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Integrating Clinical Genetics in Clinical Practice
Polygenic Variants and Future of Genetic Testing
Polygenic Variants and Future of Genetic Testing
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So, let's move away from monogenic disorder, but it's important to mention that monogenic gene phenotype does not reside in vacuum, meaning that polygenic background can have an effect on the phenotype of monogenic disorders. And there are oligogenic disorders, which are example, let's say for me, I had chylomicronemia syndrome. It's an autosomal recessive condition, but some people who carry pathogenic variant in one allele, so they are carriers and usually do not manifest phenotype. So, hypertriglycidemia is not manifested, but in certain situations with a certain background, it's possible that they can manifest in hypertriglycidemia. So, let's move to the polygenic. So, polygenic or multifactorial disorder resulting from the combination of more than one gene variant, often polymorphisms, influenced by environmental factors, lifestyles, smoking, even pollution. So, they are known as common or age-related disorders, late or at the onset. Each gene variant's contribution is very small or negligible. So, we don't even know what each gene does. I know extensive research is going on on some variants. I guess we know the function, but most of them we really are not clear on how they interact with each other either. So, no clear and discernible inheritance pattern. So, it's not like monogenic disorders. If there's a vertical transmission or some recessive, you can follow by the genotype carried by these individuals. But for the polygenic disorder, it's a little difficult, even though there may be a cluster that's carried by both individuals, but we don't really consider that clear, discernible inheritance. So, we don't really call a certain inheritance pattern. We just say familial clustering. There's like family who may have these polygenic disorders. And these are quantitative trait and continuous phenotype, and phenotype may be different in different environments. So, there is a lot of influence from external environment on the manifestation of polygenic disorders. So, genome-wide association study, first published in 2005, during my studies, it was called population genetics. I think now it's called genetic epidemiology. It's a research approach to identify gene variants, typically using SNPs, which are statistically associated with the risk of developing a particular disease or trait. So, results represent disease trait correlation, not causation. So, you can't really say these variants cause the disease, but they are associated with the disease. So, what they do is you have a co-photo individual with a certain disease, and you have a co-photo individual without disease from similar background. And you pick certain SNPs and do it in a SNP array and examine the differences between these control cases. GWAS data was really instrumental in generating and distribution of diseases within a population study, but then that's the caveat, within a population study. So, outside of this population, this may not apply, but distribution can be created like a bell-shaped curve. The highest risk people have certain combination of SNPs, and then lowest risk for the disease, these individuals may carry a different combination of SNPs. So, certain combination of variant increase the risk for certain disease. So, these SNPs are used with a bioinformatic analysis and create the polygenic risk score for individuals. And it only applies to the patient individuals with a similar background. So, GWAS is mainly conducted in European populations. So, we have a lot of information on these individuals, but for other populations, we don't have much. And these polygenic scoring systems may not apply to people from other populations. So, research right now is going on to try to study these individuals for different populations. Other factors such as the environment, lifestyle are likely to play a role. So, there are a lot of variabilities for sure. So, the important concept I just wanted to mention is polygenic risk score is describing relative risk for certain disease within the population study. So, outside the population, this may not apply. And polygenic risk score or polygenic score always indicates probabilities, susceptibilities, or never certainties. Only shows correlation, not causation. An individual's risk compared to others with a different genetic constitution within a population study. No information on baseline or timeframe of the disease progression, which is in contrast to more of the absolute risk of meningitis disorder. So, it's a likelihood of a disease development. Individual risk with carrying a disease cause a variant not relative to others in the group. You don't have to compare with other people. And there may be some historical information that we can provide on baseline and timeframe of disease progression. If a certain, you know, that information is available for a certain genotype. But we cannot do that for the polygenic risk score. So, they are totally different. And in my mind, I'm a clinical geneticist. So, I might be a little bit biased, but I feel like they're comparing apples and oranges. But some people may disagree. So, next is the last study I just wanted to briefly touch on is direct-to-consumer genetic testing, which offers prediction about health information about common traits and clues about an individual's ancestry. So, they are marketed directly to consumers. Tests can be purchased online or in stores. Convenient, very much. Individuals who are consumers send a DNA sample directly to the company. An individual receives results via a secured website or in a written report. So, there seems to be, from the consumer's point of view, it seems like there's privacy. However, I'm a little concerned about how they handle the genetic test results. So, there's no involvement of healthcare providers or health insurance company, provide only partial information about your health. Not all tests performed are clear certified. So, that's a concern. They have to be tested in order to be used clinically. And regulations have not been well-established. So, that's