Actionable variant – a mutation that is either pathogenic or likely to be pathogenic, and for which intervention can be undertaken.
Allele – a gene or DNA sequence (locus) that has an alternative form (through altered sequence). Alleles can produce observed variations of a trait (phenotype). Trait differences that arise due to differences in the same gene (or locus) are referred to as allelic. Trait variations that arise from different genes or different loci are referred to as nonallelic.
Annotation – commentary that provides insight into the function of a DNA sequence (such as what gene it represents, the architecture of the gene it represents, the amino acid sequence of the protein coded for by the gene).
Autosomal dominant variant – an autosomal variant that results in specific trait development when inherited from a single parent.
Autosomal recessive variant – an autosomal variant that results in specific trait development only when inherited from both parents.
Call – assignment of a nucleotide base (A, T, G, C) to a specific position in a DNA sequence during sequencing.
Carrier – person who carries a single copy of a genetic variant known to contribute to a disorder inherited in a recessive fashion. Recessive diseases can be developed only if two copies of the mutant allele are present in the genome. Carriers do not display the disorder but can pass on the genetic variant to their offspring. An offspring who inherits a copy of the variant from each parent will develop the disorder. The chance of two carriers having a child with the disorder is 25%.
Causative variant – a variant that has been established to lead to a specific trait, including disease.
Coverage (sequencing coverage, coverage depth) – the number of independent times a DNA segment (typically a fragment of a specific genome location) is sequenced. The higher the coverage, the higher the accuracy of the nucleotides being called correctly in that DNA sequence.
Curation – manual review of available scientific information (published literature, databases, use of predictive modeling programs, or other qualified data sources) to help determine whether a specific variant could be pathogenic or benign.
Direct-to-consumer genomic services – services outside of medical or academic oversight. This means the decision making resides with the consumer, not with another individual or an institution. It also means the procedure is not bound by the regulations that bind medical or learning institutions.
DNA sequencing – method for determining the nature and order of nucleotides present in a DNA sequence.
Exome – the entire protein-coding portion of the genome.
Gene – DNA sequence that codes for protein production. Only about 1–2% of the human genome codes for expressed proteins.
Genome – the entire DNA sequence in an organism.
Genomic counseling – informative session provided by a professionally accredited genetic counselor to an individual who is considering or who has undergone genome sequencing. The session aims to educate a prospective client with regard to potential psychosocial impacts of genomic testing and the significance of informed consent for genomic testing. It explains genome based disease risk assessments, their medical and familial implications, and some ways in which these implications can be managed. Genomic counseling can differ substantially from traditional genetic counseling in that genomic counseling emphasises the entire genome, whereas genetic counseling emphasises individual genes.
Genomic medicine – medical management of an individual based on knowledge of the individual’s genome; examples include screening for disease conditions, diagnosis of disease, disease treatment choice, or counseling.
Genotyping – genome-wide probe for previously discovered single nucleotide variants.
Germline variant – a variant present in the genome from the moment of fertilization and passed on through cell division to every cell in the body.
Haplotype – a group of variants in the same section of a genome that are inherited together as a group.
Incidental findings – unexpected positive findings, however, in context of genomics it can refer to actively sought pathogenic or likely pathogenic DNA alterations beyond reasons for which the sequencing test was ordered.
Locus (plural loci) – the physical location of a gene or other identifiable DNA sequence on a chromosome.
Next generation sequencing – a new method of sequencing DNA that allows for analysis of millions of DNA fragments at the same time (high-throughput) at much lower cost and more rapid pace than the traditional sequencing method of one DNA strand at a time. Due to the ability of sequencing millions of DNA segments simultaneously, this technology is also sometimes referred to as massively parallel sequencing.
Pathogenic variant – a genetic mutation with a direct consequence to human health. A pathogenic variant can be considered “actionable” if the condition resulting from the pathogenic mutation is treatable or “nonactionable” if the condition resulting from the pathogenic mutation is untreatable.
Penetrance – the extent to which a disease will be manifested.
Personalized medicine – health care strategies tailored to treat a single individual.
Pharmacogenomics – study of correlations between variations observed in a human DNA sequence and drug efficacy or risk of adverse events related to drug use. Specific variants in an individual’s genome can point to how that individual might respond to a specific medication.
Phenotype – physiological trait; observable or measurable biological attribute.
Sex chromosome variant – a variant present on the X or Y chromosome.
SNP – single nucleotide polymorphism; observed variation of a single nucleotide among a population in a specific DNA location. SNPs can lead to variations in observed traits.
Somatic variant – a spontaneous mutation that was not inherited from parents. Such mutations can appear in the genome of any cell in the body at any time during a person’s lifespan. Some somatic mutations can affect cell cycle regulation leading to cancerous phenotype.
Structural variant – a type of variant that involves alteration of a large segment of DNA; examples are duplications, deletions, inversions, and transfer to a different genomic location.
Variant (previously mutation or polymorphism) – a DNA sequence that varies from the sequence commonly found in the population; variants can involve one (most common) or more than one nucleotide.
Whole exome sequencing – detection of the nature and precise order of nucleotides in the entire protein-coding portion of the genome (termed exome).
Whole genome sequencing – detection of the nature and precise order of nucleotides in the genome, or the entire DNA content in an organism. In humans, certain sections of the genome (for example, DNA consisting of many repeat fragments) may not be sequenced with standard methods, therefore, components of the genome might be absent in a present-day whole genome sequence.
Zygosity – an inheritance configuration typically denoted for a specific DNA site which is linked to a condition of interest but also used to describe the inheritance pattern of the condition itself.
The history of human whole genome sequencing is relatively short, emerging only in the 21st century. The Human Genome Project, a huge scientific effort to decode the entire human genome, commenced in 1990 and was completed in 2003.1, 2 This large scale endeavour has led to the development of novel technologies in DNA sequencing, termed next generation sequencing, that would eventually lead to an era of rapid, inexpensive, accurate genome sequencing and personal genome analysis of today.
The first next generation sequencing platform was marketed in 2004 and commercially introduced in 2005.3 The first whole human genome sequence, obtained in 2008 using this technology, was the genome of Dr. James Watson, one of the codiscoverers of DNA in 1953.4 Whereas The Human Genome Project took 13 years to complete and cost nearly $3 billion, the advent of next generation sequencing allowed the Watson genome to be completed in just two months at a cost of under $1 million dollars.
Today this task can be achieved in mere hours with a cost that is rapidly approaching $1000.
Since the advent of next generation sequencing technology, the impact has been felt in practically every field of biological research, from human genomics, to plants and agriculture, the study of microbes, viruses, and infectious diseases, and in every niche of the environment with the genomes of thousands of species being sequenced at an ever increasing pace.5 The influence of next generation sequencing technology on understanding biology has been so vast it can truly be described as revolutionary.
One of the greatest utilities of next generation sequencing is the ability to sequence genomes of individuals to assess personal information related to their specific health. This is often described as the concept of “personalized medicine.”
