Annual Report 2001/2002

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. Dr. Rosenblatt is currently also Chair of the Department of Human Genetics at McGill. The laboratory was established with the help of an endowment to McGill and is presently housed on the fifth floor of the Hersey 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/).

Highlights: Research

Dr. Thomas Hudson discovered that a genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease.

Dr. Kenneth Morgan and collaborators discovered that a missence mutation in TRIM32 is the cause of autosomal recessive limb-girdle muscular dystrophy in Manitoba Hutterites.

Dr. David Rosenblatt, David Watkins Ph.D. and colleagues completed studies on the range of mutations responsible for methionine synthase deficiency (cblG). This will allow for easier carrier detection and prenatal diagnosis. In addition, the first mutations in glutamate formiminotransferase deficiency and the gene responsible for the cblA class of cobalamin-responsive methylmalonic acidemia were described.

Highlights: Clinical

After more than a year, clinical services for medical genetics within the McGill University Health Centre (MUHC) are still in the process of being restructured. There is a Medical Genetics Program within the MUHC, but at the moment it exists in name only. The hope has been that this program would have responsibility for the entire range of medical genetic services across all ages within the MUHC. The details of how the program will work and its interactions with the Department of Human Genetics at McGill are still not clear. Therefore medical geneticists have not yet been able to be particularly effective in the planning for medical genetic services for the new hospital site. Should the MUHC and the University become able to function together, there would be an excellent environment for the recruitment of medical geneticists to McGill hospitals. It is unfortunate that the current medical leadership of the MUHC does not have the vision to allow the specialty of medical genetics to develop independently.

Within the MUHC, most medical geneticists have accepted payment for medical acts by "Remuneration Mixte". This has resulted in a substantial increase in clinical earnings, which are now competitive with those of other specialties. In addition, there are positive signs that the Ministry of Health of Quebec (MSSS) is prepared to invest in the structure of genetic services in Quebec.

Highlights: Teaching

Dr. Mary Ann Thomas completed her RIII year and is currently an RIV and Chief Resident in Medical Genetics in our program. Dr. Chantal Morel is currently completing her RII. Dr. Teresa Rudkin and Dr. Fatma Bastaki have completed their RI year and we expect two new residents for the academic year 2002-2003, Dr. Nicolas Ah Mew and Dr. Fathiya Al-Murshedi. We are delighted to have six medical geneticists in our program. John Hilton completed his M.Sc. under the supervision of Dr. Rosenblatt. His project involved the first description of mutations in glutamate formiminotransferase deficiency. One of the most important developments for the future of the Division of Medical Genetics was the accreditation of the McGill program in genetic counselling by the American Board of Genetic Counseling.

Honours and Awards:

Dr. William Foulkes was made a Principal Investigator of the Canadian Genetic Diseases Network, Director of the newly formed inter-departmental Program in Cancer Genetics (Departments of Human Genetics and Oncology) and was invited to be a member of the writing committee for a Cancer Genetics Certification Examination, Institute for Clinical Evaluation, American Board of Internal Medicine.

Dr. Brian Gilfix was awarded an Aitken Fellowship.

Dr. Thomas Hudson, Dr. William Foulkes, and Dr. Patricia Tonin were all promoted to Associate Professor with Tenure at McGill effective June 2002.

Dr. Thomas Hudson was awarded the 2002 Burroughs Welcome Fund Clinical Scientist Award in Translational Research. This is a highly competitive international award.

Dr. David Rosenblatt was elected President of the Association of Medical Geneticists of Quebec effective May 2002.

Dr. Patricia Tonin was a recipient of The Stewart Fellowship in Research/Clinical Hematology & Oncology, McGill University Health Centre, 2000-2003 and The Fraser, Monat, & MacPherson Scholarship, McGill University, 2000-2003.

Research Interests and Accomplishments of Individual Members

Dr. Valérie Désilet is the Director of prenatal diagnosis at McGill. She has played an active role in assuring the highest quality of care by this service. Her research interests are in the area of nuchal translucency measurement as a method to look for aneuploidy and fetal cardiac malformations in the general population.

Dr. Eleanor Elstein has continued her research on genetic modulation in the cardiovascular system. She is pursuing the study of genetic factors modulating the development of obstructive vasculopathy in cardiac allografts. She has looked at the levels of various aminothiols in homocysteine metabolism in heart transplantation.

