Scientific & Annual General Meeting

15th October 2002

Baltimore, MD, U.S.A.


Invitation to Submit Abstracts
Scientific Meeting
Sunday 27 April 2003
Cancun, Mexico

Posted 21 November 2002

This was held in Baltimore, MD, 15th October 2002 as a satellite meeting of the American Society of Human Genetics. This meeting attracted 58 registrants from around the world. Abstracts were presented in the morning and during the afternoon productive discussion occurred. The program with abstracts is presented here.



Mutation nomenclature; a literature survey shows a low penetrance of the recommendations

Johan T. den Dunnen
Human and Clinical Genetics, Leien University Medical Center, LEIDEN, Nederland;,

A recent literature survey showed that, although an increasing number of articles refers to the papers describing the nomenclature rules, many mistakes are made. Nearly all papers fail to give a clear and direct link to the Reference Sequence used for numbering. When a link to a database sequence file is given, it is not made clear that the numbering used is different, e.g. starting with 1 at the translation initiation codon. From papers describing mutations in recessive diseases, it is often very difficult or even impossible to determine which combination of mutations were found in the patients analysed. When mutations which (might) affect splicing are reported, the tabular overview of changes identified mostly fails to indicate whether experimental proof was obtained or not. When the "Type of mutation" is reported, a strange mixture of the consequences at DNA, RNA and protein level is given and it is unclear why some changes end up in a certain category; where will a substitution (DNA) which causes the shift of a splice site (RNA) and thereby premature translation termination (protein) end up ?. Mistakes in the description include minor typographical errors and recently also partial and thereby confusing incorporation of new recommendations. The most problematic description is that of insertions, mostly reported in the format "123insG" leaving it unclear whether the insertion is at or after nucleotide 123. This issue becomes even more complex when a change is reported as "123-5insG". Reading papers describing mutations a clear desire can be noted to deduce from the nucleotide numbering used the position in the cDNA/gene which is affected, i.e. coding, untranslated, intronic or gene flanking.

To improve the use of the nomenclature rules several actions are envisaged. An online version of the rules will be made, originating from the HGVS WWW-site. The information provided will include a historical overview of the changes and additions made over time, the reasons behind the choices made and examples showing descriptions of all possible changes at DNA, RNA and protein level. The pages should serve as a platform where problems can be discussed and omissions pointed out. Publishers could be contacted and invited to add the nomenclature rules to their author's instructions, preferably with a direct link to this HGVS WWW-site. Another option is to point publishers to mistakes and inconsistencies which occur in papers published by them. New publications which spread the nomenclature rules should be actively pursued.

Database of DNA Variation in Genes Encoding Blood Group Antigens

Olga O. Blumenfeld and Santosh Patnaik
Departments of Biochemistry and Cell Biology, Albert Einstein College of Medicine, New York, NY, U.S.A

Over the years, a number of blood group antigens have occupied a predominant place as markers in association studies and linkage analyses. More recently, the knowledge of the nature of blood group systems and antigens and the molecular basis for their variation has grown vastly. Here we briefly review the properties and chemical nature of blood group antigens and describe the database that documents their DNA variation. Among human genes, those that encode the blood group antigens constitute a special group. All their direct or indirect products reside on the erythrocyte membrane and can be detected serologically. They represent the human gene repertoire and encode enzymes, transporters, channels, adhesion molecules, receptors, etc; in most cases the altered products do not result in disease. Products of the genes either carry epitopes on the extracellular domains or are glycosyltransferases that give rise to surface epitopes. DNA variations of the cognate genes results in structural change of the epitope, and hence a different blood group phenotype. The "Blood Group Antigen Gene Mutation Database" ( compiles information on 16 blood group systems comprising 26 genes, and documents DNA and translation variation on a total of 512 of their common and rare alleles. The DNA alterations in the database are documented mostly in the coding regions, and their type varies from gene to gene (in some, most are missense mutations, in others - gene rearrangements); the overall pattern of mutations is similar to the average observed in any group of genes (see HGMD). In most cases the common alleles of blood group antigen-encoding genes have been documented to occur in all world populations, and their frequencies in various populations have been established. These and certain other alleles of a significant number of genes have been shown to occur at high frequencies in certain specific populations. As such, DNA sequence variations at sites responsible for epitope expression constitute a unique set of SNPs, that remain worthy candidates as common or population-specific genomic markers; in addition, patterns of variation, or arrays of SNPs documented in each gene, may complement those listed in SNP databases for construction of haplotype maps. Acknowledgements: Departments of Biochemistry and Cell Biology, Albert Einstein College of Medicine, New York, NY.