It was only in 2009 that genomic sequencing was first utilized to guide a clinical diagnosis.6 In 2011, for the first time in history, DNA sequencing technology was used to save a human life … a child's life.7
Since then, the clinical utility of next generation sequencing in guiding the diagnosis, risk assessment of disease development, and treatment delivery has been demonstrated numerous times, and the technology is being adopted in hospital laboratories around the world. Publicly-funded initiatives to sequence entire populations have commenced as a form of proactive screening to deliver benefits to the entire population.
The growing influence of genome sequencing can be appreciated through some compelling statistics. At the start of The Human Genome Project, the genomic causes of 61 diseases were known, whereas the genomic causes of more than 5000 diseases have now been identified.8 For 60% of these diseases, gene mutations that contribute to the disease phenotype have been described. Nearly 150 000 variants with potential roles in disease development have been described, although the majority of these await future clinical validation.9
- Lander ES, et al. 2001. Nature 409(6822): 860-921
- Venter JC, et al. 2001. Science 291(5507): 1304-51
- Margulies M, et al. 2005. Nature 437(7057): 376-80
- Wheeler DA, et al. 2008. Nature 452(7189): 872-6
- Choi M, et al. 2009. Proc Natl Acad Sci U S A 106(45): 19096-101
- Worthey EA, et al. 2011. Genet Med 13(3): 255-62
Your genome by the numbers
A human genome consists of two copies of 23 chromosomes consisting of 3.2 billion nucleotides for each set of chromosomes, for a total of over 6 billion bases in a human genome.
A typical human genome consists of 3–5 million single nucleotide variants. Approximately 150 000 of these variants are not expected to have been seen before.
Each person is expected to have approximately one de novo variant in his or her exome (gene coding portion of the genome) that is not found in either parent and therefore has arisen from a mutation of the DNA. About 100 de novo variants are expected in the entire human genome.1
The National Institutes of Health estimates that 1 in 10 people have a rare disease.2 Frezzo et al. (2003) reported that 20% of primary care patients have an undocumented risk for a disease.3 A current estimate of monogenic diseases (caused by a single defective gene) is approximately 1 in 100 live births. According to the World Health Organization, such monogenic diseases contribute to a heavy loss of life.4
- Richards S, et al. 2015. Genet Med 17(5): 405-24
- Frezzo TM, et al. 2003. Genet Med 5(2): 84-91
Advantages of sequencing one’s genome
The primary purpose of sequencing one’s genome is to obtain information of medical value for patient care. Nonmedical information can also be obtained, such as heritage background, nonhealth related trait information, or information with indirect medical impact, such as a predisposition to obesity. As your genome is the same throughout all the cells in your body, and is specific to each individual, accurate whole genomic sequence need be obtained only once; it is a repository of biological information that will never have to be resequenced. Genomic information is available for interpretation in perpetuity, providing an opportunity to learn new information as more scientific knowledge of the genome emerges.
Whole genome sequencing is different from genotype screening tests or sequencing of individual genes. Whole genome sequencing looks at the entire DNA whereas genotyping or sequencing a panel of desired genes looks only at chosen fragments of the genome. Such fragments are selected to obtain specific information about a physical trait, but can run a risk of missing information important for appropriate analysis. It is also biased towards predetermined choice of which segments should be analyzed.
This point can be illustrated using BRCA genes mutations, which confer high risk of breast and ovarian cancer development in women. Early discovery of these mutations provides options of prophylactic actions. However, it is known that not all such mutations will result in cancer development, and not all prophylactic actions will guarantee the prevention of future cancer developments. A term referred to as penetrance is used to describe the variable impact on disease development observed with a specific mutation. Complete penetrance indicates that the mutation will definitely result in disease development. BRCA genes mutations display incomplete penetrance. While such a singular variant can be assessed by either genotyping or genome sequencing, it is possible that with time additional variants might be discovered that could explain the variation observed with the penetrance of BRCA genes mutations. If that were to happen, previously sequenced genomic DNA could be analyzed for such additional information, whereas a genetic screening test for such new variants would have to be performed anew.
Genomic sequencing can provide information on genetic variants that can lead to disease or can increase the risk of disease development, even in asymptomatic people. Thus genomic sequencing has the potential to increase the ability to act preemptively prior to disease development or commence earlier treatment of a disease that has not yet been diagnosed.
Numerous health-screening tests exist to monitor health quality in individuals for whom an increased risk of disease has been established, such as glaucoma, macular degeneration, type 2 diabetes, heart attack, and colon, breast and prostate cancers. Genomic sequencing can be used to detect appropriate health care tests for each patient, and to leap-frog over the usual trial and error approaches for seeking a detailed diagnosis.
Another advantage of genome sequencing is obtaining information on drug efficacy or risk of adverse events related to drug use. This practice is called pharmacogenomics.
Merogenomics’ genome sequencing procedure
The first step in the process of undergoing DNA testing is to educate oneself about the test benefits and its limitations, as well as the process of sequencing and the expected role of the physician. Merogenomics’ website is one great resource to use in order to start familiarizing oneself with the genetic literacy concepts.
Merogenomics offers a free consultation to every prospective client which we recommend to take place after one reviews the Merogenomics website to ensure that focused and specific questions can be answered with regards to the DNA testing procedure and the expectations surrounding the process.
As all DNA tests promoted by Merogenomics require a physician to sign a test requisition form, a meeting with a family doctor or treating physician that will be ordering the test will be necessary.
If the client is confident that they wish to proceed with genome sequencing, the sample collection kit (either saliva or blood, depending upon the client’s preference), can be send to the client or to the ordering physician.
The test requisition form that is signed by the ordering physician will also need to be signed by the client and this will typically act as the signing of the informed consent and an agreement for testing. The client will also be responsible for sending the sample to the laboratory for testing with the free shipping provided.
The laboratory will process the sample, isolate the DNA for sequencing, check for quality to ensure the success of the procedure, and then decode the DNA using the latest technology available for human genome sequencing. Once the DNA code is available, bioinformatic computer tools are used to determine how the DNA sequence correlates to human conditions. As all of the DNA tests promoted by Merogenomics are clinical in nature, the final list of DNA alterations associated with potential medical impacts are overseen by a certified medical geneticist prior to the final report being delivered to the ordering physician.
The ordering physician (and in some instances, the ordering pharmacist if the test is a pharmacogenomic test), will receive the Analysis Report that will contain the medically relevant results, as well as web portal access for an electronic review of the DNA code and its interpretation. The client does not obtain direct access to these products, and has to await a post-test visit with the ordering physician to learn about the details of the Analysis Results. Access to the electronic DNA code is reserved for clinicians only.
The DNA sequence data is permanently stored by the service provider of the test. However, the client will have an opportunity to obtain their own digital copy of the sequence, either as a complimentary part of the service or for a fee, depending on the provider of the type of file requested. Merogenomics encourages all clients to consider obtaining backup data for additional security.
