Finestone Laboratory Annual Report 1999/2000

Annual Report 1999/2000

Annual Report
Highlights: Research
Highlights: Clinical
Highlights: Teaching
Honours and Awards
Research Interests and Accomplishments of Individual Members:

The Hess B. and Diane Finestone Laboratory in Memory of Jacob and Jenny Finestone was established to promote the field of medical genetics at McGill University. Dr. David S. Rosenblatt has been the director of the Laboratory since its inception. The laboratory was established with the help of a million-dollar endowment to McGill and is housed on the fifth floor of the Hershey Pavilion of the Royal Victoria Hospital. Funding from the Finestone Laboratory is used to advance the academic goals of the Division of Medical Genetics in the Department of Medicine of the McGill University Health Centre (MUHC). This report serves as the Annual Report of the Division of Medical Genetics of the Department of Medicine. It is available on the Internet (http://www.mcgill.ca/finestone/).

Dr. Thomas Hudson and his colleagues played a major role in the cloning of the gene responsible for autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSAC). Kenneth Morgan, PhD contributed to the identification of mutations in the gene that encodes the ATP-binding cassette transporter (ABC1). David Watkins, PhD and Dr. David Rosenblatt defined a novel inborn error of cobalamin metabolism causing methylmalonic aciduria (cblH). Patricia Tonin PhD established the frequency of the common mutations in the BRCA1 and BRCA2 genes in the French Canadian population in unselected ovarian cancer cases.

Genetic counselling for breast, ovarian and colon cancer is now well established within the Division of Medical Genetics with activity at both the MUHC and Jewish General Hospital. Gene sequencers suitable for clinical purposes are now in use in the molecular diagnostic laboratories of both hospitals. Medical Genetics is now a mature clinical specialty in the Province of Quebec and for the first time specific billing codes have been established in the province for both clinical and laboratory acts. There remains the need to integrate all the clinical programs in medical genetics at McGill under the umbrella of the Department of Human Genetics. If this can be achieved, McGill will be a most attractive place for the recruitment of medical geneticists.

Dr. Gordon Gowans (RVI) completed his training in Medical Genetics at McGill and has accepted a position at the University of Kentucky. Dr. Melanie Bedford completed a year of training in Medical Genetics (RIV) and will spend next year at the University of Toronto. Dr. Mary-Ann Thomas became the first RI from a Quebec medical school to be accepted as a first year resident in the McGill Medical Genetics residency program.

Dr. Thomas Hudson was named "Un des 50 jeunes québecois de l'avenir" by Revue Commerce & Radio Canada and "Canada top 40 under 40" by the Globe and Mail and Caldwell Partners for vision, leadership and innovative achievement.

Dr. William Foulkes and Dr. Patricia Tonin were recipients of research awards from the Montreal General Hospital. They have both maintained their peer reviewed external salary awards.

Dr. Valerie Desilets has played a major role in the re-organization of prenatal diagnosis services within the McGill system. In addition to her role as co-ordinator of the program which is based at the Montreal Children's Hospital site of the McGill University Health Centre, she has ensured that there are genetic counselling facilities available at the both the Royal Victoria Hospital site of the MUHC as well as at the Jewish General Hospital. Her research interests continue to be in the area of first trimester ultrasound screening for fetal malformations and the use of nuchal translucency as a method to look for aneuploidy and fetal cardiac malformations in the general population.

Dr. Eleanor Elstein maintains a clinical interest in adult genetic disease associated with cardiac manifestations. Her research focuses on genetic modulation in the cardiovascular system with emphasis on genetic factors involved in the development of obstructive vasculopathy in cardiac allographs. She is also studying the genetic determinants of the responsiveness of the vascular endothelium to various stimuli. She has shown that there is a differential vasodilatory response to ACE inhibitors based on the ACE genotype of the individual. Her laboratory is also interested in the genetic predisposition to the development of dilated cardiomyopathy.

Mary Fujiwara participates either directly or indirectly in all of the grants and academic programs to which Kenneth Morgan, PhD contributes. Her areas of expertise includes genetic epidemiology, analysis of genealogies, linkage analysis and database management.