RettBASE: The IRSA MECP2 Variation Database: A new Mutation Database in Evolution

John Christodoulou1,2, Andrew Grimm1, Tony Maher3, Bruce Bennetts1, 2
1Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney; 2 Dept of Paediatrics & Child Health, University of Sydney; 3BioLateral Inc, Sydney AUSTRALIA

Rett syndrome (RTT) is a neurodevelopmental disorder affecting primarily females, with an incidence of around 1 in 15,000 females. In 1999 mutations in the X-linked gene methyl-CpG-binding-protein 2 (MECP2) were first reported in RTT subjects, and since that time there have been a number of publications describing cohorts of patients and their mutations. Phenotype-genotype correlation studies by different research groups have failed to yield consistent results, probably because of the complex interrelationships between the site and type of the mutation, the modulating effect of skewing of X inactivation, and possibly other genetic and epigenetic factors. In addition, it is becoming increasingly difficult to publish reports of MECP2 mutations in RTT patients unless there is something novel about the case. This will result in incomplete mutation prevalence figures, and equally important, there would be no complete resource listing all known non-pathogenic sequence variations.

To overcome these concerns, we have established a web-based database, which provides lists of all published MECP2 gene variations (including polymorphisms), but in addition has the facility to accept unpublished data.

The major design goal of RettBASE (URL: is to create a simple, secure web site with fast access to data over low bandwidth connections. The database and web interface is based loosely on the PAHdb site. Following the lead of that site, the major components are a MySQL relational database and a CGI based web interface. The database query capabilities have been improved over the PAHdb site by allowing for multiple search criteria to be specified for a single query.

Researchers wishing to submit their data to RettBASE will be able to do so in one of three ways:

    • submission of existing databases or spreadsheets of mutation results to us in a single document
    • completion of the on-line submission form
    • printing a data submission form from the website, completing it, and faxing it to our secure fax line

New submissions will be curated and uploaded into RettBASE within 3 - 5 days of submission, and contributors will be duly acknowledged.

To address the issue of patient confidentiality we have incorporated an Excel spreadsheet algorithm that allows the generation of a unique number based on the subject's name and date of birth. With this, laboratories can submit their mutation data along with the unique identifier number, thereby protecting the patient's identity. In addition, we have made our system flexible enough so that it can be integrated with a clinical database that is currently being developed, potentially providing a much more powerful mechanism for examining the complex issue of phenotype-genotype correlations.

We have also included hotlinks to a number of sites that could be of value and interest to researchers and clinicians and to the families of patients with MECP2 mutations. These links will be expanded as new relevant links are developed.

KMDB / MutationView : An Integrated Knowledge-Base for Variation in Human Disease Genes: Data Expansion and Further Development

Minoshima, S.1, Ohtsubo, M.1, Mitsuyama, S.1, Ohno, S.1, Kawamura, T.1, Ito, S.2, Ito, F.3 and Shimizu, N1.

1 Department of Molecular Biology, Keio University School of Medicine, Departments of 2Environmental Health Science and 3Biochemistry, Setsunan University, Japan More than 1100 disease-causing genes have been molecularly cloned.

