Human genome sequencing is the process of decoding the order of nucleotide bases in the entire human DNA to gain information of interest. Variations observed in the DNA between different individuals afford insight into the variation in specific traits of these individuals. As some traits have an impact on human health, genome sequencing can provide valuable information about human disease that would otherwise be hidden until symptoms appeared. Whole genome sequence data can identify the following types of genomic alteration (those that involve large number of nucleotides are referred to as structural variants):
- Single nucleotide variants (alterations that affect only one nucleotide at a time, also termed single nucleotide polymorphisms or SNPs)
- Insertions and deletions (which can vary in size) in the DNA
- Copy number variants (frequency of repetition of a particular DNA segment)
- Translocations (rearrangements of genes or entire chromosome segments)
The client will determine what type of DNA testing is appropriate for the subject of the genome sequencing procedure. The type of genome sequencing selected (partial or full) will depend on whether the subject is asymptomatic (expected to be healthy) or has disease symptoms. The options selected can impact both the genome sequencing procedure and the data analysis. Merogenomics will help the client access a third party service provider that matches the desired criteria at the highest standard and technological accuracy available. The cost of a single test can range from below $400 to several thousand dollars, depending on the technical demands of the test. The following options are provided.
Genome Sequencing Procedures for Individuals with Symptoms
Genome Sequencing for Cancer Profiling
An individual who has been diagnosed with cancer can consider undertaking molecular profiling of the cancer sample through genome sequencing if that option has not be exercised in his or her clinical care. Access to such information can help pinpoint biological pathways affected by the cancer which could help identify personalized treatment options.
The cancer sample can be analyzed by itself or, for results of higher accuracy, in tandem with a normal tissue sample for comparison. A blood sample is required for normal tissue genome sequencing. A physician is required for client sample acquisition, and to interpret the genome sequencing report.
The cancer sample analysis might not provide information of value if there are no known approved or investigational therapies associated with the molecular profile of the cancer, or if the information conflicts with a therapy selected by the healthcare provider.
Additional tests can provide a more detailed molecular profiling of the cancer sample. This can include transcriptome sequencing (sequencing of RNA transcripts found in cancer tissue as a product of genome expression; such transcripts act as templates for protein production) and/or proteomics (which determines the identity and quantity of proteins found in cancer cells; such proteins are the most common targets of cancer drugs). The combined data analysis is generated using computer algorithms that parse available scientific information. Integration of multiple test procedures can enhance the accuracy of data interpretation and the success of outcome prediction.
Individuals diagnosed with cancer are encouraged to consider the advantages of utilizing RNA transcriptome sequencing, which can provide:
- Information about the state of disease that cannot be derived from genome sequencing; for example, abnormal RNA transcript fusion that could be a contributing factor to cancer development
- Validation of somatic variants (spontaneous mutations that were not inherited from parents) discovered in the cancer tissue genome
Merogenomics can also assist clients to investigate diagnostic options such as the use of cancer specific gene panels in addition to the whole genome sequencing procedure. Cancer targeted gene panels are tests that investigate only preselected genes. The whole genome sequencing procedure involves analysis of the entire genome in the cancer sample, providing a broader survey than the gene panels.
Integration of DNA based cancer molecular data into a personalized therapy plan is determined by a healthcare provider or oncologist.
Individuals who consider undergoing cancer genome sequencing should familiarize themselves with the limitations and risks associated with the procedure.
The options of gene panel and full genome sequencing are also available to individuals who have not been diagnosed with cancer, but who have a family history of cancer, in order to determine if a genetic cancer predisposition is present.
Genome Sequencing for Disease Diagnosis
An individual who suffers from a disease for which the cause has not been diagnosed can seek a genomic cause of the condition with a demonstrated success rate of up to 70%. Merogenomics will connect the client with a medical service where the subject’s genetic information will be analysed under the supervision of a clinical geneticist and a dedicated bioinformatician. The procedure requires personal trait information from, and a medical history of, the affected individual. Additional family members might need to have their genomes sequenced for comparative purposes. To ensure the highest level of accuracy, a blood sample will be required for DNA isolation to determine the genome sequence. The procedure involved in tracking the genetic cause of a disease requires more resources and involves higher financial input than does a straightforward genomic sequencing procedure.
The client will receive a digital copy of the entire DNA sequence in the subject’s genome, and an Analysis Report based on data derived from the genome sequence (please see below for details). Additional family members who have had their genomes sequenced will receive results independently. The medical team overseeing the genome sequencing procedure will have access to the produced genome DNA sequence and its interpretation.
If the diagnostic quest is successful, the supervisory medical team will suggest options of future steps (if any) that the client could undertake to deal with the newly categorized condition.
