The type of information that can be garnered through genome sequencing will vary between individuals. The Analysis Report is a document that provides the interpretation summary of the genome sequence of an individual. Content of the Analysis Report can vary in detail depending on the type of sequencing procedure that is used. The content of a typical genome sequencing report is outlined below.
Expected Content of an Analysis Report
Predisposition to disease development
The most significant section of the Analysis Report based on the full genome sequence interpretation is dedicated to the uncovered pathogenic findings. This section of results will be presented first in the report, indicating that such results require the utmost attention. Typically, only pathogenic or likely pathogenic variants are listed, which are mutations that have either definitive or well-established evidence proven in certain disease or medically-relevant condition development. The discoveries will be almost exclusively in monogenetic conditions, meaning diseases that result from DNA changes in a single gene or location in the genome. It can include findings for untreatable conditions which might require the alteration of the medical management of a patient or afford access to clinical trials. It can also include findings for treatable conditions with available intervention. The client can decide whether or not to receive information related to untreatable conditions, information that can carry a significant negative psychological impact.
Occasionally, variants with less established evidence might be listed if a patient exhibits the traits of a condition for which the mutated gene is suspected to be involved in.
If a genetic predisposition to cancer development is uncovered, such information will also be presented in this section, and a hereditary predisposition to different types of cancers is one of the top findings among individuals choosing to screen themselves with full genome sequencing.
A client who receives an Analysis Report that contains results with medical potential should also book an appointment with a genetic counselor to answer disease risk related questions.
Carrier status of conditions that might lead to disease development in offspring
Carrier DNA status denotes variants that an individual carries without a biological impact to themselves, but if such a variant is passed onto a child, along with a similar or same variant in the same gene from the other parent, then the offspring could develop a disease. This is due to the fact that certain conditions, termed “homozygous”, only develop when mutated copies of the same gene are inherited from each parent. A carrier has only one of the genes mutated, with the other copy being normal, and is generally not at risk of being affected. Carriers are said to be “heterozygous” for a specific disease variant. However, the frequency of carriers of different diseases being discovered is high in the population, and the discovery of carrier status can have important reproductive implications for prospective parents. The vast majority of the population is expected to be a carrier of some disease, and this information is typically listed next after the pathogenic findings.
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. 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 is in contrast to the currently used “one size fits all” approach even though it is known that drugs do not work the same way for everyone. Therefore use of genetic differences that are known to affect response to medications can be used to predict how effective a medication could be for a specific person.
Additional trait information section
Additional trait information can at times be provided with a clinical test, although this would be expected in a situation where the medical results are provided to the ordering physician, while non-medically relevant information is delivered to the client. This type of information can include variants associated with aging and longevity, nutrient absorption and metabolism, fitness, color blindness, or taste perception, however, the degree to which such outcomes have clearly been scientifically linked to specific variants can vary and be questionable. But because full genome sequencing captures all of the DNA information, the client always has the option of using reputable third parties to analyse the data for such information once the genetic links to specific traits become understood. Merogenomics strongly discourages uploading personal DNA information to any third parties without a prior quality assessment of the service provider.
In a similar vein, full genome sequencing could provide information related to ancestry, although this should never be expected when ordering full genome sequencing tests. Once again, the client would have to rely on further analysis of the DNA data by a separate provider.
The client can choose the kind of information included in the report, as some information could be disruptive to the emotional well-being of the client or the client’s family. The types of information that the client can choose for delivery include:
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, for both the client as well as other family members. Therefore, a client must carefully consider whether the receipt of nonactionable pathological information is warranted.
Pathogenic and actionable (treatable) conditions
“Actionable” incidental findings are mutations that are either pathogenic or likely to be pathogenic where intervention can be undertaken, such as cystic fibrosis or phenylketonuria. Therefore, pathogenic variants for conditions with potentially beneficial medical management available are always reported, and can be considered the most valuable information to be obtained from the genome sequencing data analysis. This includes the 59 genes published by the American College of Medical Genetics and Genomics as the minimum standard for patient notification, as well as all of the other genes for which the most up-to-date information is available from public databases.