The client can use the obtained DNA sequence data for future reanalysis, especially if the test is a full genome sequence which captures the entirety of one’s personal DNA information, allowing for any future analysis to be tied to DNA interpretation based on the latest understanding of the human genome.
How many people have sequenced their genomes thus far?
Illumina, the world’s biggest maker of DNA sequencing machines, has estimated that by the end of 2017 more than 1.5 million full human genomes would be sequenced, and that number is expected to rise to many tens of millions by the end of the 2020s.
Perceived disease risk as a motivation for genomic sequencing
Individual disease risk perceptions are complex and multifactorial. People find it difficult to accurately quantify disease risk, or to understand if the risk is presented in a numerical format. Data suggests risk perception is not formed in a rational way, rather, it is influenced by past experience (especially family history of disease, and how affected relatives experienced the illness) and personal emotional mechanisms used to cope with the perceived risk. Environmental factors such as occupation, diet, and physical resemblance to an affected relative can also affect an individual’s perception of disease risk. Studies have demonstrated that people tend to overestimate risk, especially if a family history of disease is present. However, a perception of high risk can adversely affect psychological well-being.
Conversely, individuals with a high level of anxiety can inappropriately reduce the significance of their risk of disease development as a means of coping. This behaviour has been observed in some women at risk for breast cancer development.
Evidence exists that genetic counseling can lead to a more accurate perception of risk, although not all data support this. Importantly, reduced perceived risk has been shown to be associated with improved psychological well-being, highlighting the importance of genetic counseling.
As individuals use their understanding of inheritance and disease to interpret disease risk and its management, it is important that the knowledge that suggests there is a disease risk is accurate. That is where genomic sequencing can be of value. There is evidence that risk perception is an important influencing factor in the uptake of health seeking behaviours and preventative surgery.
How does the genome inform about disease risk?
Decoding of the human genome allows genetic mutations (variants) observed in the DNA sequence to be correlated with risks of disease development. Diseases that result from a single DNA variant are known as Mendelian and are also referred to as rare, simple, or monogenic diseases because they result from the mutation of a single gene. In such diseases, inheritance of the genetic variant (mutation) conveys a very high chance of disease development. Examples of Mendelian diseases are Huntington disease, cystic fibrosis, and sickle-cell anaemia. Multigenic, or non-Mendelian (also called common or “complex”) diseases result from many different DNA variants. Examples of complex diseases are diabetes, cardiovascular disease, many cancers, autism, and Alzheimer disease. Multigenic factors can predispose an individual to disease development in varying degrees. Typically, variants that contribute to complex diseases individually impart a very low increase in relative disease risk. Genome sequencing can provide definitive information about inheritance of Mendelian diseases, however, determining the risk of complex diseases is not straightforward because so many factors influence the final outcome (sometimes hundreds or even thousands different variants are involved), including environmental influence. Studies indicate that even microbiota (the bacterial composition inhabiting our bodies) makeup can influence the development of complex diseases.
Therefore variants that contribute to common complex diseases have insubstantial predictive power, and current models that attempt to combine multiple variants into a cumulative risk score are no better at predicting disease than traditional risk factors such as family history or clinical phenotypes. Even if they exhibit a high level of heritability in the population, at best they predict up to 10% of the observed phenotypic disease variations.
The occurrence of non-Mendelian disease can be illustrated by disease concordance in twins. Dizygotic (fraternal) twins share the same parents but arise from two separately fertilized eggs. Dizygotic twins therefore have different genomes, and if one twin develops a complex disease such as Parkinson or Alzheimer, there is a ~ 5% chance that the other twin will develop the same disease. The odds of a random person developing the same non-Mendelian disease are even smaller in the general population. Monozygotic twins on other hand develop from a single fertilized ovum and therefore have identical genomes, but still the odds of both twins developing same disease are only around 10–30%. Therefore, genomic sequencing to estimate the risk of development of complex diseases might not be informative.
Because genomic causes of many diseases are still in the process of discovery, the U.S. Centers for Disease Control and Prevention recommends against the use of next generation sequencing for risk prediction of common diseases that lack well established clinically validated supporting evidence. Use of such technology can still be endorsed for population research. The discovery of novel variants that lead to Mendelian or complex diseases among the population is important because it provides awareness of their impact on public health while providing clues to potential intervention.
How is client sequence analyzed?
When a client orders a DNA test two processes take place:
- The client’s DNA sequence is decoded so that the order of the DNA sequence is uncovered
- The client’s DNA sequence is analyzed for any known correlations to human diseases
In a clinical setting the analysis of the genome sequence is done in two stages:
- Computational analysis of the medical databases of DNA alterations linked to human diseases in comparisons to the subject's own DNA sequence data. This process selects multiple candidates for reporting
- Manual oversight of the preliminary list of suspected pathogenic DNA variants by a certified medical geneticist to generate the final manually curated report to be delivered to the ordering physician
In a clinical setting, analysis of the complex results of genome sequencing is performed by a team of qualified people that include bioinformaticians and clinical geneticist with skills in bioinformatic methodologies, pedigree analysis and interpretation, and familiarity with a broad range of inherited disorders. These experts interpret the genome sequencing results and suggest appropriate medical decisions.
What is the current genomic knowledge that is of medical value?
While genomic sequencing technology is still a relatively new invention, it has had such a profound impact on the study of human conditions that databases of pathogenic mutations linked to human diseases have been developed, with a continuing contribution from a global network of laboratories. The scientific community is continuously discovering novel mutations that lead to disease (causative variants), as the pace of sequenced human genomes increases, resulting in more published data.
In addition, the American College of Medical Genetics and Genomics (ACMG) published clinical guidelines for informing patients of mutations that lead to a disease state in 59 genes for either children or adults. However, based on combined international efforts, currently the list of reportable gene-associated disorders involved over five thousand genes, with more than 150 of which could be considered actionable.
How is genomic sequencing different from traditional medical genetics?
The focus of traditional clinical genetics has been two-fold. One purpose is to screen asymptomatic individuals for potential disease detection for which intervention is available. Such programs have been available for over 30 years, and include prenatal screening for chromosomal abnormalities, or newborn screening for genetic disorders at preselected genes known to be involved in disease development.
The second purpose is the identification of rare genetic disorders not typically screened for at birth. In such cases genetics tests are done on individuals suspected of bearing certain diseases based on clinical symptoms, prior family history, or belonging to a particular ethnic group known to exhibit increased risk for a particular disease. Typically such tests are done as needed per single gene or a panel of genes of interest.
Genomic sequencing can perform these functions in a single test because nearly the entirety of the DNA sequence is decoded, including all of the genes (which only comprise ~2% of the human genome) plus all of the noncoding areas of the DNA. This has the added advantage that complete DNA information is obtained about an individual instead of just a fraction. The results of this procedure are not limited by the chance that incorrect segments of the human genomes were chosen for analysis.
