unique mouse model where PiC can be inducibly deleted in the heart (the PiC-CKO mice). Using these animals as a genetic tool to hone in on molecular changes specific to PiC deletion and mitochondrial energy dysfunction, we found that mitochondrial proteins from the PiC-CKO mice are highly modified by malonylation, a newly discovered protein modification that has been shown to have a regulatory role on metabolic proteins. We hypothesize that the malonylation contributes to the decline in cardiac function following PiC deletion and that reducing cardiac malonylation will blunt disease progression. In this study we will test this hypothesis by using a cardiac gene therapy strategy to reduce malonylation in the PiC-CKO animals. We believe that completion of this project will provide important groundwork to establish the therapeutic potential of targeting malonylation as a new treatment strategy for MPCD patients.
Which patients with Lennox-Gastaut syndrome will benefit from deep brain stimulation? Predicting treatment outcomes using advanced brain imaging.
This project aims to improve the treatment of a rare and severe epilepsy, Lennox-Gastaut syndrome, by investigating whether pre-surgical information gathered from brain imaging can predict which patients are likely to benefit from deep brain stimulation. Deep brain stimulation is an emerging surgical treatment for epilepsies that do not respond to standard medications, such as Lennox-Gastaut syndrome. Electrodes are neurosurgically implanted deep inside the brain to deliver electrical stimulation to areas responsible for seizures, inhibiting the epileptic network. Previous studies show that some patients have fewer seizures following deep brain stimulation, while others do not appear to benefit. Currently we have no methods to predict which patients with Lennox-Gastaut syndrome are likely to respond. To address this need, we will study patients before they have surgery using simultaneous electroencephalography and functional magnetic resonance imaging (EEG-fMRI). EEG-fMRI is a non-invasive brain imaging technique that can 'map' the brain network involved at the time of seizure activity. Deep brain stimulation is thought to be most effective when it is delivered to the specific brain areas driving seizures. Therefore, we hypothesize that patients in whom the epileptic network (determined by EEG-fMRI) matches the site of stimulation will show the greatest improvement after surgery. Outcomes of this project may have substantial impact in the treatment of Lennox-Gastaut syndrome, and of rare diseases more broadly, by matching patients to the most effective therapies available. Specifically, we seek to develop a ‘precision medicine’ approach, where deep brain stimulation can be targeted to brain networks maximally involved in the disease process. For patients and families, prediction of treatment response will assist with optimally selecting among multiple different treatment options.
Genetic characterization of patients affected with a myopathy
Next-generation DNA-sequencing has largely contributed to gene discoveries in rare diseases. However, many rare diseases are still without a molecular cause due to heterogeneity and limitations of the approach. In the case of myopathies, it is estimated that at least 25% still lack a molecular diagnosis after exhaustive clinical and genetic evaluation. The combination of multiple omic approaches is now necessary to identify the molecular cause in these unresolved cases. Using transcriptome analysis we have been able to identify novel variants in known myopathy genes and novel candidate genes in 7 out of 8 patients. Validation of our findings using other experimental methods is necessary to confirm our findings. Our project will have a direct impact of patients affected with a myopathy and their family. Obtaining a molecular diagnosis will allow a proper genetic counseling, better risk assessment and clinical management as well as reducing the psychological hardship associated with the long diagnostic odyssey. In addition, defining the genetic etiology of myopathies will contribute towards a better understanding of biological processes underlying these diseases and could ultimately result in the identification of biomarkers and viable therapeutic targets. Research on rare diseases has had implications that have shaped the medical biology field for decades, by shedding light on normal and abnormal physiology as well as contributing to our understanding of common disorders. More specifically, the study of rare myopathies has the potential to increase the knowledge of normal muscle function and provides insight in more common muscle defects.
Adenine base editing as a potential therapeutic for Gaucher disease
GD is a rare genetic LSD, which results from the progressive accumulation of a cellular waste product, glucocerebrosides. GD results from a single gene mutation that causes an essential enzyme to become non-functional. Patients with the acute neuronopathic form (type II) experience severe neurodegeneration, ultimately resulting in death within the first few years of life. Currently, treatment of GD is limited due to a protective barrier between the brain and the body that blocks access for enzyme replacement therapies, a common treatment of other related diseases. Gene-editing technologies, which work like ‘molecular scissors’, target, cut, and remove the disease-causing mutation from DNA and are promising potential therapeutics for MPS disease. If successful, correction of the mutation in stem cells derived from patients with GD would allow for the production of functional enzyme. However, traditional gene-editing is very inefficient. We propose the use of a new form of gene-editing, Adenine Base Editing, which fixes DNA mutations with much greater efficiency and accuracy. Through transplantation of gene-edited cells back into the patient, a long-term supply of functional enzyme would be produced within the brain. This would result in a reduction of disease symptoms and an increased quality of life for patients with GD.