Adult onset conditions
These types of results would be considered being omitted from the report if the subject of the DNA testing is a child, with the purpose of protecting the child from the undue psychological consequences of discovering that they are predisposed to a disease in the later stages of life. There is an ongoing debate in the scientific community on the ethics concerning withholding such information, which has a child’s well-being as the central premise. Arguments for withholding the information include protecting the child from the psychological burden of being diagnosed with a condition that perhaps might not even materialize, and that the child has the right to make the decision on their own whether they want to obtain such information or not, once reaching the proper age of maturity to make such a decision. The primary argument for collecting information about adult onset conditions in children would be to discover if any additional family members might require potentially life-saving intervention. An example of that would be the discovery that a child has a hereditary predisposition to developing cancer, and such knowledge helps identify one of the unsuspecting parents as a carrier of the same pathogenic variant. While intervention for the child might not be necessary, it would be potentially of great importance to the parent.
As a consequence, the Canadian College of Medical Geneticists’ guidelines state that adult-onset genetic conditions should not be communicated unless that disclosure could prevent serious harm to the health of other family members, and unless such disclosure is desired by the parents. Similarly, the American College of Medical Genetics and Genomics possess a stance on the topic in that there should be no age limit for the return of incidental adult-onset health risks if such results are likely to have important implications for other family members.
Risk for multifactorial common diseases
As mentioned above, the clinical genome sequencing testing provides results based on monogenic conditions, or those that produce a health-related effect based on a DNA change in a single specific location. However, there are many health conditions that have their roots in both multi-factorial genetics and through environmental influences, and that includes some of the most common health issues such as heart disease, diabetes, and stroke. With respect to the DNA influence toward the development of such conditions, the science indicates that unlike monogenetic conditions, many different mutations throughout the genome can have small contributing factors, sometimes even hundreds and thousands of such sites, meaning such conditions are polygenic. As a consequence, for the majority of such common diseases, there is no understanding on how to best to utilize the genetic information in conjunction with environmental factors to be able to help predict the disease outcome. With no clinical validity or unclear validity, testing for such variants is not typically offered in a clinical setting. Clients of DNA tests for conditions which are polygenic in nature should be beware of such a product, and investigate the validity of such claims.
Nevertheless, the development of polygenic risks for different conditions is under intense scientific investigation, and is an exciting area of DNA testing that is expected to be offered in the future as a standard component of DNA sequencing results. Merogenomics will aim to help clients gain access to such products once they are commercially available, or if they become available in a research setting at reputable institutions.
Scientific Meaning of the Analysis Report
The Analysis Report is intended to help the client understand the potential interpretation of the subject’s genome sequence. The Analysis Report will contain a noncomprehensive list of genetic variants discovered in the subject’s DNA sequence for which a meaningful interpretation of scientific interest exists. The data will incorporate current scientific information, and will be stratified from the most to the least clinically validated. Each client has an opportunity to act proactively to treat potential health complications or to reduce the impact of negative outcomes through the guidance of a health care practitioner. Only information regarded to have sufficient scientific validation can be considered “clinically actionable". A client with a medically informative Analysis Report can book an appointment with a genetic counselor (also available through Merogenomics at extra cost) to answer health risk related questions.
Whole genome sequence data identify the following types of genomic alteration. Each alteration might be linked to a specific trait or a disease based on available scientific evidence:
- 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)
- Copy number variants (a frequency of repetition of a particular DNA segment)
- Translocations (rearrangements of genes or entire chromosome segments, offered in only certain DNA tests)
Alterations of the genome that involve large number of nucleotides are referred to as structural variants and can include insertions, deletions, copy number variants or translocations.
Layout of Scientific Information
The genome analysis information that the client can expect to receive in the Analysis Report can include the following information (some of which might be important for interpretation by a licenced health care professional).
- Variant information, including
This information identifies the specific chromosomal location where the variant is found.