Databases for mutation in these disease-causing genes are indispensable for the diagnostics, therapeutics and basic research of the diseases. We previously reported KMDB, a mutation database for human disease-causing genes using a software MutationView. Here, we report an upgraded version of the database with increased amount of data and enhanced function of search and display. Currently, KMDB/MutationView stores 8176 entries of mutations (including 1622 polymorphisms) from 1531 literatures, dealing with 214 genes involved in 200 kinds of diseases. We collected data focusing on 11 categories including Eye, Heart, Ear, Brain, Cancer, Syndrome, Autoimmunity, Muscle, Blood, Kidney and Neuron, which are accessible through the category-based databases such as KMeyeDB and KMheartDB. The characteristic features of the KMDB/MutationView are as follows: (1) Several ways are available to have an access to the gene of interest through the chromosomal map of the gene or disease, anatomical charts of disease-associated organ or tissue, and schematic diagrams of causative gene products and related proteins. (2) Various functions of data display and analysis are available: Genomic/cDNA structure of normal gene, functional domain and motif of protein, zooming-in and -out of the nucleotide and amino acid sequences, plotting mutations with the histogram of case number, changes in the nucleotide sequence and restriction sites, classification based on mutation type, dominant/recessive and symptom, experimental information such as PCR primers and reaction conditions. (3) Mutation data can be placed in any web server and therefore MutationView system is ideal to link global mutation databases managed by LSDB curators. Softwares are available to any qualified research groups if they are interested in establishing a world-wide distributed database for disease gene mutations. Access to KMDB is open to the public but the commercial use is prohibited. The user ID and password are issued upon formal application through the same URL. As a related effort, we are planning to implement the data exchange function in the XML to cooperate with the WayStation/Central Database project. (We thank Chi Co., Ltd. for their extensive collaboration. This work was supported in part by a fund for the "Research for the Future" B Program from the Japan Society for the Promotion of Science (JSPS) and Ministry of Education, Culture, Sports, Science and Technology (MEXT), and a Grant-in-Aid for Scientific Research on Priority Areas from the MEXT.)

A Comprehensive System for the Worldwide Informatics of Retinoblastoma

Brenda Gallie



Functional Annotation and Analysis of Single Nucleotide Polymorphisms

Sean D. Mooney


Allelic Variation in Human Gene Expression

Hai Yan1, Weishi Yuan2, Victor E. Velculescu1, Bert Vogelstein1 and Kenneth W. Kinzler1
1The Sidney Kimmel Comprehensive Cancer Center and the Howard Hughes Medical Institute, Johns Hopkins Medical Institutions, Baltimore, MD 21231, U.S.A 2Department of Mathematical Sciences, Johns Hopkins University, U.S.A E-mail:

Understanding the genetic basis of human variation is one of the most important goals of modern biomedical research. Studies in other organisms suggest that differences in protein sequence account for only a fraction of normal variation and that differences in gene expression levels account for a major part of the variation within and among species. To address this issue in humans, we developed methods to quantitatively evaluate allelic variation in gene expression and applied them to the analysis of 13 genes. We found that allelic variation in expression levels occurred in at least six of these 13 genes and showed that these variations were often heritable. The results suggest that genetically-determined variation in expression levels is an important component of human diversity and have significant implications for normal and abnormal human physiology.

Active L1 Retrotransposons in the Human Genome

Brook L. Brouha


A single Nucleotide Polymorphism in the 3'-untranslated region of CDKN2A gene is associated with Multiple Primary Melanoma as well as Breast Cancer

Monisa Houseknecht, BS, Robin Holmes, MS, Pat VanBelle, PhD, David Elder, MB ChD, DuPont Guerry, MD, Peter Kanetsky, Ph.D, Arupa Ganguly, PhD University of Pennsylvania, Philadelphia, USA

Background: The CDKN2A gene encodes a cyclin dependent kinase inhibitor and mutations in this gene have been identified in a subset of familial melanoma kindreds as well as in many melanoma cell lines. There are 3 common single nucleotide polymorphisms (SNPs) in the CDKN2A gene, 1 in the 5'-untranslated (5'-UTR) region and 2 in the 3'-untranslated (3'-UTR) region. We investigated whether these SNPs were associated with multiple primary melanoma (MPM) as well as coincidence of melanoma and other forms of cancer including breast cancer.

