Annual Report 2002/2003

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 Director of the laboratory since its inception.  Dr. Rosenblatt is currently Chair of the Department of Human Genetics at McGill and his mandate has been renewed for a five-year term beginning in June 2005. The laboratory was established with the help of an endowment to McGill University and funding 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).  As such, this report also serves as the Annual Report of the Division of Medical Genetics of the Department of Medicine of the MUHC. It is available on the Internet (  Since the University Division in Medicine also has included the Division at the Jewish General Hospital, this report also encompasses parts of that activity.  Within the past few years, major advances have occurred with the creation of the Department of Medical Genetics at the Jewish General Hospital.

Highlights: Research

Dr. Thomas Hudson and his laboratory continued its asthma, diabetes and other complex trait mapping projects.  Work in 2004-2005 led to the discovery of links between vitamin D related genes and asthma, and a detailed map of transplantation antigens and their role in multiple sclerosis (soon to be published in Nature Genetics).

Dr. Patricia Tonin was awarded the 2004 Merck Frosst Award for Excellence in Research, by the Department of Medicine, McGill University

Highlights: Teaching

A notable and very sad event last year was the untimely death of Jamie C. Tirone, a Ph.D. student with Dr. Rosenblatt.  He will be greatly missed.

Dr. Mary Ann Thomas completed her final year of Medical Genetics residency and her first year in the cytogenetics program of the CCMG. Dr. Chantal Morel has completed her RV year in Medical Genetics.  Both Dr. Thomas and Dr. Morel successfully completed the examination of the Royal College and CMQ in Medical Genetics.  Dr. Teresa Rudkin and Dr. Fatma Bastaki completed their RIV year, with Dr. Rudkin serving as Chief Residents.  Dr. Nicolas Ah Mew completed his RIII year and will serve in the upcoming year as Chief Resident.  Dr. Philippe Campeau, as part of an agreement between Laval and McGill, completed his RII year in Quebec City.  Dr. Rudkin will be the Chief Resident in the coming yea.  Dr. Maha Al-Awadi and Dr. Khalid Al-Thihli completed their RI year in the Medical Genetics residency.  Our trainees in graduate programs in the Department of Human Genetics are all doing well and are listed in the annual report of the Department of Human Genetics.

Highlights: Clinical

After more than four years, clinical services for medical genetics within the McGill University Health Centre (MUHC) are still in the process of being restructured.  The administration of the MUHC has started to put together a committee to search for a Program Director for medical genetics.

We have been successful in recruiting Marc Tischkowitz, M.B., Ph.D. from the United Kingdom.  He is fully trained clinically in the area of medical genetics and also has a special interest in cancer genetics.  He will be primarily based at the Jewish General Hospital where he will be the first full time medical geneticist since the retirement of Dr. Leonard Pinsky, the founding Chair of the Department of Human Genetics.  Dr. Tischkowitz will also be the first full time medical geneticist in the newly created Department of Medical Genetics at the Jewish General Hospital.  He will hold a hospital appointment in the Division of Medical Genetics at the MUHC and will hold university appointments in the Departments of Oncology and Medicine, as well as in the Program in Cancer Genetics of the Departments of Human Genetics and Oncology, led by Dr. William Foulkes.  The recruitment of Dr. Tischkowitz adds to our existing strengths in both the basic and clinical areas of cancer genetics and general medical genetics.  He is expected to begin work in the fall of 2005.

Research Interests and Accomplishments of Individual Members:

Dr. Ken Dewar and his laboratory have entered the 2nd year of a 4 yr NIH project to develop SNP-based genetic mapping tools for the vervet monkey.  Of note, their analysis of using rhesus and human genome data to predict SNP locations in vervet sequence was the focal points of presentations given at the Cold Spring Harbor international genome biology meeting.  A complementary project to compute a physical map for the vervet monkey genome is under evaluation by Genome Canada, with a co-funding grant also submitted to the NIH.  As a comparative mammalian genomics bioinformatics exercise, they developed and published a strategy to develop dolphin genetic markers with associated positional location as inferred from human and cow genome assemblies.  As part of a larger Regulatory Genetics project, they have identified a novel level of genomic organization (long-range conserved genomic spacing) and are preparing a manuscript summarizing their results.

Dr. Eleanor Elstein continues her interest in caridovascular genetics, with particular emphasis on genetic factors modulating the development of obstructive vasculopathy in cardiac allographs, and on the levels of aminothiols in heart transplantation.

Dr. Brian Gilfix follows a cohort of patients with homocystinuria in the adult genetics clininc.  He is using this opportunity to explore new treatments for this disease and to investigate the effect of elevated homocysteine on other risk factors for cardiovascular disease.  He also is developing and implementing assays based on hybridization probes to replace molecular diagnostic assays based on restriction length polymorphisms.  The benefit of this is decreased net cost and faster turn around times.

Dr. William Foulkes’ main research accomplishment this year was the publication of several papers further describing the clinico-pathological features of hereditary breast cancer.  In particular, he has helped to define the basal pehnotype of BRCA1-related breast cancer.  He  co-ordinated the publication of the largest allelic association study of prostate cancer to date.  Finally, with Dr. Steven Narod,  he co-authored a 10-year anniversary review of BRCA1/2.

T. Mary Fujiwara studies 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.  She also collaborates with Dr. Daniel Bichet on a world-wide collection of families with nephrogenic diabetes insipidus.  They have shown locus heterogeneity, a wide spectrum of mutations, and mutation-dependent mode of inheritance.

