What is a carrier status in DNA sequencing?
DNA testing to be proactive about your health
When you are planning to sequence your whole genome, decoding the sequence of your entire DNA, reproductive planning might not be on the top of your list of motivating reasons in which to do so. Many might not even appreciate that is actually one of the major benefits of genome sequencing. First and foremost, what people will focus on is learning about their predisposition to diseases, and for a good reason: doing DNA testing for such a purpose allows you to be proactive about your own health management. Not many medical tests provide you with that option. Another major way of being proactive with regards to DNA sequencing is in learning about one’s personal way of responding to certain medications. A personal DNA code can inform a given person on what medication they should take or avoid, and at what drug dose they should be taking it for improved effect.
But another way of being proactive, and a very important one that might often be neglected at first glance, is figuring out how partners who want to have kids can match their DNA against the odds of passing on mutations to their children that could cause diseases.
In the past, this was completely impossible to investigate, with the exception of studying your family history, which in itself could not guarantee that you inherited disease-predisposing mutations or not. But now you can determine these factors with a very high accuracy through DNA testing for diseases.
In the previous post we wrote about what we believe to be the first family in Canada to screen themselves with full genome sequencing, which spans three generations! We wanted to take advantage of this unique moment, and discuss some of the findings in order to exemplify the concept of carrier status. The entire family that participated in this sequencing has granted us permission to write about their genetics to help educate others about the potential utility of genome screening in presumed healthy individuals and family groups, especially since no pathogenic results were found in any of the family members.
Let us start with the titular question then.
What is DNA carrier status?
Carrier status denotes what mutations a person has that do not result in a disease, but if both biological parents of a child were to have the same mutation, they would run the risk of potentially producing a disease in the child. In other words, for these diseases to materialize they require the same gene to be affected in each of the parents, and then to be passed onto a child. When both inherited copies of the same gene need to be mutated to produce a disease, such conditions are referred to as “autosomal recessive”. If you only require one of the same genes to be inherited from one parent to lead to a disease, such conditions are referred to as “autosomal dominant”. Autosomes are any chromosomes that are not sex chromosomes. Sex chromosomes, are the X and Y chromosomes that define the biological gender of a person, with typically XX for females and XY for males. You can also be a carrier of a gene mutation on X-chromosome, if the condition requires both genes inherited from the parents to be mutated. In this case, such conditions are called “X-linked recessive”, and would only affect females, since the individual would have to inherit an X chromosome from each parent in order to result in disease, and as we just said, two X chromosomes lead to female gender development.
Since the carriers of these genes are unaffected, the pairing of two carriers of the same affected gene can result in a disease in the child seemingly out of nowhere. This is not as uncommon as you may think.
The most commonly observed carrier status, for serious conditions, based on testing nearly twenty-four thousand individuals, is for alpha-1 antitrypsin deficiency, a genetic disorder that may result in lung disease or liver disease, and was found in 1 out every 13 people! The second most common carrier status is even more famous: cystic fibrosis! This condition especially affects the lungs through the overproduction of mucous, resulting in incessant infections, and currently has no cure, significantly decreasing the lifespan of affected individuals. On average, 1 in 28 people are carriers of this debilitating condition. Non-syndromic hearing loss and deafness is the third most common carrier frequency among people, characterized by congenital mild-to-profound sensorineural hearing impairment. Nearly 1 in 43 people are carriers.
|Alpha-1 antitrypsin deficiency||7.6%||0.2%|
|Non-syndromic hearing loss and deafness||2.3%||0.02%|
|Spinal muscular atrophy||1.8%||0.06%|
|Familial Mediterranean fever||1.6%||0.02%|
|Sickle cell disease||1.4%||0.04%|
Adapted from Lazarin GA Et al. 2013. Genet Med 15(3):178-86
It can get even more interesting than that. Although the above study only looked at a fraction of the known diseases for carrier status (108 conditions while there are thousands of genetic diseases), for those that were assessed, 18.9% were carriers of a single disease of some kind, 4.3% were carriers of two diseases, 0.7% were carriers of three diseases, and 0.1% were carriers of four or more conditions. This resulted in a total of 5.2% of those tested proven to be a carrier of two or more conditions. If assessing for all of the different conditions through full genome sequencing, these numbers are much higher, where almost everyone is a carrier of disease-related mutations.