a big issue because there's no analytical validity can be obtained from those you know, obtained from those testing. So, potential benefit maybe there may promote awareness of genetic diseases, help individual to be more proactive about their health, which is really good. And no approval required from healthcare provider and health insurance company. So, people might like that. Not included in medical records, which may be important for some people because some people don't want things to, especially genetic information, to be included in medical record unless results are shared. Often less expensive, making testing more accessible to people with no or limited health insurance. So, you know, you really need to know what kind of tests you're ordering from these companies though. So, concerns and risks are, I believe, are plenty. Genetic cancelling is not always provided. Lack of informed consent processing or guidance. Tests may not be available for the health condition or traits of your, you know, that you're interested in. Cannot tell definitively whether you will or will not develop a particular disease. Results often need to be confirmed at a clear laboratory. Disease-causing variant can be missed only SNPs are tested. This is important for me because when people do SNP testing, they're totally missing the monogenic variants. And if the person has monogenic variants that's, you know, that has stronger phenotypic consequence, then those should be tested first. Unexpected information about your health, family relationships, or ancestry may be revealed. This is the same with any kind of genetic testing. We always warn patients about this. And some tests are unproven or invalid. Lack of scientific evidence. This is really concerning to me too. Some companies may advertise, oh, we can test for this, test for that. And, you know, maybe they advertise some tests that are not proven scientifically, but maybe popular among people. They, you know, so maybe they market it that way so that people will spend money. And privacy is another concern. That still, you know, not enough regulation for this kind of testing. So my vision for the precision medicine of future, not everybody may agree, but you'll have informed consent decision-making process during pre-test cancelling. So if the disease in question has monogenic component, those should be tested first. Then if whole exome, whole genome testings were done, then secondary finding, if that's available, that should be also considered if requested. And analysis of a polygenic risk score of the disease in question is available for that particular person that can be included. So genetic report, it may include monogenic finding plus secondary finding of polygenic risk scores. And then you may have to incorporate other risk, clinical risk factors, and then, you know, create overall risk assessment. Then what you have to do at the end is incorporate patient's preference for medical management. But it is important that in every step patients are informed about all the risks associated, benefits associated with it, so that they are making decisions for themselves, not somebody else forcing them to have one. So looking forward into the future, use of clinical genetic testing will sure to expand. And precision medicine requires better understanding of how best to integrate genomic and other factors to formulate the most appropriate management plans for an individual. And security, privacy, insurability, and handling of personal information associated with the genetic data may require further policy requirement. This is, I definitely believe that also like insurance for other, you know, life insurance and so forth. I want people with genetic disorders not discriminated in any ground. Important for all health care providers to be familiar with genetic related basic concept, so that, you know, each health care providers can like do informed consent process. Although when necessary, consult clinical genetics professionals. Genetic counselors are very helpful, but I understand there's a scarcity of genetic counselors, so that it's important for each health care providers to be familiar and be able to guide their patients accordingly. So these are some of the genetic websites that I use. Some of the genetic websites I've used frequently, but some of them are very useful for me. But there's so many more genetic websites. I cannot keep up with advance advancement since when I finished clinical genetic training. This is like explosion of genetic website research. So I thank you to the collaborator for allowing me to use a case for presentation and their astute finding of their physical feature of the patient was really instrumental in arriving at the correct diagnosis. Ankit Shah and Chouka, he was a fellow of endocrinology at the time. They were really great in identifying patients' features so that we were able to provide the patient and family with a different diagnosis.
Video Summary
The video discusses the relationship between monogenic disorders, polygenic disorders, and direct-to-consumer genetic testing. Monogenic disorders are caused by a single gene mutation, but their phenotype can be influenced by polygenic background. Oligogenic disorders, such as chylomicronemia syndrome, involve a combination of monogenic and polygenic factors. Polygenic disorders result from multiple gene variants and are influenced by environmental factors. Genome-wide association studies (GWAS) are used to identify gene variants associated with disease risk, but results only show correlation, not causation. Direct-to-consumer genetic testing offers predictions about health and ancestry, but there are concerns about privacy, accuracy, and lack of healthcare provider involvement. The future of precision medicine involves integrating monogenic and polygenic testing with clinical risk factors and patient preferences. Policy regulations are needed to address privacy and handling of genetic data. Healthcare providers should be familiar with genetic concepts and may consult genetic professionals.
Keywords
monogenic disorders
polygenic disorders
direct-to-consumer genetic testing
oligogenic disorders
genome-wide association studies
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