Thus, once a personal genome has been decoded, no additional DNA decoding will be necessary to test for any inheritable conditions. This also means that as new information is discovered in the future, such developing knowledge can always be retroactively analyzed against one’s genome.
How is genomic sequencing already used in medicine?
The use of genomic sequencing to guide medical decisions is rapidly being adopted in clinics and hospitals around the world. Medical applications of genomics include disease diagnosis and classification, identification of genetic susceptibility to disease, improvement in treatment design, and improvement in clinical trials design towards future therapies. Widespread clinical use of genomic medicine is hindered by the cost of technology, the translation of research findings into practice, and a lack of adequate education among healthcare providers.
The most widespread adoption of DNA sequencing in the healthcare system has been observed in genomic testing for cancer. Genome sequencing has also become a standard tool in the diagnoses of rare diseases that otherwise have eluded physicians who use traditional approaches (including genetic testing). For this reason, an Undiagnosed Diseases Network of clinical and research centers across the United States was established in 2014 by the National Institutes of Health to leverage the power of genome sequencing in diagnosis of rare and new diseases. In 2018, clinical researchers at the Toronto Hospital for Sick Children proposed that full genome sequencing replace the traditional step-wise approach of genetic testing as the first-tier genetic test based on its superior performance and faster diagnosis.1 An emerging use of this technology also includes infectious disease diagnostics.
The advantages cited for the benefit of patients are:
- Identification of druggable targets
- The reduction of redundant testing by eliminating the single gene test approach
- Earlier diagnosis
- Lionel AC, et al. 2018. Genet Med 20(4):435-443
What type of variants/alterations are discovered by genome sequencing?
Whole genome sequence data identifies single nucleotide variants (alterations that affect only one nucleotide at a time) or alterations that include multiple nucleotides. Multiple nucleotide alterations include insertions and deletions (which can vary in size), copy number variants (a frequency of repetition of a particular DNA segment), and certain translocations (rearrangement of genes or entire chromosome segments). Any such alterations could be linked to specific traits or diseases. Alterations of the genome that involve large number of nucleotides are referred to as structural variants.
What does it mean if variants are found in my genome?
Every single human being carries millions of variants—alterations in her or his DNA compared to the DNA of other individuals. Every person is expected to have some new variants that were not inherited from a parent but that occurred by simple mutation. Therefore the number of variants in a human genome is not a concern. The purpose of genome sequencing is to discover variants that could impact the subject’s health or performance. If such variants are discovered, the client will need to consider the following:
- Impact on personal health
The client should verify the variant information with an additional test, and seek the counsel of a medical genetics professional to find out what options are available.
- Passing of variants to offspring
Each variant has a 50% chance of being passed on to a carrier’s offspring. Depending on the biological impact of a variant, considerations with regards to reproductive decisions might be of importance.
- Relatives might be at risk for genetic conditions discovered in the subject of genome sequencing
As the vast majority of variants are inherited (as opposed to arising spontaneously), the presence of debilitating variants in an individual suggests that they could also be present in closely related family members.
What does it mean to be a carrier?
A carrier has a variant (mutation) in her or his genome that has the potential to cause a disorder. If the variant is autosomal recessive and the carrier has only one copy, the carrier will not display the disorder. Such variants can lead to disease development if two copies of the variant, one copy from each parent, are present in the genome. A variant has a 50% chance of being passed on to a carrier’s offspring, therefore the chance of two carriers having a child with the disorder is 25%. The chance that two random adults will be carriers of the same autosomal recessive variant is 0.5–1%.
However, not all patterns of inheritance are so straightforward. Some disease conditions arise due to a change in the number of copies of a gene. The copy number of a gene can be altered when a gamete (sperm or egg cell) is produced. A person who has a number of gene copies associated with increased risk of disease is considered to be a carrier of such risk. Huntington disease is a result of a repetitive DNA sequence that is not as frequent in healthy individuals or carriers.
The discovery that an individual can be the carrier of a debilitating genetic condition will influence reproductive decisions due to the increased risk of disease development in an offspring. Such discovery can have profound emotional implications for an individual, such as feelings of guilt and anxiety of potentially affecting the offspring.
How do genomics provide clues to medical advancement?
Discovering how genetics contribute to a particular disease state can point out which biological process is affected. It can also provide completely new knowledge or understanding of how the biological process actually occurs. Such information can be pooled to find out how a biological process can be medically manipulated.
What are pharmacogenomics and personalized medicine?
Pharmacogenomics is a study of the correlation between the variations observed in the human DNA sequence and either adverse drug reactions, or drug efficacy. Such a correlation indicates how an individual with a given mutation might respond to a specific medication. This field of science is evolving rapidly with the advent of next generation sequencing technologies. The biggest hope of the pharmacogenomics field is fulfilment of the concept of personalized medicine. That is, an ideal choice of drug for an individual patient can be determined based on the patient’s genome information. Furthermore, a drug dose can be chosen to match the individual metabolism phenotype, while avoiding adverse effects associated with lack of efficacy or toxicity.
This concept can be well exemplified with drugs approved for use in cancer treatment. On average, the use of drugs does not extend patient survival by more than a few months. The poor success statistics reflect the fact that such drugs are effective only in select subtypes of cancer in a small subset of a population. Next generation sequencing can now be used to identify patients who might benefit from cancer drugs. This is a major positive medical impact of genome sequencing.
In another example, one or more variants are implicated in the patient response to five common prescription drugs in more than 90% of all patients.
How is personalized medicine currently applied in pharmacogenomics?
Since the first draft of a human genome sequence was published, many discoveries have been made correlating variation in genomic sequence and drug response. Stanford University manages a public database of variants that influence drug response (PharmGKB).1 As of 2019, 593 entries have been collected from different international medical agencies (U.S., Canada, Europe, and Japan), including 264 drugs with pharmacogenomics labeling for safety or efficacy listed by the U.S. Food and Drug Administration.2 Many medical centers have commenced using personal genomic information to guide prescription choices in a clinical setting, expecting to reduce treatment costs by enhanced monitoring against the lack of efficacy and toxicity. A survey of over 10 000 physicians in the United States showed that 98% expected patient genetic profiles to influence drug therapy.
Is genome sequencing for everyone? Are there gender or ethnicity differences?
Currently, anyone can benefit from having his or her genome sequenced and analyzed in comparison to the available scientific data; no scientific data demonstrate benefits of such knowledge to one gender over another.
However, many studies have demonstrated that associations between variants and disease can be also specific to specific ethnic populations. As European-decent groups have been studied the most, the available understanding of pathogenic mutations is of highest benefit to this racial group. However, data continue to accumulate at a rapid pace for all major ethnic groups on the planet.