The above study also showed how often partners of a given condition were identified, however, the authors claimed this is likely underreported, as people were tested individually and the data was only collected based on the self-reporting of relationships. Nevertheless, these numbers are close to what we previously reported in another post that discussed the likelihood of genetic carriers pairing up together which runs between 0.5-1%.
Thus checking your carrier status prior to having kids is important.
So what did the family who got sequenced together find?
The molecular underworld
We will start with the wife of our youngest couple tested in the family - there were three generations tested, a young wife and husband, the husband’s parents and his grandmother.
She had returned a couple of reported results. One was for a carrier status and the other was a flagged variant of unknown significance, meaning the impact of the mutation was not certain, but the gene itself is potentially involved in a genetic predisposition to ulcerative colitis, an inflammatory bowel disease in which the lining of the large intestine is chronically inflamed. The reason why that was important is because she was diagnosed with ulcerative colitis in her early adulthood. However, at the moment, there is not enough evidence to be able to link that mutation to her condition. Nevertheless, this genetic data, along with her medical history, will be added by the company to public databases in support of building evidence towards understanding the role between the gene, in this case MUC3A, and the potential health outcomes. It is a perfect example of how sequencing one’s DNA can contribute towards the future understanding of the genome.
After all, the cause of ulcerative colitis is currently still unknown.
The MUC3A gene is responsible for the production of epithelial glycoproteins which are involved in mucus gels thought to provide a protective, lubricating barrier against particles and infectious agents. Epithelium, on the other hand, makes up different tissues that line the outer surfaces of organs and blood vessels throughout the body, so you can see how this might be potentially involved in the development of ulcerative colitis if perturbed. And to clarify all definitions, glycoproteins are proteins (or molecular robots if you will, and as we always refer to them, tiny machines that perform the majority of cellular work and function), that are also coated in sugar molecules. Yes, it sounds yummy, but in this case their purpose is to alter their final three dimensional structures to enhance their properties.
In a molecular world, it is all about the 3D structure of these molecules. On such an atomic level, it really comes down to electromagnetic properties, or how likely the atoms of these molecules are going to attract each other or not. And the 3D structure determines how the attractive forces are distributed throughout the structure, as well as the lock-and-key type of interaction between these molecules. Think of it as an intricate LEGO system, which really is all that biology is: the connection between different molecules that together, in unison, amongst thousands and thousands of components found in each of the cells, provide the illusion that something is actually alive. But in reality, it is just a bunch of atoms playing with each other! Except that play can be quite sophisticated and complex.
Proteins are made of building blocks called amino acids, and there are 20 of these. When the genetic code (the DNA sequence), specifies the blueprint of how to build a protein, it is by indicating which amino acid is to be added to the next one in a specific sequence. Once you make that sequence, since each amino acid is made up of bunch of atoms, all with their own electromagnetic attractions, all of these amino acids will start interacting with each other, and with other molecules in the surrounding environment, to create a 3D structure called protein. These can be small or huge, and they can interact with many other biological molecules. Much like Optimus Prime of Transformers fame, who is actually composed of multiple separate pieces, protein complexes can use multiple separate components to make a final functional assembly. On top of that, you can enhance their 3D structure with the addition of other chemicals. Sugars are just one family. Proteins that are heavily adorned with sugar molecules are called glycoproteins.
But going back to the gene itself, this is also an example of how important it is to provide accurate clinical information about yourself when choosing to use genome sequencing for screening purposes. Without that information, it is likely that this variant of unknown significance would not even be reported to the doctor in the report. If the couple in question plan to have children, it will be interesting to see if this particular mutation will be passed onto a child (50% likelihood), and whether the child will exhibit the condition. While environmental factors are knows to play a role in ulcerative colitis development, this would be a very strong indicator of genetic predisposition. Needless to say, the hope is that this will not be the case.