Variant identification number (dbSNPrs#)
The variant identification number is a variant identification tag that is listed in a public archive of all identified genetic variations collected by the National Center for Biotechnology Information. Variant identification numbers can be obtained at http://www.ncbi.nlm.nih.gov/SNP/
Risk/protective allele designation
The risk/protective allele designation provides the scientific background that has been collected on the variant outcomes, including risk of disease development. References to scientific reports should be included.
Allele frequencies within the population
Allele frequencies within the population denotes an estimated percentage of the population (subcategorized by ethnicity if such information is available) that carry the indicated variant. The more frequent a variant is, the less likely it is to be responsible for a damaging biological effect.
Estimated accuracy and read depth
The “estimated accuracy” provides the odds that a variant was identified correctly by a sequencing platform. The “read depth” depicts how many independent times a DNA strand containing the indicated variant was sequenced by a sequencing machine (i.e., the coverage). The higher the coverage, the higher the probability that the nucleotides were called correctly in that DNA sequence. This type of information might only be available for DNA tests that probe for a limited number of variants, and would not be expected for a full genome sequencing test.
- Genotype with qualitative interpretation
Interpretation of the combined effect of inheritance from both parents of the specific genomic location that includes identified variant of interest. A variant outcome can be different depending on what DNA sequence has been inherited from either of the parents.
- A brief overview of the condition associated with discovered variant(s) and U.S. incidence rates when available
Summative risks of different variants associated with a given condition are usually not provided due to current lack of definitive evidence for how such variant associations can be accurately combined to estimate risk (unless scientific evidence to the contrary exists); if polygenic conditions assessment is available, instead, the risk for each variant would be listed individually.
The report will also include background information on the data generation procedure, potential technical limitations, and information intended to help the client make an informed decision about whether to publish information based on the DNA sequence data to a public database.
Special Considerations for an Analysis Report Based on a Cancer Sample
This section refers to patients diagnosed with cancer who are undergoing DNA sequencing of their cancer sample to potentially uncover the causative mutations behind the cancer development. It does not refer to individuals screening for hereditary cancer predispositions, covered in the above sections.
The cancer sample analysis is presented in a format distinctive from that of saliva and blood samples. It might include information from the normal tissue to demonstrate data analysis outcomes that are unique to the cancer sample. The following information can be expected in an Analysis Report based on a cancer tissue sample.
Somatic variants are variants that have not been inherited and are produced after conception. Such mutations can appear in the genome of any cell in the body at any time during a person’s lifespan. Some mutations can affect cell cycle regulation leading to a cancerous phenotype.
Many somatic mutations can be expected in a cancer sample. These can be grouped into five categories:
- Variants involved only in the subject’s cancer sample
- Variants affected in many cancers
- Variants involved in specific cancer types
- Variants listed in cancer related databases but not associated with cancer
- Other somatic mutations
Prediction of Drug Response
Variants are listed that are associated with cancer sensitivity to or resistance to FDA-approved or investigational therapeutics. The information provided in the Analysis Report does not recommend any specific treatment, but can suggest personalized treatment options that might be undertaken with medical oversight. Clinical trial information for experimental drugs in development is provided with relevant contact information.
Prediction of Toxicity
Variants that have been associated with drug toxicity according to FDA labeling are listed. This information can be used to select optimal medication, dosing amount, and treatment duration. This information can be combined with the subject’s normal tissue variants (germline variants meaning variants that have been inherited) to obtain a more detailed background.
Variants are listed that have been previously associated with clinical outcomes; for example, overall survival or recurrence-free survival. Information with positive or negative prognostic implications is included.
How an Analysis Report is Generated
The initial analysis of the DNA sequencing test is performed outside of a clinical setting and relies on automated bioinformatic methodologies. In a clinical setting, an additional manual oversight of the generated data can be expected (the software-generated data is inspected by medical genetics doctors). Merogenomics aids clients in accessing clinical DNA testing options that involve data overview by medical experts.
Interpretation of the genome sequence is performed by specialized computer programs that compare the obtained client DNA sequence with information available in databases that have been built with information published in the scientific literature, or observed in a clinical setting and reported by DNA testing service providers. Such programs also analyse the DNA sequence of variants that might be suspected to be pathogenic in nature based on the predicted damage caused by the mutation relative to the biological importance of the gene or genome location affected. Because this latter form of information is without supporting evidence, it is considered only as a guide for the assessment of a qualified medical geneticist who could establish correlating evidence.