Mary Fujiwara has research interests that include the study of the distribution and maintenance of genetic variability, including deleterious alleles in well-defined populations, in particular, the Hutterite population of North America - an inbred population isolate. This work is done in collaboration with Kenneth Morgan. Collaboration with Daniel Bichet (Hôpital Sacré-Coeur de Montréal) has shown locus heterogeneity, a wide spectrum of mutations, and mutation-dependent mode of inheritance on a world-wide collection of families with nephrogenic diabetes insipidus (see http://www.medicine.mcgill.ca/nephros/).

Dr. William Foulkes has continued to focus on the historical cohort of women with breast cancer ascertained at the SMBD-Jewish General Hospital, and has also continued work on hereditary colorectal cancer with Dr. Georges Chong and colleagues at the SMBD-JGH. His publication highlight for 2001 was a study suggesting that TP53 mutations in BRCA1/2-related breast cancer have a distinctive spectrum and structural distribution.

Dr. Brian Gilfix has received funding from the "Réseau de médicine génétique appliquée" (Fonds de 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. In addition, his laboratory currently has an ongoing pilot study examining the frequency of several gene polymorphisms related to obesity in a morbidly obese population.

Dr. Cecilia Greenwood together with her research assistant, Mathieu Lemire, has developed an approach for incorporating multivariate phenotype information into a genetic linkage analysis. This approach works with pedigrees of any structure, and identifies phenotypic groupings that show the most evidence for linkage. They have used a recursive partitioning algorithm to find interesting clusters of phenotypic measurements. Their approach finds gene-environment interactions. The recursive partitioning model can be replaced with different models if desired. Refinements of the approach and simulations are ongoing. She has presented the methodology and some results at an international conference, and at three invited seminars.

Dr. Greenwood is co-supervising two Masters students in the Department of Epidemiology and Biostatistics, McGill. Both have made good progress during the last year and expect to finish their theses within the next few months. Nooshin Ahmadipour has fit covariate models to linkage disequilibrium analysis of candidate genes for tuberculosis; Tanya Murphy has been comparing parametric and nonparametric analysis methods in genetic linkage analysis of asthma families.

Together with other members of the Genetic Analysis Group, she published a paper on linkage analysis of asthma in a complex interconnected pedigree of Hutterites. In addition, she presented some results at the annual meeting of the Canadian Genetic Diseases Network.

Dr. Thomas Hudson and his laboratory continued its complex trait mapping projects: asthma, coronary heart disease, diabetes and inflammatory bowel disease. The latter project included the elucidation of the genetic variation in the 5q31 cytokine gene cluster that confers susceptibility to Crohn disease and was reported in Nature Genetics. This work generated significant data on human genome variation, and allowed the formulation of a new paradigm in human genetics and the proposal to generate a Haplotype Map of the Human Genome. The asthma team concentrated its effort on chromosome 12. Polymorphism at the resistin locus was shown to be associated with obesity. The Montreal Genome Centre (Directed by Dr. Hudson) expanded its genotyping, sequencing and DNA chip capabilities and became the core of the operations of the Genome Quebec Innovation Centre. Over 80 laboratories used the expertise of the Centre. Construction has started for a new building on the McGill campus to house the Montreal Genome Centre and the building is proposed to be ready for the fall of 2002.