Quantitative texture-based computed tomography analysis in hypersensitivity pneumonitis
Hypersensitivity pneumonitis (HP) is a rare immune system disorder that affects the lungs. It causes inflammation in the lungs that occurs when a person’s immune system is triggered by certain substances (antigens) in the environment. Common HP antigens include: bacteria, fungi, mold, proteins, and chemicals; all of which an individual comes in contact with on a daily basis. In chronic HP, a constant low-intensity exposure to the antigen results in long-term inflammation that leads to permanent scarring of the lungs. This scarring commonly progresses to the point where patients need a lung transplant or die from the disease, even after avoiding exposure to the antigen and taking medication. It is also difficult to diagnose HP as it can be easily mistaken for other lung diseases and has no current established diagnostic criteria. Despite these challenges, approximately 5-10,000 Canadians are affected by HP according to the Canadian Registry for Pulmonary Fibrosis (CARE-PF). The current methods of measuring HP severity and progression are influenced by multiple factors, making it hard to monitor the disease. However, recent advances in imaging technology provide a more direct method of measuring the severity of HP. This strategy is based on computed tomography (CT) scans, which provide detailed images of the lungs. We previously developed a computer program to automatically identify abnormal areas of the lung on CT scans of a similar type of scarring lung disease. However, it remains unknown how these abnormal areas affect the function of the lung in HP. We will therefore modify our previous program and apply it to CT scans of patients with HP. This will allow us to identify patterns on CT images that can have a negative impact on the lungs. The results of this study will clarify the significance of this new imaging tool in measuring disease severity. This study has the potential to change how we diagnose and care for patients with lung disease.
Drug-based modulation of primary cilia in Townes-Brocks Syndrome kidney models
Townes-Brocks Syndrome (TBS1) is a rare developmental disorder (1:350,000) that can affect formation of thumbs, kidneys and ears, and often causes hearing loss and declining renal function as affected children age. We have linked TBS-causing mutations of the gene SALL1 to defects in primary cilia, small projections on the body’s cells that receive signals like antennas, allowing proper formation of tissues and organs during development. We will examine how SALL1 mutations affect the cilia in kidney cells and in the kidneys of mice genetically modified to mimic TBS. We will also test the effects of two drugs that can modify cilia function and alleviate symptoms in a related model of kidney disease, to see if they give beneficial effects in the case of TBS. These are initial steps toward possible clinical trials for TBS individuals presenting with kidney dysfunction.
In vivo uptake of Naglu-PTD4 into mucopolysaccharidosis type IIIB fibroblasts
Our goal is to improve the delivery of Naglu across biological membranes using PTD4 with the intention to create an enzyme replacement therapy that is able to reach and treat the brain of MPS IIIB patients. Enzymes are proteins that perform essential functions in our bodies. When an individual doesn’t make enough of a certain functional enzyme this causes disease. 0.08 to 0.78 in 100, 000 individuals are deficient in Naglu, an enzyme that breaks down cellular waste. Without Naglu these cellular wastes accumulate damaging the brain and causes Mucopolysaccharidosis (MPS) type IIIB. Patients with MPS IIIB experience progressive mental deterioration, severe behavioural problems and loss of motor function and often succumb to this disease before their third decade of life. Although other diseases can be treated by giving the patient the deficient enzyme by injection (enzyme replacement therapy) this is not a viable treatment option for MPS IIIB. This is because the administered enzyme is unable to cross the blood-brain barrier, which prevents active enzyme from getting to the brain and treating the neurological symptoms that effect individuals with MPS IIIB. Our lab is looking to improve delivery of enzyme replacement therapy to the brain for the treatment of MPS IIIB. We have fused Naglu (the enzyme missing in MPS IIIB) to PTD4, a protein transduction domain that has been shown to deliver large fusion proteins to the brain. We aim to examine the ability of PTD4 to aid in the delivery of Naglu across biological membranes like the blood-brain barrier. If it does help deliver Naglu to the brain, it could have the potential to make enzyme replacement therapy a viable treatment option for MPS IIIB.
Personalized treatment approach in patients with Long QT Syndrome
Inherited arrhythmias (IA) are a rare cause of sudden cardiac death (SCD) and is associated with significant morbidity and increased mortality. The most common type of IA is Long QT Syndrome (LQTS) and this electrical disorder of the heart affects 1 in 2,500 Canadians in Canada. It is linked to a malfunction in the ion channels or structural proteins existing in the heart that are critical for the overall conduction system. There has been limited use of drug therapies to treat LQTS and surgical treatment options with cardiac sympathetic denervation or implantable cardioverter defibrillators remain the mainstay therapy to date. Since it is not practical to obtain heart tissue from patients, recent advancement in stem cell technology has now made it possible to study heart cells outside of the body by obtaining a simple blood sample from a patient. Using this application, we will test antiarrhythmic drugs to see if we can halt the abnormal rhythm and revert it back to a normal state to avoid the need for surgical interventions. This provides an innovative way to treating patients at an individual level and a potential new avenue for Geneticists to care for families suffering from life threatening genetic conditions.