Genetic predisposition to iron-overload
In terms of the carrier status discovered, the wife happened to be a carrier of a potentially serious condition termed hereditary hemochromatosis. This condition can be affected by a number of different genes, and in her case it was the HFE gene, affected at c.187C>G (H63D). The first number denotes the mutation in the DNA while in brackets is the corresponding amino acid change observed in the protein produced from the gene code. The protein is believed to be involved in regulating the circulating iron levels. If she had inherited two bad copies of this gene, one from each parent, the resulting disease could lead to aberrant iron accumulation in the body, which overtime can damage normal organ function. However, it gets bit more complicated than that. The majority of cases of genetic onset hereditary hemochromatosis stem from a different mutation in that same gene, C282Y (meaning the mutation is in a different area of the gene, affecting a different area of the same protein). Thus people who have a C282Y mutation in both copies of the HFE gene inherited from their parents, are referred to as “homozygote” for that mutation. This is the most frequent genetic make up behind this condition. Her particular mutation is considered a more benign form, and could lead to the disease if combined with a C282Y mutation, meaning one HFE gene from one of parent would have the C282Y mutation and the other HFE gene from the other parent would have the H63D mutation. Such a combination of two different mutations in two copies of the same gene is referred to as “compound heterozygote”. Such a combination is seen less frequently. The final option is of course both HFE genes carrying the H63D mutation, but this combination rarely appears to result in the condition.
That brings us to another concept because… it can get even more complicated from here!
There is such a thing as disease penetrance, and this is good time to introduce it. Disease penetrance refers to the varying degree of disease symptoms that can materialize, ranging from severe to no disease symptoms at all, even for the same underlying mutations!
And hereditary hemochromatosis is a perfect example!
For the majority of people diagnosed with the hemochromatosis condition, they have an underlying genetic predisposition, in about 85% of cases. However, for those who have the genetic mutations for the condition, only about 25% of those individuals will end up exhibiting the clinical symptoms of the disease. This is what is referred to as “disease penetrance”, and it is not fully understood what the factors are that influence the expressions of the disease. But everything in medicine is all about probabilities, as there can always also be environmental or biological influencing factors affecting the weight of the disease.
Nevertheless, the fact that our young wife is a carrier means that one of her parents is either a carrier or has a disease (because one of them had to pass on the mutation, unless the mutation arose spontaneously - more on that in the moment).
This could mean that both of her parents could check their iron levels or review if they have ever been notified of high iron blood levels. This could be done proactively in order to rule out that one of the parents, the one that passed on the mutant gene to our young wife, does not actually have the disease, because the long-term outcomes can be quite detrimental. Whether the population should be screened for hemochromatosis is a controversial topic, and perhaps a review of the family’s medical history could guide the decision as to whether the parents should screen themselves or not. The symptoms of hemochromatosis range from chronic fatigue, hyperpigmentation, and joint and bone symptoms to diabetes, and liver diseases, such as fibrosis, cirrhosis, and hepatocellular carcinoma, and thus the condition can turn deadly. On the other hand, it is fairly common to be a carrier of hemochromatosis among people of Northern European descent. In one of the largest studies on the topic, 34% of white people were hereditary hemochromatosis carriers, for the two most commonly encountered mutations, including the one observed in our young wife! This is a bizarrely high rate, and you will see in a moment perhaps why this is the case.
So what does it mean for the wife now that she knows that she is a carrier of this condition?
It means there is a 50% chance that she will pass it on to her child, and therefore it means there is a 50% chance that her child will be a carrier. Luckily her husband was not a carrier (you will see further expansion on the reasons why in the next post), of any of the mutations leading to hemochromatosis, and therefore the future child can only be a carrier in the worst case scenario. There is also a 50% chance that such future children will be totally fine and will inherit the good normal gene copy that our young wife also has.