Kenneth Morgan, PhD has major research interests in the areas of population genetics, pedigree analysis, and genetic modelling. 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. His group is involved in the management of data generated in the CGDN Genotyping Core Facility and in the genetic analysis of Mendelian and complex traits. He has collaborated extensively on the genetic analysis of traits in man, mouse and chicken. Highlights of research activity during the past year include: 1) Mapping loci for Mendelian diseases in the Genotyping Core Facility of the Montreal Genome Centre: a genome-wide scan of Hutterite families with 2 different Mendelian diseases was completed (collaboration with Cheryl Greenberg and Klaus Wrogemann, University of Manitoba); 2) Mapping susceptibility genes for persistent Salmonella infection in mice in collaboration with Danielle Malo (McGill): analysis of genome-wide scan data from F2 progeny of C57BL/6J and 129sv strains identified 3 putative susceptibility loci [Caron et al., Genes and Immunity 3:196-204, 2002]; 3) A missense mutation in TRIM32, a putative E3 ubiquitin-ligase gene was identified as the cause of an autosomal recessive limb-girdle muscular dystrophy in Manitoba Hutterites ) [Frosk et al., American Journal of Human Genetics 70:663-672, 2002] (collaboration with Klaus Wrogemann and Cheryl Greenberg, University of Manitoba); 4) Postdoctoral fellow, J Loredo-Osti and Dr. Morgan collaborated with Carmen Sapienza (Fels Institute for Cancer Research and Molecular Biology, Temple University) on genetic modeling and analysis of modifiers of the DDK syndrome. The main characteristic of this syndrome is early death of embryos with incompatible ovacytoplasm and an 'alien' paternal Om allele [de la Casa-Esperón et al., Genetics, in press]; 5) Postdoctoral fellow Loredo-Osti developed a suite of programs called Pedfiddler for manipulating pedigree data and drawing complex pedigrees. He also developed two other programs: Parente, a program for computing Malécot's kinship and inbreeding coefficients and Jacquard's condensed identity-by-descent coefficients; and Imaqtl, a robust quantitative trait locus interval mapping program for F2 experimental crosses. (See http://www.medicine.mcgill.ca/statgene/software.html)

Dr. David Rosenblatt along with David Watkins, PhD were involved with the study of patients with inherited disorders of cobalamin (vitamin B12) and folate. The laboratory at the MUHC is a world referral centre for patients with these diseases. With their colleagues, they have published a summary of a large number of causal mutations in methionine synthase deficiency (cblG). They have also found that the P1173L mutation is common and recurrent, being present on at least two different haplotypes. In addition, with John Hilton and colleagues, they have found the first mutations in glutamate formiminotransferase deficiency, the second most common inborn error of folate metabolism. With Tim Wai and the laboratory of Roy Gravel at the University of Calgary, they have found the gene for the cblA class of cobalamin-responsive methylmalonic aciduria and described the first mutations in this disease.

Dr. Guy Rouleau has made significant research contributions in the mapping and isolating of both the neurofibromatosis type 2 (NF2) gene and the oculopharyngeal muscular dystrophy (OPMD) gene. He as well 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 ectodermald 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.

Patricia Tonin, PhD is involved with two principal areas of research in her laboratory. 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.

1. 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 and colleagues have shown deletions in low grade, early stage tumours and therefore have 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 a CIHR funded projects, are to refine the localization and then clone the putative chromosome 3p and 17q tumour suppressor genes. Previously, they published a deletion map of chromosome 3p deletions observed in a large series of epithelial ovarian tumours. In addition we are applying a candidate gene approach and have excluded known candidates, such as TGF-ß-RII. In 2001, they have further refined their deletion maps of regions they have defined on the short arm of chromosome 3 (3p) and the long-arm of chromosome 17 (17q25). They have also extended their study of the ovarian cancer problem to include novel technologies such as large-scale expression microarrays (Affymetrix GeneChips®) with the aim of applying this technology to rapidly assess candidates in the region of interest. In 2001 they reported in Oncogene that microarray analysis of gene expression mirrors the biology of ovarian cancer model (Tonin et al., 2001).
   
   
2. Hereditary breast cancer accounts for approximately 5% to 10% of all breast cancers and 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. Previously, Dr. Tonin and her colleagues established the spectrum of BRCA1 and BRCA2 mutations found in high-risk families of French Canadian descent. Recently, they have extended this study to established the frequency of common mutations in unselected breast cancer cases diagnosed below age 40 years (Tonin et al., 2001). The results reaffirm their previous findings that a small number of specific mutations in these genes account for the majority of inherited cases of breast cancer diagnosed below the age of 40 years. These findings will improve genetic counselling by facilitating mutation detection. They have also extended their analysis of origins of common mutations, found in the French Canadian population of Quebec, and have reported that carriers of the most common BRCA2 mutation (8765delAG) likely arose from common ancestors within the French Canadian population, and that they differ from the origins of the same mutation in the Yeminite population (Manning et al., 2001). In collaboration with the Breast Cancer Linkage Consortium (BCLC) they have established the variation cancer risks by mutation position in BRCA2 mutation carriers. (Thompson et al., 2001). In collaboration with Dr. Steven Narod, they investigated tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers (Narod et al., 2001).
   

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