Annual Report 2000/2001

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

Annual Report 2000/2001

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 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 (  As of March 2001, Dr. Rosenblatt has been appointed, Chair of the Department of Human Genetics at McGill.

Highlights: Research

Celia Greenwood, PhD was recruited this year to add to the existing strength provided by Kenneth Morgan, PhD and Mary Fujiwara in the area of genetic epidemiology.  David Watkins, PhD and Dr. David Rosenblatt published their description of a novel complementation class associated with vitamin B12-responsive methylmalonic aciduria (cblH).  Dr. Rosenblatt and his colleagues expanded the spectrum of mutations causing severe MTHFR deficiency and found that P1173L is a recurrent mutation in patients with methionine synthase deficiency (cblG).  Dr. Thomas Hudson and collaborators identified important loci involved in both asthma and diabetes.  The Montreal Genome Centre, which he directs, expanded its capacities and was used by over 50 different laboratories.  Patricia Tonin, PhD published a deletion map of chromosome 17 shown to harbour a tumour suppressor for ovarian cancer.  She also collaborated on a study that looked at the effect of tamoxifen on the risk of contra lateral breast cancer in carriers of BRCA1 and BRCA2 mutations.  Kenneth Morgan, PhD and his collaborators mapped a gene for the autosomal recessive form of childhood cirrhosis in aboriginal Quebec families.  His analysis of families with a distinctive spastic ataxia contributed to the fine mapping and identification of the sacsin (SACS) gene.  Dr. William Foulkes published two papers this year on the penetrance and clinical aspects of hereditary breast cancer.  

Highlights: Clinical

The entire structure of clinical services for medical genetics within the McGill University Health Centre (MUHC) is in the process of being restructured.  In the future, there will be a Medical Genetics Program within the MUHC.  It will 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 currently being defined. This will also allow medical geneticists to participate actively in the planning for medical genetic services for the new hospital site.  With the recognition of the specialty of Medical Geneticists within Quebec, medical geneticists have been offered the possibility of being paid by "Remuneration Mixte".  Most accepted this form of payment and this has resulted in a substantial increase in the potential for clinical earnings.  This should result in a better environment for the  recruitment of medical geneticists to McGill hospitals.

Highlights: Teaching

Dr. Mary-Ann Thomas completed her RI year and is currently an RII resident in Medical Genetics in our program.  She is the first trainee that has been allowed to start at the RI level at McGill.   Dr. Chantal Morel is currently completing her RI year and we expect two new residents for the academic year 2001-2002.  It is with great enthusiasm that we look forward to shortly having a full complement of residents at the RI through the RV levels.

Honours and Awards:

Brian Gilfix
    Dr. John and Clara M. Fraser Award  
    Admission to the National Academy of Clinical Biochemistry  
    (Fellow  of the National Academy of Clinical Biochemistry)    

Research Interests and Accomplishments of Individual Members:

Dr. Valérie Désilets has played a major role in the re-organization of prenatal diagnosis services within the McGill system.  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 focused 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 participates in all of the grants and academic activities of Kenneth Morgan, PhD.  Her areas of interest include genetic epidemiology, analysis of genealogies, linkage analysis and database management.

Dr. William Foulkes has continued to focus on the historical cohort of women with breast cancer ascertained at the SMBD-Jewish General Hospital, and also started work on the significance of particular mutations in HNPCC. His publication highlights for 2000 include two papers on survival in hereditary breast cancer, a collaboration with the International Consortium for Prostate Cancer Genetics, further work on familial Wilms tumour, and studies in head and neck cancer.

His main research area in 2000 has been the further description of the clinicopathological features of hereditary breast cancer. In addition, he has started a microarray project in squamous cell carcinoma of the head and neck, in collaboration with Dr. Moulay Alaoui-Jamali at the Lady Davis Institute. A new development has been the identification of  mutations in individuals with hereditary non-polyposis colorectal cancer (HNPCC) in collaboration with Dr. Georges Chong and colleagues at the Jewish General Hospital. He continued to work with colleagues in Canada and elsewhere on large multicentre studies of penetrance and clinical aspects of cancer genetics.

Dr. Brian Gilfix became a Diplomate of the American Board of Clinical Chemistry (Molecular Diagnostics).  He is one of the first six individuals to hold certification in this area (certificate #2), and is the only holder of this certification in Canada.

Dr. Cecilia Greenwood started her position September 1, 2000; this summary covers developments in the fall of 2000.  She has been working on developing flexible new methods to incorporate many phenotypic measurements into linkage analysis.  Using classification and regression trees, she hopes to develop an approach that will adaptively identify phenotypic subgroups that show strong evidence for linkage.  In December 2000, she hired a research assistant to help in the programming of this endeavour.  In the fall of 2000, she submitted an operating grant application to CIHR, and salary award applications to CIHR and FRSQ.  (In April 2001, she received an FRSQ chercheur-boursier award).   In November 2000, she was a co-investigator on a (successful) application to Génome Québec, headed by Dr. T. Hudson, that proposes to identify regulatory polymorphisms.

