CHROMOSOME 18 CLINICAL RESEARCH CENTER

Creating individual action plans based on the chromosome 18 gene dosage annotation maps


If you use the information from this website please cite: Cody JD, Carter EM, Sebold C, Heard PL, Hale DE.
A gene dosage map of Chromosome 18: a map with clinical utility. Genet Med. 2009 Nov;11(11):778-82.doi:10.1097/GIM.0b013e3181b6573d. PMID: 19745747


One of the components of our goal to make the chromosome 18 conditions treatable is to create action plans. Because almost everyone with a chromosome 18 condition has a unique group of genes either deleted or duplicated, the action plan for an individual must also be unique. It must be based on the potential effects of the genes within their unique chromosome change.

We have created a map-based tool that annotates the genes and chromosome regions with clinical relevance when either duplicated or deleted. As the clinical effects are due to abnormal gene dosage, we are referring to this tool as a gene dosage maps.

These gene dosage maps have been created using sets of genome annotation tracks on the UC Santa Cruz Genome Browser. These tracks display the genes and phenotype regions based on their chromosomal location with links to information about their potential role in generating an abnormal phenotype. We have created two types of tracks.

Gene Dosage Tracks. Each gene is depicted by location and classified with regard to the likelihood of being dosage sensitive. There is 1 track for the effects of hemizygosity (gene deletion) and one for suprazygosity (gene duplication).

Phenotype Track. This track indicates the locations of the regions for specific phenotypic features that are linked to a region of chromosome 18 but for which the causative gene has not yet been identified.

Gene Dosage Maps

The step by step directions for how to use the maps can be found here
Users can enter the genomic coordinates of interest to visualize the genes in the region. The genes are color coded based on the likelihood that the gene product produces a phenotype when duplicated or deleted. By clicking on a specific gene, a "details page" will appear with additional information. Information curated by the Chromosome 18 Clinical Research Center can then be accessed by clicking on the gene name next to "Outside Link." This will take you to the gene dosage details page. Only information relating to the effects of gene dosage are described. For other information from numerous other resources (OMIM, PubMed etc.) on the biological role of the gene's product and potential role in disease through mechanisms other than copy number changes, use the "UCSC Genes" track in the browser.

Literature regarding all the genes on chromosome 18 is reviewed on an annual basis. As the understanding of the effects of gene copy number changes evolves, the gene dosage codes will be updated to reflect the latest knowledge. Therefore most all classifications are provisional based on the most current data.

The gene dosage codes are as follows:

Hemizygosity Classes

  1. No clinical effect – due to hemizygosity
    1. There is a measurable effect but without clinical significance
    2. CNV in multiple individuals or normal human knockouts identified
    3. Null mouse has no abnormal phenotype
    4. Heterozygous knockout mouse has no abnormal phenotype
  2. Risk factor for disease from hemizygosity but only in combination with multiple genetic or environmental factors
  3. Conditional cause of disease from hemizygosity but only in the presence of another  specific genetic or environmental risk factor.
    1. Trans – a mutation in another gene.
    2. Cis – a mutation in the remaining copy; a revealed recessive mutation.
    3. Environmental – phenotype only present in conjunction with an environmental factor.
  4. Low penetrance disease occurring in fewer than 50% of people with hemizygosity.
  5. Causal of disease if hemizygous with a penetrance of at least 50%
    1. Based on our study data
    2. Based on data from the heterozygous knockout mouse
    3. Based on human disease literature
  6. Haplolethal
    1. Knock-out mouse hemizygous prenatal lethal
    2. In a critical region never found in hemizygosity in people
  7. Unknown – no data are available regarding the effect of hemizygosity or heterozygous loss of function