If her husband was a carrier, then there would be a 25% chance that the child would be afflicted with the disease, a 25% chance that the child would get good copies from both parents and thus would be totally fine, and a 50% chance of just becoming a carrier. Thus two carriers of a mutation reproducing together does not guarantee the resulting child will have a disease, and is also not a guarantee that the child will be a carrier. There is an equal chance that they could be totally fine as there is of them inheriting both bad copies that could result in the disease.
Now, here is another tricky part.
Are DNA carriers also at risk?
Remember what we mentioned about disease penetrance earlier? For some conditions, the carriers can also develop some mild form of the disease! However, it is quite negligible so it is usually ignored. Here is an example of that: looking at some of the scientific literature, one study from Italy showed that 8.5% of patients who were heterozygous for the same mutation in the HFE gene as the wife presented with hemochromatosis phenotype (3.8% in women), while of those males who exhibited actual iron-overload, 1.7% were heterozygotes for that same mutation. In another massive study from Canada and the US looking at nearly 100,000 people, of the patients diagnosed with iron-overload (364 cases), 40 of them, or 11%, were heterozygotes for the same H63D mutation as our young wife protagonist. Only 29 of these, or 8%, were actually C282Y homozygotes (both HFE genes affected), 0.8% compound heterozygotes, 1% H63D homozygotes, and 4% C282Y heterozygotes. So those that are heterozygotes could also manifest the disease in theory.
The only problem with that statistic is that 75% of the people with iron-overload had no mutations at all in their HFE genes! So other factors can lead to this condition, and the question remains, were the heterozygotes affected because of the mutation, or because of these other factors? That we currently cannot know. But we do know that the bulk of those affected without the mutations in their genes were not Caucasians, and these mutations only seem to be having an impact in white people! They are almost never found in other ethnicities in a homozygous state, and 90% of the time they are only seen in white people! So ethnicity definitely plays a role in genetics, and we cannot know why other ethnicities are affected without the same mutation seen in Caucasians. It is possible that other mutations might be involved that we simply have not yet discovered, because other ethnicities have not been investigated genetically to the same degree as Caucasians.
It is not understood what these additional factors could be which are pushing towards these symptoms. Severe alcohol intake might be one predisposing factor (as noted in the Italian study, just in case you were wondering where that came from).
How do you treat this condition?
Phlebotomy, which is a fancy way of saying donating blood is the main method of treatment. So if you are a male diagnosed with hereditary hemochromatosis, that is your ticket out. If you are a woman, well, nature takes care of things for you, so women don’t need to worry. Although that might be problematic in that a woman who has this condition, as it might never be diagnosed because her iron levels will not spike due to menstrual bleeding, but then post-menopause, when one might not expect anything, “suddenly” the disease shows up. For men, if the condition is not diagnosed, the condition might not become apparent until serious clinical symptoms begin to appear.
As the doctor receiving these results commented, this is one of the benefits of genetic testing early in life, because it allows the potential condition to be discovered early and not when we stumble across clinical symptoms when the impact of iron overload has already started to take its course.
Wait, it gets even better!
Do DNA carriers gain benefits?
One of the reasons why carriers of hemochromatosis are observed so frequently among the Caucasians, is because it is believed that being a carrier of hemochromatosis is beneficial! Because you might have extra iron that your average person will not and that can provide other benefits, such as being more fit! Another one might be a reduced chance of infections! The same massive study of nearly 100,000 people mentioned above looked at the potential benefits of different genotypes of hereditary hemochromatosis (so all of the different mutation combinations we discussed), as compared to the regular population without the affected HFE gene, and found that if you are a heterozygote for the H63D mutation as our young lady is, then as a woman, you have a slightly decreased risk of developing diabetes, liver and heart disease or experiencing infertility. Men with the same mutation fare bit differently: they have a significantly decreased risk of heart disease, and a similarly decreased risk of diabetes and infertility, but have an increased risk of developing liver disease. In this battle of sexes, men appear to be more complicated!