The most important criterion to consider in genome sequencing is the potential emotional impact the discovery of upsetting information could have on the client and people close to the client. The medical benefits of genome sequencing might not be valuable if the resulting emotional cost could have a negative impact on a person’s life. People who have experienced prior episodes of emotional instability, or who chronically experience anxiety should carefully consider the emotional risk of genomic sequencing.
Should children have their genomes sequenced?
DNA testing for diagnostic purposes delivered for a child with symptoms of a suspected genetic condition is considered equivalent to any other medical diagnostic evaluations.
Genetic screening of newborns or children that are asymptomatic and presumed healthy, however, is typically discouraged, as DNA is reserved for when a medical benefit could be provided as a result of the test outcome. In some instances this might be of importance in families with a history of a condition. In such situations, the predictive testing is expected to be for childhood-onset conditions with acceptable intervention available for the identified affected child.
Currently, guidelines typically do not endorse DNA testing in children for screening purposes. This position statement might eventually be challenged based on the findings that the first clinical testing of full genome sequencing in presumed healthy newborns with no family history revealed that nearly 10% of those tested had DNA alterations associated with an increased chance of childhood-onset disease.1
In situations when the parents insist on genome sequencing their child without any medical indication for testing, the benefits of DNA testing for the child should be weighed against the potential harms.2
Medical benefits include:
- Therapeutic interventions (for diagnosed conditions)
- Targeted surveillance (for predisposition to condition development)
- Improved prognosis
- Clarification of diagnosis (for what conditions are identified versus which are not)
- Identification of other family members for testing
Medical harms include:
- Increased frequency of false-positives (with an increasing number of tested conditions)
- Misdiagnosis (genotype does not correlate with the symptoms presented)
- Ambiguous results (the outcome cannot be predicted)
- Use of ineffective or harmful preventive or therapeutic interventions
Psychosocial benefits include:
- The reduction of uncertainty and anxiety
- Psychological adjustments
- The ability to make realistic life plans
- Sharing the information with family members
Psychosocial harms include:
- The alteration of image by self and others
- Distortion of parental perceptions about the child
- Increased anxiety and guilt
- Stress related to the identification of other at-risk family members
- The detection of misattributed parentage
There is a considerable ethical debate in the scientific community about the need to and right to inform minors of genetic indications that could impact their future health (conditions that are adult onset) as obtained from genomic sequencing. The stance taken by the American College of Medical Genetics and Genomics (ACMG) is that no age limitation should be set on the return of incidental findings that suggest a future health risk, as such results are likely to have important implications for other family members. The example the ACMG cites is that the discovery of increased risk of adult-onset cancer predisposition may be medically important to one of the parents of the child from whom the offspring inherited the mutation. In such a scenario, the ACMG reasons, withholding the result based on the child’s right to not know is superseded by the parent’s opportunity to discover a potential life-threatening risk factor. However the ACMG acknowledges that, due to the novelty of human genome sequencing, there is a lack of available data “about the actual harms of learning about adult-onset conditions in children,” and such psychological impacts need to be taken into consideration when considering the use of such services.3
Others argue that disease might never materialize, therefore a child should have a right not to be given information that could negatively impact his or her quality of life. The Canadian College of Medical Geneticists’ guidelines state that adult-onset genetic conditions should not be communicated unless disclosure could prevent serious harm to the health of other family members, and unless such disclosure is desired by the parents. It is suggested that based on the child’s age and maturity, the child’s opinion in the matter should be considered.4
Thorough genetic counseling is essential before DNA testing to ensure all of the necessary steps have been taken to safeguard the well-being of the child.
- Ceyhan-Birsoy O, et al. 2019. Am J Hum Genet 104(1):76-93
- Ross LF, et al. 2013. Genet Med 15(3):234-45
- Green RC, et al. 2013. Genet Med 15(7): 565-74
- Zawati MH, et al. 2014. J Med Genet 51(1): 68-70
Prenatal screening considerations
Pregnancy outcomes vary according to multiple factors, including parental age, ethnicity and medical and family history. Most forms of prenatal diagnosis require invasive procedures for fetal-sample collection and, while safe for the parent, involve 0.11–0.22% risk of fetal loss, for amniocentesis and chorionic villi sampling, respectively.1
During pregnancy, fetus DNA is released into maternal blood circulation, and increases as the gestation period progresses. Fetus DNA is detectable as early as day 18 and is used in clinical practice as early as week 7. Testing is typically available from 10 weeks of gestation. Because only maternal blood is required for fetal DNA inspection, noninvasive prenatal testing is a safe and effective alternative for screening purposes. Sequencing of fetus DNA from maternal blood has been adopted by a number of countries for high-risk populations to determine sex and rhesus D antigen status and to assess aneuploidy (abnormal number of chromosomes). Access to such knowledge allows expectant parents to be informed about possible fetal outcomes, and available treatment or management options if a disease condition is uncovered. Based on the nature of uncovered conditions, parents can be advised whether there is a risk of recurrence of such conditions in future pregnancies, and be better informed about available reproductive decisions.
The American College of Obstetricians and Gynecologists, the Society for Maternal Fetal Medicine, the International Society for Prenatal Diagnosis, the National Society of Genetic Counselors, and the Society of Obstetricians and Gynecologists of Canada now all recommend that aneuploidy testing in a clinical practice is the most effective population screening method for common trisomies (21, 18 and 13). In 2013, the Newborn Sequencing In Genomic Medicine And Public Health (NSIGHT) program was set up in United States to explore sequencing of newborn genomes as a potential alternative to current newborn screening for medical information.2
- Akolekar R, et al. 2015. Ultrasound Obstet Gynecol 45(1):16–26
Limitations of genome sequencing
How accurately and reliably genome sequencing measures gene variants is termed “analytical validity.” Analytic validity depends on how many times a nucleotide base is read by the sequencing platform during the sequencing process. The more times a particular base is read, the higher the accuracy that it was measured (also termed “called”) correctly at that particular position. This is also referred to as “read depth” or “coverage depth.” A certain minimum coverage depth is required as the acceptable threshold to be confident that the nucleotide base was called correctly. Because the DNA is not read at uniform coverage across the genome, it is possible that segments of the genome could be read below the minimum coverage depth. If the depth coverage is not sufficient, it is possible that a base will be identified that is not actually present in a person’s genome.
While technologies used to sequence DNA are highly accurate at deciphering the sequence, the majority of available technologies have limited scope in being able to determine so called structural variants. These are alterations that affect large segments of DNA at a time, such as duplications, deletions, and inversions. Such structural variants can still have important impact on health, but due to the limited scope in determining such structural genomic rearrangements by current sequencing technologies, such biological events might not be fully interpretable for the benefit of a client.