Genome Sequencing Procedures for Asymptomatic Individuals
Genome Sequencing for Pregnant Mother / Fetus
A pregnant woman who wishes to investigate the genetic risk factors of her fetus has two options available to her: a non-invasive procedure to analyze the fetus for chromosomal alterations such as trisomies (a trisomy refers to the presence of three chromosomes, rather than the usual pair of chromosomes), as well as subchromosomal rearrangements (the partial duplication or deletion of a chromosome that can lead to a disease), or an invasive procedure for fetus DNA sequencing for specific genetic conditions.
Non-invasive prenatal screening (NIPS, also referred to as NIPT for non-invasive prenatal testing), requires only the mother’s blood, which contains DNA sources of both the mother and her future offspring, and therefore the procedure is absolutely safe for the fetus. The fetus’ data will include sex assessment (which is optional unless sex chromosomes are involved in the suspected condition’s diagnosis), and chromosomal aneuploidies and rearrangements (within the scope of technical capability), that can inform one about potential developmental complications such as Down syndrome (trisomy 21).
NIPS is typically available from 10 weeks of gestation onward. NIPS should not be considered a stand-alone test, and the client should be familiar with the test’s limitations, including the chances of a false-positive result, a false-negative result, or even no result being determined. However, studies indicate that the test possesses a very high sensitivity rate in the range of 98-99% for the most common trisomies (trisomies 21, 18, and 13), and offers a specificity of around 99.95%. For these reasons, NIPS is now considered the most accurate pregnancy screening method for these trisomies. In addition, all other chromosomes can be investigated for aneuploidies (the altered number of chromosomes). The sensitivity of subchromosomal alterations can range from 50–100%, depending on the size of the impacted genomic area and the depth of sequencing coverage.
Invasive prenatal DNA testing, whether full genome sequencing or partial genome sequencing (exome sequencing) can be undertaken if a genetic condition affecting the fetus is suspected, based on an abnormal finding of prenatal screening results, including NIPS.
Pregnant women considering fetal DNA testing should familiarize themselves with the limitations and risks associated with the procedure.
Genome Sequencing for Individual Screening
Any individual can choose to undergo a genome sequencing procedure to obtain information of value, including health related information for potential future care. The list of potential benefits is provided below. A client seeking such information about themselves (or a dependent) must provide a sample of saliva or blood. A blood sample is preferred because blood provides higher quality data than saliva. Saliva samples can contain bacterial contamination which can impact the accuracy of the genome sequencing.
What Client Obtains
The client can receive a digital copy of the entire DNA sequence of the subject’s genome (available for download via a secure website portal), while the ordering physician will obtain an Analysis Report based on the latest scientific interpretation of the DNA sequence data. Each of the covered sections of the benefits of genome sequencing can also be obtained independently as a stand-alone DNA test.
Predisposition to disease development
This information lists the types of DNA alterations that have previously been associated with disease development. This includes the 59 genes published by the American College of Medical Genetics and Genomics as the minimum standard for patient notification. The largest suggested list of genes with clinical implications contained over 2000 genes, including more than 150 actionable genes (medical intervention is available). The discovery of pathogenic or potentially pathogenic variants could lead to a disease state in either children or adults. The gene variants listed are based on the latest scientific interpretation of the DNA sequence data, and are stratified from the most to the least clinically validated in terms of their contribution to disease development. Proper interpretation of such results will require the oversight of a genetic counselor and/or appropriately trained healthcare provider. Although variants whose significance is currently unknown are not included in the list, future discoveries could link such variants to specific traits.
The information in this section is further subcategorized based on chosen client preferences (pathogenic actionable and nonactionable as well as adult-onset information).
Carrier status of conditions that might impact an offspring
Variants that we inherit from our parents can be either homozygous (identical variant copies were inherited from mother and father) or heterozygous (nonidentical variant copies were inherited from mother and father). Many inherited diseases are exhibited only if they are inherited in a homozygous state, that is, a deleterious variant was obtained from each parent. A heterozygous combination of variants might have no obvious clinical manifestation, whereas a homozygous combination of variants might lead to disease. Therefore, a healthy individual can be a carrier of a variant that can lead to disease in future generations. Current estimates suggest that 0.5–1% of the random couples will be carriers of same disease variants. Such couples have a 25% risk of having an affected offspring (that is, a one in four chance because each parent also carries a nondeleterious variant). Foreknowledge of carrier status can impact reproduction decisions.
