Deciphering Molecular Lab Reports
The genetics lab reports for the newly diagnosed families are now able to include very precise determinations of the location of the person’s chromosomal region of deletion or duplication. In an effort to provide information about the utility of the report, these reports often include information about the genes within those regions. However, for someone with a deletion or duplication this information can be misleading in a couple of ways.
First, genomic laboratory reports often mention the number of OMIM genes within the region of deletion or duplication. OMIM is a database of genes for which there is some information regarding the gene’s function. Since the function of many genes is unknown, this means that all genes are not OMIM genes and reports listing only OMIM genes do not include all genes. For instance, chromosome 18 includes 263 genes, but only 69 of them are listed as OMIM genes. Additionally, being an OMIM gene does not have any bearing on whether that gene has a negative effect when present in a gene copy number other than two (i.e., a deletion or duplication of that gene). OMIM is an amazing resource and the folks that run it have a mammoth task of tracking and synthesizing the mountains of data published daily. However, for lab reports to only list the OMIM genes, this information can be misleading unless it includes an explanation of what is and is not considered an OMIM gene.
Additionally, some reports just include the number of genes within the deletion or duplication as if this is information with clinical relevance. The number of genes, whether they are in OMIM or not, is misleading and irrelevant to predicting the magnitude of the clinical consequences. Somone missing 30 genes or with a duplication of 60 genes might be able to live an independent life, while someone with a deletion including one gene may only be able to achieve a developmental age of 3 years. It is not the number of genes, but rather the specific genes within the deletion or duplication that matter. Granted, however, the larger a deletion or duplication, the more likely it is to include one of the critical genes. Therefore, sometimes size matters and sometimes it doesn’t. This means a list of the genes or merely citing the number of genes is not informative.
For example, of the 263 genes on chromosome 18, we are finding that most of them have no deleterious effect when there are too few or too many copies of that gene. In the case of deletions, 241 genes have sufficient information to imply its role when present in a single copy. (Usually, it is that the gene plays no deleterious role). Similarly, in the case of the duplications, we are finding that 160 of the 263 have sufficient information to suggest its role when present in three or four copies. Likewise, the majority are thought to play no deleterious role in duplications. These findings come from data showing there are many individual genes that are deleted or duplicated in perfectly healthy people. Even though we may not know the function of those genes, we do know they are not a major concern. Thus, enabling us to create a more complete list of genes that does have relevance to someone with a deletion or duplication.
The second reason the interpretation information can be misleading in a molecular lab report is that some reports include a list of disease-causing genes within the region of deletion or duplication. This statement causes the most confusion for newly diagnosed families. Being a “disease causing gene” may have no bearing on whether or not that gene might have an impact when present in a number of copies other than the normal two copies. This is because there are numerous mechanisms by which genes can cause disease. Having too few or too many copies of an otherwise perfectly normal gene is only one of those mechanisms. In fact, some “disease causing” genes do cause disease by this mechanism; however, it is the least common mechanism of disease.
Some genes are labeled as disease genes because they have a mutation that makes them gain a new abnormal function that is detrimental. A “disease gene” by this mechanism is not relevant to someone with a gene deletion or duplication. An even greater number of genes are labeled as disease genes because they cause disease when both copies of the gene have a mutation rendering them non-functional. Again, this is not the case for some with a deletion or duplication of one copy of that gene. The disease-causing genes that cause disease by either of these last two more common mechanisms are the ones we do not need to worry about. This makes it even more misleading when all known “disease genes” at listed in a molecular lab report that diagnoses a gene deletion or duplication.
These arguments stress the need for anyone with a genomics lab report finding of an abnormality to meet personally with a medical geneticist or genetic counselor who can explain the report and interpret the individual findings. They can be aided in this with regard to the chromosome 18 conditions by going to our website on which the Clinical Dosage Maps for deletions and duplications are linked. https://wp.uthscsa.edu/chrome-18/research/