Dr. William Foulkes is the premier cancer geneticist at McGill and an internationally recognized expert. He has established an excellent clinical service with specialized interest in hereditary breast, ovarian and colon cancer. He is particularly interested in how individuals who carry a major cancer susceptibility gene vary in their pathology and prognosis when compared to others with cancer who lack an identifiable major genetic predisposition. Under his supervision, molecular testing for hereditary colon cancer has been established at the Jewish General Hospital.

Dr. Brian Gilfix completed a project at St. Anne's Veterans Hospital (with Dr. L. Briones) on the utility of APOE genotyping in the diagnosis of dementias. This has involved genotyping 194 individuals for polymorphisms in apolipoprotein E and a number of other genes related potentially to dementia. The same subjects have been genotyped for a polymorphism in CYP2D6 in collaboration with Dr. J. Nalbantoglu (Montreal Neurological Institute). In collaboration with Dr. I. Wainer, he has studied the changes in drug metabolism that occur in AIDS. He has completed a 3 year project to examine the relationship between polymorphisms in a number of genes of the renin-angiotensin system and the occurrence of cardiovascular disease in chronic hemodialysis patients. He has received funding from the "Réseau de médicine génétique appliquée" (Fonds da la recherche en santé du Québec) to allow the establishment of techniques and services for the identification of genetic causes of thrombosis among family members. He also has received funding from the Fraser Funds/Royal Victoria Hospital Research Foundation for a pilot study examining the frequency of several gene polymorphisms related to obesity in a morbidly obese population.

Dr. Thomas Hudson and Kenneth Morgan,PhD established a state-of-the-art genotyping facility at the Montreal General Hospital Research Institute in 1996. Dr. Morgan supervises the informatics and computer core which has implemented programs to process the genotype data. Activities of the informatics group include database development, analysis of pedigree and population data, and the analysis of radiation hybrid mapping. In the first three years of operation, twenty-four young scientists have been recruited and trained in these new biotechnologies. Dr. Hudson has been successful, along with colleagues at McGill and the Centre Hospitalier de l'Université de Montréal in obtaining a major infrastructure award from CFI and the FRSQ to expand the facilities at the Montreal General Hospital to become the Montreal Genome Centre. This centre was awarded $8.25 million in order to provide technological support to the Montreal community. The establishment of core facilitates for large-scale sequencing, high throughput genotyping, DNA chip technologies, and bioinfomatics is crucial for keeping Montreal researchers at the leading edge of genetic research. Dr. Hudson's general area of interest involves common diseases with an important genetic component including asthma, lupus, early-onset heart disease, non-insulin dependent diabetes mellitus and inflammatory bowel disease. In 1999, the Centre played a leading role in the cloning of an ataxia gene which is common in Northeastern Quebec.

Kenneth Morgan, PhD has major research interests is the areas of population genetics, pedigree analysis, and genetic modelling, and he collaborates extensively on the analysis of genetic data in the human and the mouse. Major highlights of his research activity during the past year include linkage analysis of families with Tangier disease and familial HDL-cholesterol deficiency that contributed to the identification of mutations in the gene that encodes the ATP-binding cassette transporter (ABC1). This was a collaborative study with investigators in the Canadian Genetic Diseases Network and Xenon Bioresearch Inc. Location score and haplotype analyses of families with a distinctive spastic ataxia that is common in Northeastern Quebec contributed to the fine mapping and identification of the sacsin gene (SACS) and two disease-causing mutations. The genetic analysis utilized Markov chain Monte Carlo methods to narrow the candidate region and identify ancestral haplotypes. He leads the Genetic Analysis Group that participates in two Networks of Centres of Excellence programs: the Canadian Genetic Diseases Network (CGDN) and the Mathematics of Information Technology and Complex Systems. The group is involved in the management of data generated in the CGDN Genotyping Core Facility and in the mapping and genetic analysis of Mendelian and complex traits. Members of the group also participate in the International Genetic Analysis Workshops and in the analysis of case studies of the Canadian Journal of Statistics.