Suprazygosity Classes

  1. No clinical effect 
    1. There is a measurable effect but without clinical significance
    2. Whole gene CNV in multiple unaffected people
    3. Transgenic mouse has no abnormal phenotype
  2. Risk factor  in disease from suprazygosity but only in combination with multiple genetic or environmental factors
  3. Conditional cause of disease from suprazygosity but only in the presence of another  specific genetic (trans) or environmental risk factor
  4. Low penetrance disease occurring in fewer than 50% of people with gene duplication.
  5. Causal of disease if suprazygous with a penetrance of at least 50%
  6. Unknown – no data are available regarding the effect of suprazygosity or gain of function

 

Phenotype Maps

These maps synthesize and present existing data linking a specific phenotype to a region of chromosome 18. The data here are from various datasets, including linkage studies and GWAS data as well as studies presenting molecularly defined critical regions for specific gene dosage phenotypes. The Phenotype Track regions are color coded using the same scheme as used for the Gene Dosage Map although not all categories apply. Also, the hemizygous and suprazygous classifications are combined here primarily because there are so little data regarding the effects of suprazygosity.

Hemizygosity Phenotype Classes

  1. Mechanism of disease not related to gene dosage 
    1. Recessive inheritance
    2. Dominant negative disease mechanism
  2. Low penetrance disease occurring in fewer than 50% of people with hemizygosity.
  3. Causal of disease if hemizygous with a penetrance of at least 50%
    1. Based on our study data
    2. Based on data from the heterozygous knockout mouse
    3. Based on human disease literature
  4. Haplolethal  
    1. In a critical region never found in hemizygosity in people
  5. Unknown – no data are available regarding this phenotype and hemizygosity or heterozygous loss of function.

Suprazygosity Phenotype Classes

  1. Mechanism of disease not related to gene dosage 
    1. Recessive inheritance
    2. Dominant negative disease mechanism
  1. Low penetrance disease occurring in fewer than 50% of people with suprazygosity.
  2. Causal of disease if suprazygous with a penetrance of at least 50%
    1. Based on our study data
    2. Based on data from animal models
    3. Based on human disease literature
  1. Unknown – no data are available regarding this phenotype and suprazygosity

Once the specific gene is identified for a phenotype, the data will be removed from this map.  If the molecular mechanism of the disease is either haploinsufficiency or suprasufficiency, the information will be linked to the appropriate gene on the "Gene Dosage" tracks.  The Phenotype track will be regularly curated as new data become available.  As chromosome 18 is relatively gene-poor, we expect to be able to regularly update the map with the latest information.  This is in contrast to the OMIM phenotype data on the UCSC Genome Browser, which will identify a region and a phenotype based on the first report and then only update their map when the causative gene is identified.   Thus, we hope to provide a unique resource for the research community.  

Gene Dosage Maps

Hemizygosity Gene Dosage Map
Suprazygosity Gene Dosage

Phenotype Dosage Maps

Hemizygosity Phenotype Dosage Map
Suprazygosity Phenotype Dosage Map

For those interested in only those genes and regions currently classified as having clinical significance, we have created a map that includes only those data.

Hemizygosity Clinical Dosage Map
Suprazygosity Clinical Dosage Map

We have 2 YouTube videos that may be helpful:
How to use the Dosage Maps 2.0  

Dosage Map 2.0 Examples  

 

For additional information about:

  • The chromosome 18 conditions (18q-, 18p-, Ring 18, Tetrasomy 18p, Trisomy 18 etc.) go to The Chromosome 18 Registry & Research Society website at www.chromosome18.org
  • The biology of a gene of interest or links to other datasets with gene-specific information follow these steps.
  • When looking at either of our tracks, scroll down below the track image to the track controls.
  • Expand the "Genes and Gene Prediction Tracks" list
  • Click on "UCSC Genes" and open it in "pack" and click on any "refresh" button.
  • Click on your gene of interest and the UCSC Gene Details page will open with summary information and links to other databases.

We invite anyone with additional information that could improve this site to contact us. We do our best to keep abreast of the literature, but we also recognize that this is a large project.  We welcome your input!  Contact us at chromosome18@uthscsa.edu