Neuronal ceroid lipofuscinosis: diagnostic yield of molecular genetic testing and phenotype, genotype and natural history of the patients diagnosed with neuronal ceroid lipofuscinosis
We want to look at how common is neuronal ceroid lipofuscinoses (NCL) in Canada in this study using Molecular Genetics Laboratory clinical database at our hospital. Neuronal ceroid lipofuscinoses (NCL) are a group of conditions that affect the central nervous system. Individuals, who have these conditions, present with various degrees of neurological symptoms, such as dementia, loss of ability to walk and talk, seizures, and vision loss. They are rare conditions and seen 1.3 to 7 out of 100,000 live births depending on the origin of countries. Genetic testing confirms diagnosis in NCL. Treatment options are limited to help relieve some of the features that individuals have. Recently, an enzyme replacement therapy was approved to treat individuals with NCL type 2. In this study, we will look at the NCL genetic test results. The laboratory where the tests were performed receives genetic test requests for NCL from all Canadian clinics and hospitals. We will consent families using a verbal telephone consent for this study after their physicians informed them for the study and the families and parents contacted us, if they are interested being part of this study. We will collect information to answer following questions 1) how many individuals did have genetic testing for NCL? 2) what subtype of NCL were diagnosed in this laboratory? 3) what are the clinical features of individuals with NCL? Additionally, we will re-analyse the genetic changes in various NCL genes to see if there are any other individuals that we can confirm the diagnosis with these rare genetic conditions. This study will help us to report all individuals diagnosed with NCL in Canada.
Long-term outcomes of patients with unresectable arteriovenous malformations: A 25-year chart review
Arteriovenous malformations (AVMs) are characterized by a tangled mass of abnormal blood vessels connecting arteries and veins. AVMs are rare (1:100,000) and can be located anywhere on the body. Those near the skin’s surface can cause bleeding and wounds, large AVMs can “steal” blood away from normal tissues causing them to fail, and if the AVM grows very large, the demand on the heart may become higher than normal leading to heart failure. The majority of AVMs can be excised resulting in a complete cure; but for 15% of patients, the AVM is too large, or infiltrates vital organs such that any attempt to completely excise the AVM would result in significant disfigurement, poor physical function, and life-threatening risks. Yet, left untreated, patients are at risk for heart failure or uncontrollable bleeding. Current management includes partial excision(s) of the AVM or medications that damage the AVM’s vessels or block its blood supply. However, these treatments aren’t without risks: tissue and nerve injury, increased blood pressure in the arteries of the lungs, blood clots, uncontrollable bleeding, and infection. Due to the rarity of unresectable AVMs combined with a lack of an animal model, there are no treatment guidelines. Although published case series have mainly shown poor aesthetic and functional outcomes for patients with unresectable AVMs, our centre has observed favourable long-term outcomes for these patients. This study aims to review the pattern of management for patients with unresectable AVMs by evaluating when and what treatments were used and for what indication (functional/aesthetic/symptomatic). We hypothesize that key treatments can be carefully timed for specific indications such that patients may achieve good functional and aesthetic long-term outcomes. The information gained from this study will inform clinicians treating patients with rare and complex unresectable AVMs as well as inform families making treatment decisions.
Assessing the genome for structural variation in familial Wilms tumour
Wilms tumour (WT) of the kidney affects about 1 in 10,000 children. Only a small fraction results from heritable genetic defects of the sort that cluster in families. Understanding these special cases is extraordinarily valuable, however. They offer the ability to identify and preventatively treat at-risk family members, as well as broader benefits that include a detailed picture of how WT develops. In the immediate term, this knowledge affords some degree of closure to affected families, providing insight into a threat that has hung over them for generations. In the longer term, it offers the promise of better therapies. The genetic defects underlying a number of forms of familial WT have already been identified. We have been studying a large Canadian kindred whose WT is caused not by one of these, but instead by something novel. Despite an exhaustive effort over many years, using state-of-the-art technologies, we have been unable to determine what it is. One explanation for this failure is that the genetic defect causing this form of familial WT is not the usual kind: that is, not the equivalent of a few misspelled words in an otherwise normal book. Instead, it might be something bigger, akin to ripping out multiple pages and putting them back in reverse order, or in the wrong place, or leaving them out entirely. Until recently, these large-scale (“structural”) variants were almost impossible to reliably detect. A new technique, known as optical mapping, offers an excellent opportunity to investigate the puzzle presented by this family. We have already demonstrated that it can be used to detect a large-scale structural change causing a different disease, one that causes blindness. We are confident that it will be helpful here, either by identifying the causal defect or by ruling out this type of structural variation. Given the significance of such a discovery and the modest cost of the proposed experiment, we believe this an investment well worth making.