Pharmacogenomics is a study of the correlation between the variations observed in the DNA sequence of an individual and the reaction of that individual to treatment with a drug; that is, whether the effect of the drug is adverse or efficacious. The pharmacogenomics science attempts to tailor a drug to fit an individual patient based on the patient’s genome information. Furthermore, the optimal drug dose can be chosen to match the individual metabolism phenotype, while avoiding adverse effects associated with toxicity or lack of efficacy. This is in contrast to the “one size fits all” approach that is currently used, even though it is known that drugs do not work the same way for everyone. Therefore genetic differences known to affect response to medications can be used to predict drug effectiveness for a specific individual.
In fact, 98% of surveyed U.S. physicians expect that patient genetic profiles, if available, would influence drug therapy. Many medical centers have begun to use personal genomic information to guide prescription choice. Treatment costs are thus reduced through enhanced monitoring of drug efficacy and toxicity.
Hereditary cancer predisposition
While technically belonging in the section of predisposition to disease development, inherited genetic cancer predisposition is such an important medical area of investigation that it is listed separately for emphasis. Full genome sequencing is the most comprehensive way to analyze for cancer predisposition, as it can stem from both the alteration of a specific DNA nucleotide, or include larger scale alterations such as insertions, deletions, duplications or translocations of DNA fragments both inside and outside of the genes that are present in the DNA sequence from birth.
This is in contrast to DNA mutations that can accumulate in the cells throughout the body during the lifetime of an individual (termed “somatic variants”), including those that can lead to cancer development. The analysis of somatic variants can be available specifically for tumor samples, and ideally should be contrasted against the inherited mutations for potential cancer therapy selection in cancer patients.
In addition, capturing the full genome sequence allows an individual to probe the DNA data for additional non-medically relevant information through independent third parties. The type of information listed below is not available in the results obtained from the service providers that Merogenomics endorses, but is listed here to illustrate what type of knowledge could be acquired by decoding the entire DNA sequence of an individual.
DNA sequence data
A client’s personal DNA sequence data belongs to her or him and the client has the right to a digital copy of their DNA sequence. Some service providers will provide a DNA data download or place it on a memory drive at no extra cost, while others might charge for it. Merogenomics recommends considering obtaining a copy of one’s personal DNA sequence data for your own safekeeping. In addition, all service providers will retain a client’s DNA data for indefinite storage. This allows for easy access to the data for future reanalysis as needed or desired. The client has the option to request for their data to be permanently destroyed by the service providers, although how quickly this can take place might depend on regulatory obligations related to the management of health-related records.
Client Information Options
The levels of concern regarding the identification of variants that clients can choose are listed below.
Pathogenic but nonactionable (untreatable) conditions
A pathogenic variant is a mutation with direct consequences to human health. A pathogenic variant is considered “nonactionable” if the condition resulting from the pathogenic mutation is untreatable. Examples include Huntington disease or spinal muscular atrophy. Knowledge of nonactionable pathogenic variants can prepare the subject of genome sequencing for a possible condition, but such foreknowledge can involve significant psychological and social challenges. Therefore, a client must carefully consider whether the receipt of nonactionable pathological information is warranted. For example, only 5–25 % of individuals at-risk of Huntington disease development chose to take a confirmatory genetic test. The likelihood of such incidental findings (~ 1–5% for all pathogenic variants) and the fact that the discovery of a pathogenic variant does not guarantee disease development also need to be considered.
Pathogenic and actionable (treatable) conditions
“Actionable” incidental findings are mutations that are either pathogenic or likely to be pathogenic where intervention can be undertaken. This includes the 59 genes published by the American College of Medical Genetics and Genomics as the minimum standard for patient notification. However, DNA tests service providers recommendations will depend on the most up to date information presented in available public databases. Examples include cystic fibrosis or phenylketonuria.
Adult onset conditions
This item can include information for actionable and nonactionable pathogenic variants. Selection of this item can be omitted if there are ethical concerns in the case of a genome sequence being determined for a child.
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 (i.e., 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. 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.
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.
Risk of multifactorial common diseases conditions
Common diseases such as heart disease and diabetes are polygenic in nature; that is, they comprise hundreds and even thousands of DNA variants whose interplay toward disease development is unclear.
Such variants can explain about 10% of the genetic component of the disease at best, even if the impact of all associated variants is combined, and therefore they have low predictive value. As these variants currently have either no clinical validity or unclear validity, testing for them is not typically offered in a clinical setting.
However, DNA-based polygenic risk scores are proving to be an exciting area of research, and it is expected that in conjunction with additional data, the risk information for common complex diseases will be routinely provided to doctors in the future. Merogenomics will aim to provide clients with access to such risk scores once they are validated and available either commercially or through research, while recognizing the potential limitations of such information.