We believe that knowing the role that each of the chromosome 18 genes play in human health and development is a first step in devising specific gene-based treatments. But which genes are the cause of which difficulties for someone with a chromosome 18 change? Luckily, over the past years, we have made great strides in answering this question. Although there are 263 genes on chromosome 18, only about 10% of those genes are the source of the problems. Still, organizing and illustrating this enormous amount of information is a challenge. However, enormity does not equate to impossibility. It just means we must devise new ways to talk about, sort through and illustrate the mountain of information.

Because the chromosome 18 conditions are often depicted using a picture of the chromosome, we have created a pictorial-based method to illustrate and access the information about these key genes. This new Clinical Dosage Map depicts only those chromosome 18 genes believed to have some effect (aka phenotype) when they are present in one copy, or three copies or four copies, or any abnormal number of copies. We call this abnormal number of gene copies “abnormal gene dosage” because the “dose” of the gene is something other than the normal of two. Therefore, we call these maps “Clinical Dosage Maps” and they are labeled based on the phenotypes.

Although we have had Gene Dosage Maps for several years, these additional new maps are different for several of reasons. First, there are two of them; one for deletions and one for duplications. Second, these maps only include information about the dosage-sensitive genes that therefore have an abnormal outcome (phenotype) which is why we call these the “Clinical Dosage Maps”. Genes on which we have data indicating they have no effect when present in an abnormal dosage are excluded. This eliminates a lot of unnecessary detail. Third, in addition to the genes, these maps also demark the small regions of the chromosome associated with the specific phenotypes for which the exact gene cause has not yet been determined. These are called phenotype regions. Fourth, these maps include information on penetrance. Penetrance is the likelihood that a gene’s deletion or duplication will result in a phenotype. Some phenotypes occur in more than 50% of the people with a deletion of the associated gene or chromosome region and some occur in less than 50% of individuals. A deletion or duplication of a key gene or phenotype region is not an absolute predictor of the outcome, which is why we include information about penetrance.

The Clinical Dosage Map is a pictorial and a global map view of the entire chromosome. Unfortunately, this makes it difficult to determine whether a gene or a phenotype region is within your region of interest. However, because these are web-based maps, if you click on any of the items in the map it will take you to a details page which will give the molecular coordinates of the gene or phenotype and the description about what is known along with the scientific citations for that information.

This will all make more sense after viewing one of the maps.

The Clinical Dosage Deletion Map can be found at:

The Clinical Dosage Duplication Map can be found at:

information updated as often as weekly as needed.

On the left side of the chromosome diagram are the phenotypes and their associated gene at the gene’s location on the chromosome. Those phenotypes shown in a bold font occur in over 50% of the individuals with a deletion or duplication of that gene; depending on whether you are viewing the deletion or duplication map. Those phenotypes shown in plain font are found in less than 50% of the individuals with a gene dosage change in that gene. Clicking on any of these on the webpage will take you to a details page with the molecular coordinates and additional information.

However, not all the phenotypes found in people with chromosome 18 changes have an identified causative gene. But most of the phenotypes do have a region of the chromosome within which the causative gene is expected to lie. These phenotype regions are indicated by a bar on the right side of the chromosome picture. The darker gray bars indicate that the phenotype occurs in more than 50% of the individuals with a deletion or duplication of that region. The lighter gray bars indicate the phenotypes associated with that region occur in less than 50% of those with a deletion or duplication of that region.

Note that many of the phenotypes that only have an associated chromosome region are low penetrance meaning that they occur in fewer than 50% of the people with a deletion or duplication of that region. Some of these phenotypes may, in fact, be rare outcomes associated with one of the previously identified dosage sensitive genes. Or these phenotypes associated with a region (as opposed to a gene) may occur only in the presence of a second genetic change on chromosome 18 or elsewhere in the genome. These are discoveries yet to be made.

One obvious point is that the duplication map has significantly fewer phenotypes associates with specific genes and with specific chromosome 18 regions. This is probably not because there are fewer genes underlying the phenotypes associated with a chromosome 18 duplication. Rather, it is likely due to two factors. First, there are fewer individuals with small duplications of chromosome 18 making it more difficult to associate a phenotype with a specific region of duplication. Second, the methodologies for determining the role of a gene and its surrounding regulatory region when present in three copies is more problematic. It is not impossible to determine, but is more complicated than it is for a deletion of some portion of a gene that renders it non-functional. Progress toward identifying the genes underlying the chromosome 18 duplications is a priority.

We’ve made tremendous progress toward identifying the key dosage sensitive genes on chromosome 18. Nevertheless, there is still much work to be done to learn how best to upregulate the single gene in the presence of a deletion or to downregulate three or four copies of the genes when present in excess. But this is the work we are dedicated to doing.