Although genome sequencing has the potential to reduce morbidity and mortality by enabling early identification of risk factors for various health conditions, and to aid identification of an appropriate treatment course, it is not an all-encompassing screen for every possible disease. The interpretation of sequencing results is limited by the current state of medical knowledge, and can range from almost certain clinical significance to almost certainly no significance. Even if the interpretation of genome sequencing results is straightforward, such information might not lead to a useful ameliorative intervention for a specific condition or disease. However, since the human genome we are born with is static (it does not change unless influenced by environmental factors, for example, in the development of many cancers), it means that obtained sequence can always be reinterpreted in the future as the scientific potential expands.
A related issue is that the amount of data that need to be analyzed and curated prior to a genome sequence being delivered to a client requires considerable computer and human resources. The bioinformatics capabilities of genome sequence analysis are continuously improving by incorporating new information, and the process is increasingly automated. As the demand for clinical interpretation of the genome increases, so does the demand for appropriate platforms to deliver a higher performance standard.
Another often cited limitation is the lack of clinical validity and utility for systematic mass scale use of genomic sequencing technology for public’s benefit, and is only being currently investigated at clinical research institutions around the world. Simply put, currently there is no gold standard against which the performance of population genomic screening can be judged. Whether application of next generation sequencing will reduce mortality and morbidity in the population the way it has been demonstrated in individual studies is yet to be established. Development of metrics that measure the health-care outcomes of genomic sequencing to validate the clinical utility of genomic medicine toward effective patient care currently remains a top challenge and a priority.
What are incidental findings?
Incidental findings are mutations that are either pathogenic or likely to be pathogenic that are discovered unintentionally. Incidental finding could include information for conditions that can be treated, and conditions that are incurable. The potential psychological impact of incidental findings should be one of the primary topics to consider before genome sequencing procedure. Genome sequencing could reveal a mutation indicative of incurable disease, and it is a difficult decision about personal readiness to receive such information. The stance on the requirement of genome sequencing incidental finding disclosure is divided. Current position of the American College of Medical Genetics states that where the “intervention may be possible, we felt that clinicians and laboratory personnel have a fiduciary duty to prevent harm by warning patients and their families about certain incidental findings and that this principle supersedes concerns about autonomy, just as it does in the reporting of incidental findings elsewhere in medical practice.”1 However, the reporting of incidental findings is not mandatory.
- Green RC, et al. 2013. Genet Med 15(7): 565-74
What are the chances that genome sequencing results will provide important incidental findings?
Scientific data continue to emerge detailing information about the frequency of actionable incidental findings. “Actionable” incidental findings are mutations that are either pathogenic or likely to be pathogenic where intervention can be undertaken. An analysis of exomes (areas of the human genome that code for proteins) of 1000 participants (500 of European ancestry and 500 of African ancestry) showed a likelihood of 3.4% frequency of actionable incidental findings in European Caucasians and 1.2% frequency of actionable incidental findings in Africans.1 However, authors added that for the individuals of African ancestry, this figure most likely reflects an underrepresentation of African participants in studies searching for disease variants, and is likely to be different. As individuals of African descent have more variants that lead to amino acid alteration than other populations, it is logical that individuals of African descent could expect at least similar levels of incidental findings as observed in other populations.2
In an analysis of exomes in 11068 individuals, 5–6 % of individuals in each ethnic group were carriers for at least one previously reported pathogenic variant.3 In another analysis of 1092 individuals who had their genomes sequenced, a 1% rate of incidental findings was observed.4 While the second study included far fewer participants than the first study, the sequence results in the second study were manually curated using more stringent criteria for defining a pathogenic variant than the sequence results in the first study, resulting in a lower percentage of pathogenic variants in the second study. Therefore based on accumulating evidence, 1–5% of individuals that undergo genome sequencing can expect to discover variants of a pathogenic nature.
These early finding continue to be supported by newly published data.
- Dorschner MO, et al. 2013. Am J Hum Genet 93(4): 631-40
- Abecasis GR, et al. 2012. Nature 491(7422): 56-65
- Gambin T, et al. 2015. Genome Med 7(1): 54
- Olfson E, et al. 2015. PLoS One 10(9): e0135193
What is the reported literature on the emotional impact of incidental findings?
There is little published information about the potential negative emotional impact of reporting mutations that are either pathogenic or likely to be pathogenic, but the emerging scientific data suggest that such emotional distress is not widespread.
The BRCA mutation test is a model for high-risk actionable genetic tests of proven clinical utility. One study showed that participants who tested positive displayed a neutral reaction rather than a high anxiety response. The test actually provided clear benefits to participants, as it had a cascading effect and additional mutation carriers were identified in other family members.1 A meta-analysis of 20 published studies of BRCA mutation testing on anxiety showed that carriers’ emotional distress increased slightly after receiving the test results, but returned to pretesting levels with time.2 Gender, race, ethnicity, and socioeconomic status have been shown to influence to varying degrees the course of emotional distress upon learning that mutations that are either pathogenic or likely to be pathogenic have been identified.2 Aside from the burden associated with informing their at-risk relatives, in males the predominant reason for emotional angst was shown to be the risk of passing on a BRCA mutation to their daughters.1
A similar experience of guilt was reported in carrier individuals who did not develop Huntington disease but could put their children at risk.3 This is an important consideration for those seeking carrier status information.
The genetic testing of people with a parent with Alzheimer disease is typically discouraged in asymptomatic persons due to its emotional impact, as no preventive measures are available for this disease. One study found that no significant short term psychological differences were observed between testees who received the test results indicating if they inherited pathogenic mutation linked to Alzheimer disease, and testees who did not obtain the results.4 The authors summarized: “subjects were not immune to the negative implications of learning that they had an increased risk [of developing disease], but these feelings were not associated with clinically significant psychological distress.”
In a first assessment of direct-to-consumer genotyping testing, which assesses for multiple variants at a time, the researchers “found no evidence that learning the results of genomic risk testing had any short-term psychological, behavioral, or clinical effects on the study subjects. The subjects in our study are probably representative of the current population of persons who purchase these tests.”5
Participants in such studies nearly always receive the benefit of genetic counseling prior to obtaining results.
Overall, findings indicate that while unexpected results could potentially lead to emotional distress, it appears that such impact is minimal and short-lived. Long-term emotional consequences of potentially threatening genomic sequencing incidental findings await the results of formal studies. It is also not known whether the disclosure of mutations that confer a possible risk of illness provides any medical benefits.
However, testing for conditions without known cures can involve significant psychological and social challenges. For example, only 5–25 % of individuals at-risk of Huntington disease development chose to take a confirmatory genetic test.6, 7 Therefore, a client must carefully consider whether the receipt of unactionable pathological information is warranted.