In the absence of a phenotype or family history, the predicted outcomes of observed variants are less clear than they would be if such information were available. For this reason, as recommended by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines, higher specificity thresholds are adopted, and more evidence is required to suggest that a variant is pathogenic.
If the results the client receives have not been interpreted or analyzed by a clinical geneticist, nor are the results confirmed by additional methods, the results should be considered educational only, and should be interpreted with caution by a treating physician. For this reason, Merogenomics recommends and aids clients in accessing clinical DNA tests that involve data overview by medical experts.
Updating the Analysis of DNA Sequence Data
The Analysis Report represents only a minor fraction of the entire genome sequence. It is an interpretation of the sequence based on the current state of scientific knowledge, which can be expected to change at a rapid pace. For this reason Merogenomics recommends storing personal genome DNA sequence data in a digital repository for future reanalysis as new scientific data emerges. Client data storage is typically offered by the service providers of the DNA tests. In addition, Merogenomics recommends considering obtaining the DNA code data from the service provider for additional independent safe storage.
Client DNA code data re-analysis is typically not automated due to the required resources, but companies can offer a complimentary one-time re-analysis at a future date. For this reason, it would be recommended to allow a certain amount of time to pass from the last analysis in order to reflect the updated scientific understanding of the human genome as it relates to human health, and should also be guided by a timely doctor recommendation.
Otherwise, re-analysis of the DNA data should take place in the following instances:
- New symptoms appear in the client that do not correspond to previous DNA diagnosis results
- A closely-related family member exhibits new disease symptoms
- Upon the request of a medical specialist desiring to incorporate medical genomics information into patient management
- New medications are being taken with a pharmacogenetic association that was previously not available
- Every few years to incorporate new scientific knowledge of genetic based diseases
The cost of the DNA data reanalysis can be expected to be fraction of the original test’s cost, as no new DNA sequence data will be generated. The reanalysis will compare the already existing client data with the latest information available in the databases used for genome sequence clinical interpretation.
Analysis Report Limitations
It cannot ever be guaranteed that the genome DNA sequence is accurate or complete. Technological limitations exist that preclude a guarantee that every single base in the human genome will be identified correctly, and that all segments of the genome will be sequenced to completion. Service providers typically will provide information regarding the limitations of the procedure, for example, the coverage depth of the sequence, or the level of quality of DNA nucleotide identification. However, the standard sought is greater than 95% of the genome being sequenced with 95% or greater accuracy. This level of identification and analysis provides a reliable basis for useful interpretation. The databases, published scientific knowledge, and bioinformatics tools that are used to generate the Analysis Report are not comprehensive, can contain errors, and are subject to change. Therefore, it cannot be guaranteed that the Analysis Report is complete although all service providers of clinical DNA tests go to extreme lengths to ensure that the information provided in the Analysis Report is absolutely accurate. All information is supplemented with citations of key studies providing the current evidence for the disclosed information, although that might not be presented in the report itself, but accessed by the ordering physician through a web portal.
Receipt of Data
Genomic information generated from sequencing and data analysis is for private medical client use, will be kept confidential until delivered to the client's physician, and will not be divulged to any public body, database, or institution unless the disclosure is requested by the client. Third party access to a client's genome will be solely for the purpose of data generation and/or analysis. Anonymized pathogenic or likely pathogenic variant information that corresponds to the client’s disease symptoms will be deposited in public databases that are used worldwide for medical genome interpretation, unless otherwise requested by the client.
The long-term storage of the DNA data is typically automatically provided at a secure digital genome repository of the test service provider. The client can also receive a digital copy of the DNA sequence. When the genome sequencing data are available for client receipt, the client will be asked to create a personal password and will be provided a link for data download from a secure portal.
Only one Analysis Report is provided per client. Service providers do not update or supplement the Analysis Report unless the client agrees to purchase a new one, or a complimentary data reanalysis is available.