Dr. Thomas Hudson directs the rapidly expanding McGill University and Genome Quebec Innovation Centre, which is the largest genomics and proteomics centre in Canada.  The high throughput core facilities in genotyping, sequencing, DNA chip and proteomics supported over 300 Canadian projects.  Dr. Hudson directs two large-scale Genome Canada projects entitled "Regulatory Genetics" and "Haplotype Map: The Regulatory Genetics project made considerable advances in identifying genetic factors that affect the level of gene expression.  The Haplotype group generated a dense map of the common haplotype of chromosome 2 and 4p, in collaboration with the International Haplotype Map Consortium that includes the USA, UK, China, Japan and Canada. This map is accessed over 10,000 times per week by genetics labs around the world.  The Hudson laboratory continued its asthma, diabetes and other complex trait mapping projects.  Work in 2004-2005 led to the discovery of links between vitamin D related genes and asthma, and a detailed map of transplantation antigens and their role in multiple sclerosis.

Dr. Kenneth Morgan has research interests in the areas of population genetics, pedigree analysis, and genetic modelling.  He lead a 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 genetic analysis of Mendelian and complex traits in humans and mice.  He is also an investigator in the McGill University and Genome Quebec Innovation Centre participating in the genotyping core facility, and in mentoring statistical genetic analysis in the regulatory genetics project.

Collaborations with researchers in Calgary and Winnipeg of Mendelian diseases in the Hutterite population included identifying a mutation in the FKRP gene that causes limb-girdle muscular dystrophy, demonstrating genetic heterogeneity as they previously identified a mutation in the TRIM32 gene.  Two autosomal recessive syndromes were mapped: Bowen-Conradi syndrome, a rare congenital malformation syndrome, and disequilibrium syndrome, a cerebellar hypoplasia [In collaboration with Dr. Alexey Pshezhetsky, Hôpital Ste-Justine, they used homozygosity mapping to map a locus for mucopolysaccharidosis IIIC (Sanfilippo syndrome)

In a continuing collaboration with Dr. Danielle Malo on the genetic architecture of host response to Salmonella persistence in mice, significant interactions have been detected.

Postdoctoral fellow, Dr. Loredo-Osti developed methodology for segregation analysis of a quantitative trait in sibships to find evidence for a major gene for urine calcium excretion in families ascertained for kidney stones, a collaboration with Alain Bonnardeaux, Hôpital Maisonneuve-Rosemont.

Dr. David Rosenblatt and his laboratory continue to be the major international referral source for the diagnosis of patients with inherited disorders of folate and vitamin B12. They are involved in studying the molecular bases of these diseases.  Dr. Lisa Worgan, a medical geneticist from Australia working with Dr. Rosenblatt completed an analysis of mutations in the MUT gene among 160 patients with classical methylmalonic aciduria (MMA). This is a rare autosomal recessive disease that is usually diagnosed in infants in the first few weeks or months of life, because of severe metabolic acidosis.  They identified one hundred and sixteen different mutations, of which sixty-eight were new.  Several mutations showed a high frequency in specific ethnic groups.  In particular, a novel mutation, R108C, was identified in sixteen of twenty-seven patients of self-identified Hispanic origin and SNP genotyping data demonstrated that the Hispanic patients who carry this mutation share a common haplotype.  This information has been transmitted to the physicians who had referred these patients to our laboratory over several decades.  Knowledge of the mutations that are responsible for MMA can help in both the detection of carriers and in prenatal diagnosis.  Dr. Chantal Morel, a fifth year medical genetics resident at McGill, published the laboratory’s experience with prenatal diagnosis in eleven at-risk families for severe methylenetetrahydrofolate reductase (MTHFR) deficiency.  This showed that in appropriate families, linkage analysis is a practical approach for the prenatal diagnosis of this disease. This is important because in many families, the mutations responsible for the disease have not yet been detected. 

Dr. Patricia Tonin and her laboratory have 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.

A.        The 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 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 a CIHR funded projects, are to refine the localization and then clone the putative chromosome 3p and 17q tumour suppressor genes. Previously, she published a deletion map of chromosome 3p deletions observed in a large series of epithelial ovarian tumours. In addition she is applying a candidate gene approach and have excluded known candidates, such as TGF-ß-RII. Shedescribed a chromosome 3 transcriptome based on the comparison of expression profiles of ovarian cancer cell lines with normal surface epithelial cells using high through put oligonucleotide expression microarrays. In this study she was able to establish the sensitivity of detection and show that subtle changes in gene copy number are detectable by microarray analysis. In an effort to characterize the putative TSG on chromosome 3p implicated in ovarian tumourigensis, she established the relationship between chromosome losses frequently associated with specific regions of the human genome (BRCA2 and 13q, TP53 and 17p, BRCA1 and 17q, and Xp11),  and that of 3p regions lost in ovarian cancer. She established chromosome 3p loss occurs independently from TP53 mutagenesis.  Most recently she reported a comprehensive analysis addressing the fidelity of expression microarrays, such as Affymetrix GeneChips, showing that rigorous investigation of target sequences representing genes on these microarrays should be pursued prior to engaging in experiments of target genes.

B.        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. Dr. Tonin and her laboratory are continuing to further define the spectrum of mutations in the BRCA1 and BRCA2 cancer susceptibility genes in the French Canadian population of Quebec. Most recently they reported a new recurrent BRCA2 mutation in the French Canadian population at risk for hereditary breast and ovarian cancer. This latest discovery has redefined mutation screening protocols and improved genetic testing, and consequently genetic counseling, for this population.

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