Methods: First, we identified a series of MPM patients. From an ongoing molecular epidemiologic study of melanoma susceptibility, we selected samples from patients with single cutaneous melanoma (SCM) and from disease-free healthy controls who were matched to MPM cases based on gender, age, and time interval between development of 1st and 2nd primary. CDKN2A genotype was compared among these groups. Second, we extended the study to include individuals (all women) with a diagnosis of both melanoma and/or a family history of breast cancer. We compared CDKN2A genotypes in this group to that observed in a group with of women with breast cancer only.

Results: A single SNP (+540C/T) located at the 3'-UTR of CDKN2A was found to be associated with multiple primary melanoma, as well as breast cancer. The T-allele was present in heterozygous state in 22% of MPM patients as opposed to 11% of SCM and 8% of controls (?2 = 6.32, DF=2; p = .03). A pedigree analysis of MPM cases revealed a higher coincidence of breast cancer in families when compared to SCM and controls. For individuals with both melanoma and breast cancer and breast cancer alone, the incidence of the T-allele in heterozygous state was 30% and 28%, respectively ((?2 = 4.32, DF=1; p = .05). There was no observed frequency difference for the other 2 SNPs in either group.

Conclusion: There is an association of +540T allele with MPM as well as breast cancer. The role of this polymorphism in melanoma is supported by the observation that tumors with LOH tend to retain the variant allele at the +540 T polymorphic site. Since the 3'-UTR polymorphism does not affect any consensus site for mRNA stability, this probably signifies this SNP is in linkage disequilibrium with a mutation in another disease gene at this location.

Specific haplotypes of the dopamine receptor 2 gene are associated with heroin dependence in two different populations

Ke Xu



A Bioinformatics resource for the analysis of genetic variants applied to research consortiums

Michael Cinkosky
Transgenomic, Inc., 1675 Larimer St, Denver, CO 80202, U.S.A. is a new web resource from Transgenomic, Inc. for people working in the area of genetic variation. The site includes entries on over 8,500 human genes. Each entry contains the genomic DNA sequence for the gene, plus variation data drawn from multiple sources. The site also includes amplicon specifications, including PCR and DHPLC conditions, to help people apply Transgenomic WAVE technology to the screening and discovery of mutations in these genes.

In addition to being a general resource for public variation and amplicon data, supports collaborative research by enabling users to add their own data to the site and to share those data selectively with other users. This mechanism is designed to support, for example, collaborative research projects spread across multiple research institutions. is one of the first biology resource web sites to be built using Scalable Vector Graphics (SVG) technology, a new W3C standard. This technology supports a richer user interface than is normally found on web sites. is freely available to the scientific community at


The BIC database: problems, pitfalls and promises on the road to clinical utility - Larry Brody

Genetics and Molecular Biology Branch, NHGRI/NIH, Bethesda MD, U.S.A.

The Breast Cancer Information Core (BIC) database was established in 1995 to capture information about naturally occurring variation in the human BRCA1 gene (BRCA2 was added to the database after it was cloned). In addition to mutation information the database contains a collection of mutation detection protocols, lists of gene specific DNA primers and published protocols. Mutation data is entered by individual investigators, hospital-based labs and a commercial lab performing the bulk of BRCA1/BRCA2 tests in North America. The database was originally aimed to fill the needs of basic scientists investigating the genetics, structure and function of the BRCA1 and BRCA2 genes. As the database has grown so has the number of registered users identifying themselves as health care providers, predominantly genetic counselors, oncologists and risk assessment specialists. While access to the BIC web site requires that users read a specific disclaimer about the use of the data for clinical decision-making, there are many reports about the information in the BIC being relayed to patients. Complexes disease such as breast and ovarian cancer are expected to have a variety of etiologies. Allelic variants discovered in families with breast cancer may be risk factors or coincidental findings. In many cases additional family members are not available rendering the results of "DNA testing" ambiguous. The BIC database does not declare whether a specific variant is deleterious or benign. Interpreting the significance of a variant is particularly difficult is the case of missense mutations. As part of an ongoing effort to enrich the data in the BIC, the Steering Committee is investigating the feasibility of using the data reported in the BIC and that gathered from outside sources to determine if a select number of specific variants are associated with cancer risk. The progress made to date on this problem will be reported. If successful, this study may help us to derive an algorithm to evaluate mutations of unknown significance in the future.


