Step 4: Gene Identification

Today, we're continuing the "Path to Treatment" series here on this blog! The aim of these posts is to talk about the various steps that researchers go through in the question for treatments of the chromosome 18 conditions. You can read the previous installments here:

Step 1: Literature Review
Step 2: Clinical and Molecular Assessments
Step 3: Syndrome Description

The fourth step, gene identification, pulls together information from the clinical and molecular assessments. In essence, this step involves trying to link different features of the condition with specific genes on chromosome 18. We take a group of people with distal 18q- (or other chromosome 18 condition) that have the same feature, for example, growth hormone deficiency. We look at the data that we gathered during the clinical assessments and identify all individuals that did not respond to the growth hormone stimulation test, and are therefore growth hormone deficient. Because there is no common breakpoint on 18q, everyone has a different deletion involving different genes. We compare the deletions of the patients with growth hormone failure and determine which area of chromosome 18 is deleted in all those particular patients. This area is called the “critical region”. We would assume that the gene responsible for growth hormone failure is located within this region.

Usually, the critical region will contain several different genes. The trick is to determine which one is most likely to cause a problem when deleted or duplicated! We expect that only 5-10% of the genes on chromosome 18 will actually be responsible for the features of the chromosome 18 conditions. Considering that there are just over 300 genes on chromosome 18, we expect to identify about 15-30 genes that actually play a role in causing the medical and developmental concerns associated with the chromosome 18 conditions.

We have a number of different ways to determine whether a gene is in fact the one that we are searching for.

(1) We research the genes in the critical region. This usually involves several visits to the medical school library! We look at what has been reported in the scientific literature to determine where the gene is usually expressed, what its function is, and whether it makes sense that a deletion or duplication of the gene could lead to the feature we’re examining.

(2) We look at animal models. These are animals (usually mice) that have been bred to be missing a particular gene. We then look at the animal to see what problems it has. If it has the same issue that we are examining, such as growth hormone deficiency or a heart defect, then this is evidence that we have the right gene!

(3) We search for people with gene deletions of or single base pair changes in the gene of interest. For example, if we think that a particular gene is the cause for growth hormone deficiency, we might look at that gene in people with isolated growth hormone deficiency. If we can find changes in the gene in any of those people, that is even more evidence that we’ve found the right gene!

Once we have found the genes that cause the features of the chromosome 18 conditions, we can progress to the next step: the creation of an individualized management plan!