- Francke U, et al. 2013. PeerJ 1: e8
- Hamilton JG, et al. 2009. Health Psychol 28(4): 510-8
- Maat-Kievit A, et al. 2001. J Med Genet 38(4): E12
- Green RC, et al. 2009. N Engl J Med 361(3): 245-54
- Bloss CS, et al. 2011. N Engl J Med 364(6): 524-34
- Creighton S, et al. 2003. Clin Genet 63(6): 462-75
- Laccone F, et al. 1999. Neurology 53(4): 801-6
Additional psychosocial impacts to consider
The inheritance pattern of a disease can be complex and may not conform to the expectations of an individual. For example, some neurodegenerative conditions (such as Huntington disease) develop as a result of expansion of a repetitive segment of DNA, and clear-cut results cannot always be obtained about disease development risk, depending on the number of DNA repeats. Especially for a condition that is believed to be inherited in a dominant fashion, an indecisive result might lead to feelings of distress, confusion, and guilt in an individual who was seeking certainty.1
Others may experience cognitive dissonance, a psychological discomfort caused by a clash between a prior set of beliefs and new contradictory knowledge. An individual who cannot come to terms with threatening or inconclusive results can resort to subconscious dismissal of such results in order to cope with psychological stress.1
In individuals tested for cancer carrier status, those who decided not to receive the information were observed to undergo worsening psychological health.2 These findings might be generalized to other individuals who are tested for a particular condition but who refuse to receive any negative information—that is, such individuals might have an increased risk of adverse psychological health.
Subtle but important impacts related to self-image can perturb some individuals. One study showed that while a majority (nearly 70%) did not perceive any life changes as a result of genomic risk testing, the most frequently cited life changes were “the way I think of myself” (15%), “body image” (8%), and “other” (increased exercise, sense of reassurance about health, sense of empowerment, and concern about planning for end of life, 9%). The study did not assess if the self-image impacts were positive or not.3
- Semaka A, et al. 2013. J Genet Couns 22(2): 200-17
- Sivell S, et al. 2008. J Genet Couns 17(1): 30-63
- Bloss CS, et al. 2011. N Engl J Med 364(6): 524-34
What behavioural changes are observed from genomic disclosure?
A meta-analysis of published scientific literature on the topic of DNA testing influencing behaviour changes showed no significant impact on smoking cessation, diet, physical activity, alcohol use, medication use, sun protection behaviours, screening for conditions, attendance at behavioural support programmes, or on motivation to change behaviour. The study also indicated no adverse effects upon the receipt of DNA testing results, such as depression and anxiety. However, the author did note that the published evidence was of typically low quality.1
The disclosure of genomic information can impact the behaviour of the recipient and other parties affected by the news. Individual risk perception of disease development has been shown to influence behavioural changes that can benefit health.
In a publication on behavioural changes following direct-to-consumer personal genomic testing, 30% of the participants reported making a change to their diet that was specifically motivated by the DNA testing results, while 26% reported changing their exercise habits.2
One seminal study on behavioural change motivation showed that risk estimates of common complex diseases (such as heart disease), which have low predictive value, had limited impact on participants’ dietary fat intake or exercise behaviour.3 However, the authors reported a correlation between positive changes in diet and physical activity and the sharing of results with a physician, suggesting that test results in combination with direction provided by a physician could provide an impetus to improve the quality of life.
After disclosure of genomic information, half of the participants in the study reported their intention to utilize available screening tests to gauge health quality. If such intentions resulted in appropriate monitoring actions, an appropriate health care test could be applied to each individual prior to the development of disease, instead of the trial and error approach of seeking detailed diagnosis once a patient is hospitalized.3
Thus, across the entire population behavioural change might be difficult to be measured to a point of significant change, but pockets of proactive individuals might be found that will decide to use their DNA test results to positively alter their lifestyle.
- Hollands GJ, et al. 2016. BMJ 352:i1102
- Nielsen DE, et al. 2017. BMC Med Genomics 10(1): 24
- Bloss CS, et al. 2011. N Engl J Med 364(6): 524-34
What are the concerns about direct-to-consumer genomic sequencing?
Direct-to-consumer genetic health information first became available in 2007 by three companies: 23andMe, DeCodeMe, and Navigenics.1 While their services were dependent on discoveries made through the sequencing of the human genome, their services did not rely on sequencing of the DNA but on genome-wide genotyping of single nucleotide variants. This technology relies on probing the DNA for approximately 500,000 variants (alterations of DNA code) of interest to consumers. This service does not provide complete DNA sequence to customers, and therefore limits the interpretation to variants that are specifically probed for. This could also mean that if negative result is obtained for a specific condition, the perceived risk for the tested condition is not eliminated but only reduced, as other potential unexamined DNA variations could be present in the sequence. Another limitation is that lack of a complete sequence does not allow for future knowledge updates of DNA sequence beyond the probed variants. For example, in one estimate, 30% of diagnoses based on exome sequencing in 2013 were based on information discovered only since 2011.2 Therefore, individuals genotyped for diagnostic purposes prior to 2011 would have missed the opportunity to discover such information, and would have to be retested. With whole genome sequencing, the sequence can always be rechecked for novel information.
Implementation of direct-to-consumer genetic health information has raised significant debate about the applicability of such technology. “Concerns expressed in a large body of literature and position statements issued by professional societies postulate that high-impact genetic information should not be disseminated [direct-to-consumer] because consumers will not be able to understand the meaning, or will misunderstand it; positive test results could cause panic and inappropriate actions, possibly putting undue burden on the health care system; and negative test results could cause false reassurance and inappropriate actions such as foregoing recommended cancer screening.”1
The biggest criticism leveraged against direct-to-consumer genomic services is testing for susceptibility to common diseases such as heart disease or diabetes. These diseases are polygenic in nature, sometimes comprising hundreds and even thousands of DNA variants whose interplay toward disease development is not understood. The vast majority of these variants have been discovered by genotyping individuals with specific conditions in the hope of uncovering novel potential associations between DNA variants and the disease. Such discovered variants can explain about 10% of the genetic component of the disease at best, even if the impact of all associated variants is combined.3 This is believed to be due to the genotyping limitations listed above for some of the direct-to-consumer services; that is, it is difficult to find all possible contributing variants (single nucleotide or structural variants). As these variants currently have either no clinical validity or unclear validity, testing for them is not typically offered in a clinical setting.
Because the statistical models used to estimate the risk of complex diseases incorporate many assumptions, their accuracy is in question. Comparison of genomewide test results for the same conditions in the same person by different companies revealed inconsistent and at times contradictory risk estimates. Thus claims that personal risk information can be provided for common complex diseases are not supported by current science.
Merogenomics acknowledges that these concerns apply to its direct-to-consumer genomic sequencing service. Whole genome sequencing has an advantage over genotyping in that the entirety of causative variants are captured in information collected during whole genome sequencing, even if their appropriate contribution to complex disease development cannot be deciphered at the moment. Although current trends appear to support the medical value of genome sequencing in the general public, many of the benefits and concerns await substantiation through scientific analysis.
