There has been some discussion lately on certain support pages online regarding the interpretation of DNA testing results. Unlike a pregnancy test, these are not simple “positive” or “negative” results and to understand what the significance of the report is, families must understand certain concepts. What is presented here is to help you wrap your mind around these concepts. Please do not assume that a result dooms you or your child to serious illness unless your geneticist has indicated that this is so. What follows is a framework for understanding one’s DNA results.
The first thing one must understand about fatty acid oxidation disorders (FODs or FAODs) is that they are autosomal recessive. This is what makes these disorders rare. Unlike some inherited disorders, FODs are passed on when both parents each have a mutation on the same gene. In the case of MCAD, that gene is the ACADM gene.
Here’s how it works. Each parent contributes half of each child’s DNA. When a parent is a carrier for an FOD, it means that the DNA they carry has one gene with a single, mutated allele. This is inherited from one of their parents, not from any environmental factor and not from any illness. So, a carrier parent has one good allele and one mutated allele. Normally, this goes unnoticed because even if the parent passes on the affected allele, the other parent usually has two unaffected alleles, making the child simply another carrier. Problems usually show up when each parent is a carrier. Such couples have a 50 percent chance of producing a child who is also a carrier and a 25 percent chance of producing a child who receives both affected alleles. The chance that a child will receive only the unaffected alleles is also 25 percent.
The reason this is important to understand up-front is that disease usually appears only in individuals with two affected alleles, not in carriers. (A later blog post will deal with the subject of affected carriers.) If a DNA test has been ordered, due to family history, for instance, and a single allele is found to be mutated on the MCAD gene, it means the child is heterozygous or a carrier and will likely not experience symptoms of MCAD or whatever the FOD in question happens to be. This may confuse parents if their child had some abnormal blood or urine test, such as the newborn screen (NBS), that spurred the DNA testing. One must understand that even a single, mutated allele may slightly affect the results of some tests and parent should take this DNA result as a good indication that their child will likely be symptom-free.
If the DNA test is returned and shows that both alleles on the ACADM gene are mutated, that indicates a more serious situation. It gets complicated because there are different types of mutations, and each one carries different risks. Once the DNA results are in, one’s geneticist will be able to pinpoint any mutations. Many MCAD patients have the same common mutation on both alleles. This makes them homozygous for MCAD. Some, however, have different mutations on each allele of ACADM, and these patients are referred to as compound heterozygous for MCAD. This is what is known as the genotype. The same holds true for other FODs; each may have differing mutations on each allele.
The DNA report may list the mutation(s) as deletions, insertions, missense, point, silent, in-frame or out-of-frame (frameshift). It will probably also give you the location on the gene where the mutation falls. This is important information because of the way genes work.
Each individual gene is responsible for making some protein or enzyme needed for some highly specialized work in the body. The ACADM gene handles fatty acid oxidation of medium-chain fats. To do this, it produces a protein that assembles itself into a shape. This is commonly referred to as folding. When a mutation occurs, it affects this folding. Exactly how it affects it is due largely to how the mutation changes the work of the gene. This is where the type of mutation may help patients and families understand the potential course of the disorder. A null mutation stops the work of the gene cold and is generally considered the most serious mutation, but out-of-frame mutations create similar problems because they stop the process prematurely. If two point mutations are identical (homozygous), they are likely to be more serious than two point mutations that fall along different locations on the gene (compound heterozygous). This is because at each of those two points, one allele is still working. Deletions create problems because the work of the gene (the amount of enzyme produced) is less, severity depends on where the deletions occur and how large (how many points along the gene are encompassed), as well as if the deletions are matched on both alleles. Insertions create problems because they disrupt the order of the work.
An imperfect analogy
If one thinks of the gene’s work as a song sung as a duet, it may be easier to understand the impact. The song progresses nicely until two matching notes (points) are missing or incorrect and the song momentarily stops or goes off-key. It will then continue. Or, two notes (points) do not match and the song may skip one voice at each point, but the tune continues in the voice of the other. The music stops entirely if there are no notes (mutation is null or frameshift). And one voice must carry the tune alone for several notes in the case of a single deletion. If two deletions overlap along the course of a gene, a single voice might carry the tune for a few beats before the music is silent. And, when an insertion occurs, the song may miss its tempo. In most cases, the song is recognizable, though faulty.
Knowing one’s genotype may or may not help understand the course of the disorder in the individual. With MCAD, there is relatively long experience with the most common homozygous mutation but unfortunately, not everyone with this genotype expresses the disorder identically. With some people, symptoms are severe and difficult to control, with others, symptoms may go unnoticed for years and many fall somewhere in the middle. When the genotype returns an “unknown” or “novel” mutation, a risk assessment is called for. This may include a test that will determine the amount of enzyme produced by the faulty gene. Simply having two different mutations (compound heterozygous) on the alleles does not necessarily mean the disorder will be more severe. It some cases, it may even be less severe.
Families must understand that while knowing the genotype may deepen understanding of the FOD, it is the phenotype, or the expression of the disorder in the individual, that one must treat. Knowing that one’s child is a carrier should set one’s mind at ease. Knowing that one’s child has MCAD or another FOD, gives families a powerful weapon because the symptoms of MCAD can be silent: lethargy, hypoglycemia, poor appetite, especially in infants. Vigilance can prevent the most serious outcomes. It is not uncommon for a family who lost a child to MCAD or another FOD at birth, to manage to have other children who survive – because everyone is alerted to the potential danger and the infant is treated appropriately.
One should not assume that all children with the same genotype, even within the same family, will present identically. Each child is different, though the disorder may present similarly. One may react more to becoming overheated while another manages well. The answers to these day-to-day problems do not lie on the DNA report; they are within each family’s experience.
Finding out what is wrong is good because it leads us to more successful treatment. Understanding is good because it makes us better advocates for ourselves and our children. Discuss your child’s test result with your geneticist in whatever detail you feel comfortable.