Describing the population of patients with 22q11.2DS in British Columbia and characterizing their care needs
22q11.2 Deletion [DiGeorge] Syndrome (22q11.2DS) affects 1:4000 children. Children with 22q11.2DS have a myriad of health and medical needs that may include: congenital heart defects, cleft palate, immunodeficiency, decreased calcium and thyroid function, feeding/swallowing/speech difficulties, epilepsy, kidney abnormalities, bleeding, cancers, and developmental disorders including autism and learning disabilities. Young adults with 22q11.2DS have an increased risk of developing mental health disorders such as anxiety, depression and schizophrenia. Although international best practice guidelines on caring for individuals with 22q11.2DS exist, the high variation in clinical presentation and diverse use of clinical specialties across this patient population makes it inherently challenging to effectively coordinate care and conduct research. In our province, there is no centralized multi-disciplinary care program for individuals with 22q11.2DS, and transitional care from pediatric to adult services is especially challenging. This study will be the first time that the population of patients seen at our hospital with 22q11.2DS will be described with respect to: how many patients exist, how and when they were diagnosed, what their specialized care needs are, and which patients have a documented pediatric to adult care transition visit. The results of this research will directly inform primary and the many specialized clinicians currently caring for patients with 22q11.2DS. This information will facilitate improved communication and across multiple providers as well as inform an improved model of care.
Investigating the role of cilia in the pathogenesis of biliary atresia
Biliary atresia (BA) is a serious childhood liver disease of unknown cause with no effective therapies. It results in aggressive scarring in bile ducts of the liver. BA is the most common indication for liver transplantation in children in Canada and globally. Fifty percent of affected individuals undergo transplantation by two years of age and 80% undergo transplantation by 20 years. In 20% of cases, BA is associated with abnormal positioning of organs in the body (laterality defects). During development, laterality is determined by cellular structures called cilia that are also present on bile duct cells. Current hypotheses include genetic predisposition, an environmental factor such as a virus or toxin, immune dysregulation or some combination of these. Recent data demonstrate changes in a cilia gene (PKD1L1) in BA patients with laterality defects. PKD1L1 is expressed on primary cilia in the embryonic node where it functions as a calcium channel, however its role in cholangiocyte (the epithelial cells lining bile ducts) cilia is unknown. We believe that defective PKD1L1 in cilia causes abnormal signaling in bile duct cells which leads to the release of chemicals that attract other cells which cause inflammation and scarring, as seen in BA. Therefore, we will use PKD1L1 knockout zebrafish model, developed by our collaborator, for our studies. We will study how PKD1L1 mutations lead to defective bile duct cell formation and function in order to understand the role of cilia in the pathogenesis of BA. Drugs already exist to target cilia signaling in adult liver diseases, and our studies will open up this novel therapeutic target for children with BA.
The youngest patients with Catecholaminergic Polymorphic Ventricular Tachycardia: Why are some children affected earlier than others?
The sudden unexpected death of a young person is a rare but incredibly tragic event for families and communities. Each year, hundreds of apparently healthy people across Canada die suddenly. Often, a heart rhythm condition is to blame. One of the deadliest heart rhythm conditions is known as Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). CPVT affects 1 in 10,000 people, most of whom are children. This condition is dangerous because it causes an abnormal heart rhythm during exercise and stress which can lead to sudden death. The most severely affected patients begin having life-threatening heart rhythm problems before the age of 10 (early-onset), although symptoms can also begin later in life (late-onset). It is not understood why some kids develop the disease early, while others do not get sick until late adolescence or early adulthood. Our aim is to find out why this happens, so we can help children earlier and prevent sudden death. We have already started working on this problem, but we need financial support to learn more. Previous findings from our research group show that some patterns in a child’s genetic code may be predictive of earlier disease onset. The genetic code is the set of instructions that are passed down from parent to child, which can have “typos.” We know that some typos are damaging and can cause CPVT. However, we do not know much about other minor “typos” that may exist, especially those that may make the disease worse. These typos can serve as a “marker” or “predictor” of life-threatening problems early in life. It is possible that patients that present with CPVT earlier in life have certain typos that are different than patients that present with CPVT later in life. We are going to look for typos using a scientific method called gene sequencing. This technique will identify the typos that are in genes related to CPVT. We will also determine how likely these typos are to cause disease by using a special computer software.