Dr. David Rosenblatt and his collaborators have a continuing program that involves cloning of genes involved in homocysteine metabolism and inborn errors of folate and vitamin B12 metabolism. His laboratory remains the only reference laboratory in North America for the study of these inborn errors and continues to receive cell lines from patients with diagnostic problems from around the world. Major advances last year include the identification of causal mutations in methionine synthase reductase in the majority of known patients with the cblE complementation group. Progress is being made on mutation analysis in patients with methionine synthase deficiency (cblG). This work allows for earlier prenatal diagnosis and for carrier detection in the affected families. In addition, work on mutation analysis in these rare inborn errors has allowed the identification of polymorphisms that will be useful in the study of more common diseases such as neural tube defects and cancer. In separate studies, Dr. Rosenblatt and colleagues at the Montreal Children Hospital have shown that patients detected by newborn screening with low to moderate levels of methylmalonic aciduria, tend to have a favourable outcome.

Dr. Guy Rouleau has made highly significant research contributions in the mapping and isolating of both the neurofibromatosis type 2 (NF2) gene and the oculopharyngeal muscular dystrophy (OPMD) gene. He also participated actively in the mapping and isolation of the chromosome 21 locus (SOD1) responsible for familial amyotrophic lateral sclerosis (ALS). Dr. Rouleau's laboratory has mapped some of the most prevalent genetic diseases in Quebec, among them, Oculopharyngeal Muscular Dystrophy, hidrotic ectodermal dysplasia and peripheral neuropathy with or without agenesis of the corpus callosum. These linkage findings have lead to the development of prenatal and presymptomatic diagnostic tests for these diseases. Dr. Rouleau also has work in progress on several other genetic diseases including epilepsy, bipolar disease, schizophrenia, restless leg syndrome, stroke and spinocerebellar ataxias. He was the recipient of the prix Leo Parizeau of the ACFAS in 1999.

Patricia Tonin, PhD focuses on two principal areas of research. The first involves the identification of genetic factors that are implicated in the development and/or progression of human epithelial ovarian cancer. The second involves the study of genetic factors that predispose to hereditary forms of breast cancer. Our knowledge of the molecular events associated with the development and progression of epithelial ovarian cancer has been limited by the lack of a suitable model system. Also, since the disease is often diagnosed at a late stage when numerous complex chromosomal changes have already taken place, the early molecular events remain largely unknown. Deletions of chromosome 3p and 17q (distinct from the BRCA1 locus) are frequent events in ovarian tumours of epithelial origin. Dr. Tonin has shown deletions in low grade, early stage tumours and therefore has hypothesized that these chromosomal regions harbour tumour suppressor genes whose function is lost early in the development and/or progression of ovarian cancer. The goals of her NCIC and MRC funded projects are to refine the localization and then clone the putative chromosome 3p and 17q tumour suppressor genes. In the previous year she published a deletion map of chromosome 3p deletions observed in a large series of epithelial ovarian tumours. In 1999 she began the process of refining these minimal regions of deletions in order to identify the tumour suppressor genes implicated in ovarian cancer. In addition she is applying a candidate gene approach and has excluded known candidates, such as FHIT (Manning et al., 1999).

Hereditary breast cancer accounts for approximately 5% to 10% of all breast cancers and a large majority of hereditary cancer families are attributed to germline mutations in BRCA1 and BRCA2 which confer an increased susceptibility to both breast and ovarian cancer. Last year, in the context of a CBCRI funded project, Dr. Tonin and her collaborators published the spectrum of BRCA1 and BRCA2 mutations found in high risk families of French Canadian descent. In 1999 they established the frequency of common mutations in unselected ovarian cancer cases (Tonin et al., 1999). These findings will improve genetic counselling by facilitating mutation detection. In collaboration with the Breast Cancer Linkage Consortium (BCLC) they have established carrier risks of BRCA2 germline mutation carriers. (BCLC, 1999). In collaboration with Dr. William Foulkes, they investigated the frequency of common French Canadian founder BRCA2 mutations in individuals with squamous cell carcinoma of the head and neck (Hamel et al., 1999).

David Watkins, PhD has been investigating genetic heterogeneity within the cblA complementation group of inborn errors of metabolism. Using somatic cell complementation analysis, he demonstrated that cells from a patient given the provisional diagnosis of cblA variant in fact represent a previously unrecognized complementation class, which has been designated cblH. He has also demonstrated that there is extensive interallelic complementation within the cblA class, which is relevant to the use of complementation analysis in making a diagnosis of cblA in clinical situations.