So this single example shows you how complicated genetics can be, and there cannot be an easy predictability for outcomes, as each outcome will truly be personalized based both on your complex private assortment of DNA mutations and the environmental factors you will expose your body and your DNA code to. And that is a very complex symphony of interactions! At the moment, we can offer averages based on ethnicities and genotypes, but as we continue accumulating data, these predictions will evolve to be ever more sophisticated, including a greater array of influencing parallel mutations found in your DNA, as well as the environmental influence which we will be able to glean from surveys and other metrics, like for example blood measurements, and heart activity. This is definitely already happening, but still in its infancy, as biology is enormously convoluted.
So these were the major findings for our wife who was tested. Besides the report, the test-ordering doctor also obtained access to a web portal showing all of the findings, including variants of unknown significance, meaning, currently there is no knowledge of their effect on health, either due to a lack of published evidence or the ability to predict deleterious outcome to the protein structure affected by the mutation.
On the top of that list was a mutation in the RYR gene, the coding for a receptor that is involved in the regulation of cellular calcium use. Calcium has a myriad of functions in our bodies, with a list so large that you can literally write massive books just on this topic alone. One of the more famous uses of calcium is during muscle contraction. This gene is so important for the regulation of calcium use that mutations in this gene can lead to a variety of different conditions. The mutation that the wife who was tested has is of uncertain significance, and has been proposed to likely be benign by the recent scientific literature’s description. But we’ll get back to this one shortly, let us explore now what we were able to learn about the husband in this family.
Genetic muscle disorders
The most significant finding for the husband was that he is a carrier of a mutation in SEPN1 gene which is involved in muscle disorders, termed multiminicore disease, characterized by muscle weakness, early-onset rigid spine muscular dystrophy, progressive scoliosis, life-threatening respiratory failure and cardiac complications. Another way to phrase it is that he had a heterozygous mutation, meaning only one mutated copy of the two SEPN1 genes was inherited from his parents. If he had a mutation in both of these, he would be a homozygous mutation carrier, and at that point he would present with a disease. Approximately 30% of all multiminicore diseases, are caused by mutations in this particular gene. The variant that was identified was c.943G>A (G315S), and it is one of the most commonly detected in affected individuals and thus believed to be the SEPN1-related myopathies founder mutation, or one of the earliest variants observed that has been propagated through the population.
Technically, no carrier of any condition is totally out of the woods in terms of reproduction, even if their partner was not a matching carrier, since spontaneous new mutations (termed “de novo mutations"), can always appear in the offspring, either in one of the germ cells (sperm or egg) or early on in the development after fertilization took place. However, some DNA areas and the resulting conditions appear to be more frequently affected by this than others, and this is especially observed in male germ cells and are thus usually paternally inherited (due to the greater number of cell divisions taking place during spermatogenesis that increase the odds of spontaneous mutation incidence). On average, approximately 40–70 new non-inherited germline mutations are present per individual, meaning these new mutations are present in the genome you were born with, and are present in all of the cells of your body. The diseases especially influenced are autism spectrum disorder, epileptic encephalopathy, schizophrenia, intellectual disability, developmental disorders, amyotrophic lateral sclerosis, myopia, retinitis pigmentosa, congenital heart diseases and CHARGE syndrome. The presence of de novo mutations help to explain the persistence of some of these disorders despite the low reproductive success they convey.
But besides that, we can now link this information back to our wife. The most common genes involved in the multiminicore disease are SEPN1 as already mentioned above, but also the RYR gene. Recall that wife is a carrier of a variant of unknown significance in that particular gene, suspected to be benign. So then the question arises, can the combination of both of these genes being mutated at the same time in the same individual produce any problems?
There does not seem to be published scientific evidence for it. But we do know that the SEPN1 gene product is required for ryanodine receptor calcium release, in human muscle, so there is clear evidence that the products of these genes are working together. In that same paper, the authors showed that when both of the SEPN1 gene copies were mutated, resulting in no functional protein, the activity of the ryanodine receptor was affected, but could be rescued by the addition of the missing protein normally produced by the SEPN1 gene.