- Francke U, et al. 2013. PeerJ 1: e8
- Yang Y, et al. 2013. N Engl J Med 369(16): 1502-11
- Richards S, et al. 2015. Genet Med 17(5): 405-24
Action taken after genome sequencing results
After receiving genome sequence information, the client should always share the results with a doctor prior to making any medical decisions or action. A doctor who is familiar with the client’s health history will ideally be in a position to integrate the genome sequence information with his or her personal medical history, the family medical history, and evaluate whether further examination is required to obtain supporting evidence of pathogenic mutations. Appropriate surveillance of or intervention with conditions revealed through genome sequencing should be considered only by a medical professional.
It should be noted that all DNA tests promoted by Merogenomics require the participation of an ordering physician to sign the test requisition form in order to initiate the testing process. The results of these tests will never be provided directly to the consumer, but rather to the ordering physician for a medical interpretation.
Other important considerations include a discussion with family members about the potential disclosure of the results and the potential testing of additional family members, as well as a discussion around the future ownership of and access to one’s personal genome sequence data.
Insurance for genome sequencing: availability and discrimination
Two issues associated with genome sequencing involve health insurance:
- Is insurance coverage available for genome sequencing?
- Will the availability of health or life insurance be compromised if pathogenic mutations are revealed in the genome sequence?
Fear of insurance discrimination based on pathological mutations in a genome sequence has received the most attention and some jurisdictions have enacted legislation in an attempt to address such public concerns. In the United States, the Genetic Information Nondiscrimination Act was introduced in 2008 to ensure that health insurers cannot deny coverage or charge higher premiums based solely on individuals’ genetic test results, although the Act does not deal with life insurance. A number of European countries prohibit the use of genetic tests by life insurers, while others have implemented a moratorium on the use of genetic tests as a means of temporary regulation. In Australia, the Disability Discrimination Act of 1992 prohibits health insurance discrimination on the basis of genetic status, but life insurers are permitted to use genetic information to assess an applicant.1
Canada has one of the most comprehensive anti-genetic discrimination laws in the world. Passed in 2017 as Bill S-201, the law bars any person or organization from utilizing DNA test results data in order to exclude someone from obtaining goods or services. This indicates that Canadians are protected from genetic data disclosure for any type of insurance purposes.
Data suggest that discriminatory insurance practices related to genetic testing are uncommon, and often there is no clear evidence that insurance coverage rejection was due to the results of genetic testing or due to access to prior family history.2 Nevertheless, rare documented cases of carriers experiencing unfair insurance problems persist and raise public concern of future negative treatment.1
Clients are empowered to challenge insurance company coverage rejection if they think it is based on genetic discrimination. Insurers bear the onus of proof of actuarial or statistical data based on genetic information that justify coverage exemption. Deliberate or accidental use of incorrect risk estimates can be dealt with under antidiscrimination legislation. Genetics health professionals can provide information and possibly assistance to challenge inappropriate insurance policy denial.
Insurance companies are aware of the expanding role of genetic testing and the sensitive nature of the testing results, which can have impact beyond the person undergoing the test. In the United Kingdom, 81% of surveyed life insurers reported that adverse genetic test results were not considered for policy assessment, even for test results that were allowed outside a moratorium.3
In the United States, the Centers for Medicare & Medicaid Services (CMS) covers multiple genomic tests; others can be covered if supporting evidence is provided.4 The CMS covers pharmacogenomic testing for drug choice or prevention of adverse events, screening for risk prediction, and for diagnostic and prognostic purposes for conditions such as cancer (e.g., breast and ovarian cancers, lung cancer, colorectal and gastric cancers, melanoma, leukemia), cardiovascular disease, infectious diseases, endocrine disorders, neurology, psychiatry, and others.
In Canada, one of the most widely adopted next-generation sequencing technologies to be used in a public setting has been non-invasive prenatal testing for high-risk women, although the availability of this procedure varies across provinces. Gene panel sequencing is also becoming more widely utilized for disease diagnosis and tumor sequencing for treatment option considerations, but the type of testing use can vary widely between the institutions. Exome or full genome sequencing is still very sporadic, with the Toronto Hospital for Sick Children taking the national lead in the adoption of genome sequencing for patients with undiagnosed diseases. The British Columbia Cancer Agency in Vancouver with their Personalized OncoGenomics program has become the nation’s leader in cancer genome testing.
- Keogh LA and Otlowski MF 2013. Med J Aust 199(5): 363-6
- Wilson BJ and Nicholls SG 2015. Risk Manag Healthc Policy 8: 9-20
- Barlow-Stewart K, et al. 2009. Genet Med 11(3): 193-201
The role of genetic counseling in genome sequencing
Merogenomics recommends two genetic counseling sessions for clients who have their genomes sequenced. First, a preprocedure counseling should be considered to prepare for potential psychological familial implications as a result of undergoing the genome sequencing procedure. Access to genetic counselors can also be requested after the test to aid the client in data interpretation and management options.
Genomic counseling is provided by a professionally accredited genetic counselor to educate the prospective client regarding the benefits and limitations of genome sequencing, potential psychosocial impacts of genomic testing, the informed consent for genomic testing, and provide access to accurate information and a support network.
In the post-test session, the counselor explains the genome based disease risk assessments, their medical and familial implications, and suggests ways to manage such information. A post-test counseling session can help prospective parents make informed reproductive decisions.
Misconceptions about genetics
Studies indicate that the general public can be quite misinformed about the expectations of direct-to-consumer genomic testing, including its clinical utility and accuracy of disease risk prediction.
The public tends to over emphasize the importance of genetics in health and disease, while discounting the significance of environmental and lifestyle influences on health. The mistaken idea that the genome is the definitive cause of all biological conditions (genetic determinism) runs the risk of developing a defeatist approach for the need to seek positive lifestyle habits. Another concern is that genetic determinism can propagate discriminatory connections between genetics and ethnicity, or the eugenic concepts of “best-fit” genetics. While it is true that genes influence the observed variation in phenotypes, the environment, too, has a profound consequence on phenotype variation.
The mode of disease or trait inheritance may not be as simple as the public might expect. We hear about recessive and dominant inheritance but traits can be multifactorial, or caused by variation in the copy number of a specific DNA segment. Such factors can influence “penetrance,” that is, how the disease will be manifested. Because a phenotype can present full penetrance or the penetrance can be reduced by degree, DNA test results might not provide the certainty a client is seeking.
The educational content of genetic concepts provided by Merogenomics Inc. is meant to inform a prospective client regarding results that can be expected from genome sequencing. The client is also advised to seek genetic counseling prior to and after the genome sequencing procedure.
Can the results be delivered to anyone else besides the client?
The genome DNA sequence and its analysis can be delivered to additional individuals agreed upon by the client. This can include any licensed healthcare practitioner authorized by the client to use the information for client’s benefit.
An additional option is to provide contact details of a next of kin recipient in case the client is unavailable to receive the results or in the event of death. The chosen recipient should be aware of the genome sequencing procedure undertaken by the subject, and understand that the test results could have an impact on his or her own health. For this reason the next of kin recipient might be required to sign a consent form in order to receive the results.