A whole-genome linkage disequilibrium SNP map and validated assay resource

Francisco M. De La Vega


The Human Craniofacial Mutation and Variation Database

Harold Lehmann, Andrew Wilkie, Ethylin Jabs
Center for Craniofacial Development and Disorders, Johns Hopkins, Baltimore MD Weatherall Institute of Molecular Medicine, Oxford UK, Contact:

Purpose: To promote public knowledge of human variations relevant to craniofacial development and disorders; To provide a centralized report to enable reporting of detailed knowledge regarding new discoveries in the genetics of craniofacial development and disorders; To enable collaborative research in this area.

Method: The HCVMDB ( was developed as a Web-based, research-community database that is partially open to the public. With curators for specific genes (currently, TWIST and FGFR2), any researcher may upload non- identifiable data about cases and variations. By uploading data and being accepted by the appropriate curator, a registered researcher gains access to cases uploaded by other registered researchers. The general public is able to view the identity of the variations and the number of cases acquired for each variation. Reports are made available at the gene, variation, and case levels. Metadata follow the recommendations of the Nomenclature Working Group for human gene mutations.

Results: The site is fully implemented within the Center for Craniofacial Development and Disorders, with a Web-based workflow and curation process. Views are available for the public, for registered researchers, and for curators. The content currently reflects the laboratory experience of two researchers for TWIST and FGFR2, with over 70 mutations and 400 patients.

Conclusion: The database is now open to all craniofacial researchers, who are enthusiastically invited to participate in this project, including curators and researchers for genes not currently represented.

Role of COMT Val108/158Met Genotype in Executive Functioning Following Traumatic Brain Injury

Robert H. Lipsky.†, Molly B. Sparling‡, Laurie M. Ryan‡, Ke Xu†, Andres M. Salazar‡, David Goldman†, and Deborah L. Warden‡,
†Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD. ‡Brain Injury Program, Departments of Neurology and Neurosurgery, Walter Reed Army Medical Center, Defense and Veterans Head Injury Program, Washington, D.C. and the Uniformed Services University of Health Sciences, Bethesda, MD.*

Catechol-O-methyltranseferase (COMT) has a role in regulating catecholamine levels and therefore catecholaminergic activity in the central nervous system. Increases or decreases in catecholaminergic activity have behavioral consequences, including effects on attention, learning, and memory. In particular, prefrontal cortical dopamine levels are thought to modulate function of dopamine neurons during executive function and working memory. High enzyme activity (COMT Val) and low enzyme activity (COMT Met) are functional polymorphisms resulting from a G to A transition in exon 4 of the human COMT gene (codon 108/158). We examined the potential role of this common functional COMT polymorphism in prefrontal cortex function in 123 individuals following traumatic brain injury (TBI). These individuals also underwent a comprehensive TBI evaluation including neuropsychological testing. Homozygotes for the higher activity allele made more perseverative responses on the Wisconsin Card Sort Test (WCST), a measure of mental flexibility, while homozygotes for the lower activity allele had the least number of perseverative responses. Heterozygotes made an intermediate number of responses. Our data support the potential influence of COMT Val158Met in cognitive function, extending the relationship to subjects in whom executive function has been impaired by traumatic injury.

Assessing Linkage Disequilibrium Intensity In and Around Fc Gamma Receptor Region in Two US Populations

Swapan K. Nath



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