So the other question then is, while carriers of either of these gene mutations appear to be fine, could having mutations in both the SEPN1 gene and the RYR gene at the same time start influencing how the proteins can interact with each other enough to affect the proper function of the ryanodine receptor? We cannot know that at the moment. There is a 25% chance that both of these mutations will combine in the offspring, and at that point, time will tell if there could be potential physical consequences. It is considered unlikely, but genetics can be weird, and RYR gene expression is a perfect example, with some published evidence that a heterozygous mutation in this gene has received preferential expression (the use of the gene as the blueprint to produce the mutated protein molecular robot), over the normal copy of the gene.
What was interesting as well was that both the husband and wife were carriers for mutations in the same genes involved in disease development, but for any of these mutations there was not enough evidence to be able to determine what the potential outcome could be, and the variants were labelled as of unknown significance. Once again, their child will have a 25% chance of inheriting both of these mutated copies of same gene from each parent. Whether that will take place, only time will tell.
What were these genes that were listed?
One was the FGB gene – this gene codes for another glycoprotein. During an injury, this protein is cleaved and a component of it is used in the clotting mechanism. You can probably see where this is going: basically people with this disease (where both mutant copies of the gene are inherited by the individual), do no clot properly and bleed excessively. The resulting condition is called hypofibrinogenaemia (the partial absence of fibrinogen, the cleaved component used in clotting), or congenital afibrinogenaemia (the complete absence of fibrinogen).
Both the husband and wife had a 4 nucleotide deletion in an intron of this gene. What is an intron? Human genes are composed of introns and exons. Exons are the components of the gene that actually act as the blueprint to produce protein, or the tiny molecular robot of interest. So what do introns do? Primarily they are there to regulate how the gene is used, and to allow for the creation of different types of blueprints from the same gene. For example, in one case only the introns are ignored, and all of the exons of the gene are used in the blueprint. But in another case, the introns can be ignored along with certain exons. This allows for an incredible diversity of genetic information with little need for coding this information into the DNA. You can literally use DNA as a shuffling board to mix and match how the gene is utilized to produce the blueprint for the protein production. Basically all human genes are used in such a way.
But how are introns used in regulation, and how their mutations contribute to disease is still quite poorly understood, and knowledge is only just emerging with the ability to sequence human genomes so effortlessly.
That same deletion mutation has been observed in many homozygotes without any reported effects, and has a very high presence in the population, so you can see why it might not have been flagged.
The other affected gene in the couple was the PGM1 gene. It seems to be becoming a theme, but wouldn’t you know it, the protein is involved in glycosylation, but indirectly it seems. Specifically, the protein is involved in manipulating the 3D structure of sugar molecules. The fancy name for the disease is phosphoglucomutase deficiency. Patients with the condition primarily develop liver disease among other phenotypes.
In this case, despite having different mutations, both the wife’s and the husband’s mutations, once again, have been observed previously in many people (in the thousands), who were homozygotes of these mutations without any effects. In addition, both of these mutations are found, once again, in a very high frequency, in the population. Basically too high to be leading to some serious conditions (although have we not seen that before?).
So it is no surprise that these were not flagged for the doctor’s immediate attention.
Incidentally, both of these genes in both the wife and the husband were manually viewed by a clinician and deemed not reportable. Currently, in order not to overburden the healthcare system, only mutations with clinical significance and support are reported to doctors, but certainly a new influx of information based on new and previously not understood mutations is expected. Let’s hope that is not the case here of course!
When DNA carriers combine
What if these mutations were serious, and the couple had to face the possible consequences? What does a couple with a matching carrier status do?
First and foremost would be to seek out a genetic counseling session. As you can see from the examples here, just because you and your partner might be carriers for mutations in same gene, there very well might not be any risk to future Genetic counsellors, are trained experts in risk assessment, and that will likely be your best bet to learn your best options moving forward. offspring.