Dr. Thomas Hudson and his laboratory continued their complex trait mapping projects: asthma, coronary heart disease, diabetes and inflammatory bowel disease. The asthma project primarily involved the analysis of a chromosome 12 atopy locus.  They performed high-density genotyping and gene re-sequencing, in a sample of 175 families from Northeastern Quebec.  They have also used this cohort to replicate a chromosome 7 asthma locus that was identified in Finland: both groups reported this work in a recent Nature Genetics issue. Polymorphisms in several candidate genes related to diabetes and obesity were reported: PPARalpha, PPARgamma, glycerol kinase, and mitochondrial glycerol-3-phosphate dehydrogenase. The Montreal Genome Centre (Directed by Dr. Hudson) expanded its genotyping, sequencing and DNA chip capabilities. Over 50 laboratories used the expertises of the Centre in 2000.

Kenneth Morgan, PhD 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 Network.  Highlights of his research activity during the past year included: the analyses of families with a distinctive spastic ataxia, that is common in northeastern Quebec, that contributed to the fine mapping and identification of the sacsin gene (SACS) and two disease-causing mutations; in collaboration with colleagues at McGill, a study of the risk of tuberculosis in an Aboriginal Canadian kindred, providing evidence that NRAMP1 or a closely linked gene plays a major role in susceptibility; in collaboration with colleagues at l'Hôpital Ste-Justine, the  mapping of a gene for an autosomal recessive form of childhood cirrhosis in Aboriginal Quebec families; in collaboration with Dr. Daniel Bichet, the report of 33 novel mutations in the arginine vasopressin receptor (AVPR2) gene that cause nephrogenic diabetes insipidus.  The majority of Dr. Morgan's work was done in collaboration with Mary Fujiwara who is also a member of the Division of Medical Genetics.

Dr. David Rosenblatt and David Watkins, PhD published their description of a novel complementation class associated with vitamin B12-responsive methylmalonic aciduria (cblH).  Dr. Rosenblatt and his colleagues characterized the mutations in most known patients with methionine synthase deficiency (cblG) and found that P1173L is a recurrent mutation that is present in many patients. With Rima Rozen, PhD six novel mutations in methylenetetrahydrofolate reductase (MTHFR) were characterized.  With collaborators in France, a novel polymorphism in the reduced folate carrier was  identified and its association with folate and homocysteine status were studied.

Dr. Guy Rouleau addresses two major themes in his ongoing work. The first theme involves studies of a number of hereditary neurodegenerative disorders.  He performs linkage analysis followed by chromosomally based cloning of the defective gene and mutation analysis.  He is currently investigating amyotrophic lateral sclerosis, spastic paraplegia, spinocerebellar ataxia, epilepsy, oculopharnygeal muscular dystrophy, manic depressive illness and schizophrenia.   The second theme includes inherited predispositions to central nervous system cancer.  The most important disorder is neurofibromatosis type 2, the gene for which he has recently cloned.  He is attempting to define the molecular events underlying carcinogenesis in the CNS.  His approach involves linkage analysis, reverse genetics, somatic cell genetics, physical mapping of human chromosomes, cDNA cloning and characterization, mutation analysis and cell biology.

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.  

Patricia Tonin, PhD  There are two principal areas of research conducted in Dr. Tonin's 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) Molecular study of Human Epithelial Ovarian 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 and her collaborators 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 goal of a CIHR funded project is 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 they are applying a candidate gene approach and have excluded known candidates, such as TGF-ß-RII (Manderson et al., 2000). This year they published a deletion map of chromosome 17q region shown to harbour a tumour suppressor for ovarian cancer (Dion et al., 2000). In an effort to characterize a tumour model for epithelial ovarian cancer they have described the characterization of four spontaneously transformed novel epithelial ovarian cancer cell lines (Provencher et al., 2000) and the unusual karyotype of trisomy 10 in a selected number of ovarian cancer cases(Wang et al., 2000).  2) Breast Cancer Susceptibility Genes: BRCA1 and BRCA2: 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 collaborators 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). These findings will improve genetic counselling by facilitating mutation detection. In collaboration with the Breast Cancer Linkage Consortium (BCLC) they have established the variation in 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).

David Watkins, PhD along with Dr. David Rosenblatt, published the description of the novel cblH form of vitamin B12-responsive methylmalonic aciduria.  He has begun projects using microcell mediated chromosome transfer to find genes involved in both inborn errors of vitamin B12 metabolism and in some forms of cancer.

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(c)2001 Finestone Labloratory