If you plan to have kids and are matching carriers with your partner, here are your options:
- Do nothing and take a chance with a normal birth. The chance is two-fold: first, as mentioned, you have a 25% chance that you will both pass the mutations onto your child that will result in a condition. The second chance is that even if you end up both passing the mutations onto your child, the disease might not materialize or be mild in its severity
- Choose not to have biological children. Instead consider adoption or using a sperm or egg donor for conception
- Consider in-vitro fertilization with pre-conception genetic screening. With this option, it will be your eggs and sperm used for fertilization, but after the fertilization takes place (in a lab), the fertilized egg is allowed to grow to a certain number of cells, and you can take one of these cells and sequence the DNA to check if the disease has been passed on. If not, you can use the fertilized egg for implantation back into the mother’s uterus. Cells with an inherited disease are discarded. We are talking about literally pre-screening for the presence of disease and selecting healthy future offspring. This is as futuristic as it gets, but it is currently available as an option
- Leave your partner! Just kidding. Don’t let DNA carrier status stand in your love’s way!
Perhaps these might not be happiest options available, but we now have a possibility to stop the propagation of diseases. This is not just some moral consideration. This is potentially to ease the burden of parenting a child with a seriously debilitating condition, and witnessing not only suffering along the way, but also premature death. On the other hand, caregivers of rare disease patients, proclaim a sense of emotional reward for being with their dependants.
In the end, that is a deeply personal decision, and a decision that has never previously been available to parents until now. How this will serve the future populations, only time will tell.
What else was found in our young couple’s genomes? All other mutations were variants of unknown significance, and in each individual, there can literally be thousands of these. For example, the husband carries a c.466G>A mutation in the DSG2 gene. Mutations in this gene are know to lead to arrhythmogenic right ventricular cardiomyopathy, which is a very serious condition that is asymptomatic and sudden death might be the very first symptom ever detected. However, this particular mutation has been submitted to databases only in three cases without any patient symptoms linking to the disease, and no publications exist discussing this particular mutation. At the moment, it is not understood what the implication of this mutation is.
His mutation in the XPC gene at the location c.2419G>C is not even listed in the databases. As far as we know, at this moment, it is a mutation unique to him! The XPC gene is involved in xeroderma pigmentosum, a genetic disease characterized by the reduced ability to fix DNA damage leading to severe sunburns in only just a few minutes of exposure to the sun. This condition results in an increased risk of skin cancer and other cancers as well. The location of the mutation, however, is in an area of affected protein that is not involved in disease production.
In total, the husband had 27 variants of unknown significance in medically important genes out of the 13,357 small sequence changes of unknown variants collected. In the wife, 20 variants of unknown significance in medically important genes were observed, in a total of 13,818 mutations.
This shows a glimpse into the complexity of medical genomics and the enormous effort and resources required to be able to characterise mutations to physiological outcomes, and therefore determine what should be reported to the doctor’s attention. And we only looked at the carrier status (while recognizing that there was no pathogenic status to be reported to the doctors). There is still the entire section dedicated to the pharmacogenetics of decoding individual’s entire DNA sequence which we did not cover here at all.
There is an option of doing a carrier screen only, but we are advocates of decoding an entire genome like this family did. Besides learning about carrier status, there are many further advantages of genome sequencing, the biggest one being having access to the DNA sequence itself. If you are interested in high quality clinical genome sequencing, Merogenomics is proud to work with one of the best providers in the world. If you want yourself and your doctor to gain access to quality interpretation, genome sequencing requires skilled clinical detectives to be involved. At the moment, because of the complexity of the human genome, the interpretation process cannot just be automated. If it is, your doctor might be receiving some spurious results that might send you on a chase to confirm a diagnosis, or worse, treat a disease that does not exist. When you decode your genome, you want to go with a reputable company that is servicing hospitals and clinics, not just some test available online. As you can see, full genome analysis is complicated and as personalized as it gets.
Happy Canada Day everyone!
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