Analysis Report

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 report is outlined below.

 

Expected Content of an Analysis Report

Predisposition to different conditions of medical interest, such as disease development

This information lists the types of DNA alterations that have previously been associated with disease development. This includes the 56 genes published by the American College of Medical Genetics and Genomics as the minimum standard for patient notification.1 The largest suggested list of genes with clinical implications contained 2016 genes, including 161 actionable genes (medical intervention is available).2 It is highly recommended that the discovery of pathogenic or potentially pathogenic variants be verified with a secondary technology, as such mutations 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).

  1. Green RC, et al. 2013. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med 15(7): 565-74
  2. Berg JS, et al. 2013. An informatics approach to analyzing the incidentalome. Genet Med 15(1): 36-44

Carrier status of conditions that might lead to disease development in 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.1 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.

  1. Gambin T, et al. 2015. Secondary findings and carrier test frequencies in a large multiethnic sample. Genome Med 7(1): 54

Pharmacogenomic information

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.

Information related to health, such as predisposition to obesity

Genetic variants that are not associated with disease development can still be informative toward important health related trends. Variants associated with aging and longevity, insulin sensitivity, nutrient absorption, metabolic rate, etc., might indirectly impact the health of an individual.

Additional trait information

This information includes nonclinical traits such as hair loss, color blindness, and taste perception which have been scientifically linked to specific variants.

Ancestral information

People with similar ethnic backgrounds are more likely to share similar genetic variation. By mapping the pattern of inheritance among different groups of people around the world, ancestry relationships can be established. When a person has his or her genome sequenced, the pattern of shared DNA can point to the person’s ancestral origin. Such insights could have health related implications, as different ethnic groups are carriers of different health impacting variants.

The Analysis Report is for educational and research purposes only; it does not constitute a medical assessment, and it is not a substitute for professional medical advice, diagnosis, or treatment. The information presented in the Analysis Report cannot be used for medical or clinical purpose unless first interpreted by a licensed healthcare professional. A client who receives an Analysis Report that contains results with medical potential can book an appointment with a genetic counselor to answer health related questions.

 

 

The client will receive research data via a secure password protected website portal) in the form of a whole genome DNA sequence plus the Analysis Report based on his or her individual genome sequence.

 

If the Analysis Report is requested, 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) [e.g., Huntington disease, spinal muscular atrophy]

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. 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.1,2 The likelihood of such incidental findings (~ 1–5% for all pathogenic variants)3-5 and the fact that the discovery of a pathogenic variant does not guarantee disease development also need to be considered.

  1. Creighton S, et al. 2003. Predictive, pre-natal and diagnostic genetic testing for Huntington's disease: the experience in Canada from 1987 to 2000. Clin Genet 63(6): 462-75
  2. Laccone F, et al. 1999. DNA analysis of Huntington's disease: five years of experience in Germany, Austria, and Switzerland. Neurology 53(4): 801-6
  3. Dorschner MO, et al. 2013. Actionable, pathogenic incidental findings in 1,000 participants' exomes. Am J Hum Genet 93(4): 631-40
  4. Gambin T, et al. 2015. Secondary findings and carrier test frequencies in a large multiethnic sample. Genome Med 7(1): 54
  5. Olfson E, et al. 2015. Identification of Medically Actionable Secondary Findings in the 1000 Genomes. PLoS One 10(9): e0135193

Pathogenic and actionable (treatable) [e.g., cystic fibrosis, phenylketonuria]

“Actionable” incidental findings are mutations that are either pathogenic or likely to be pathogenic where intervention can be undertaken. This includes the 56 genes published by the American College of Medical Genetics and Genomics as the minimum standard for patient notification.1 However, Merogenomics Inc.’s recommendations will depend on the most up to date information presented in available public databases.

  1. Green RC, et al. 2013. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med 15(7): 565-74

Pharmacogenomic information [e.g., warfarin dosing]

See above for further details.

Carrier status for recessive conditions [e.g., thalassemia]

See above for further details.

Adult onset conditions [e.g., breast cancer]

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.1 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.1

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.2 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.3

  1. Green RC, et al. 2013. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med 15(7): 565-74
  2. Dickens BM 2014. Ethical and legal aspects of noninvasive prenatal genetic diagnosis. Int J Gynaecol Obstet 124(2): 181-4
  3. Zawati MH, et al. 2014. Reporting results from whole-genome and whole-exome sequencing in clinical practice: a proposal for Canada? J Med Genet 51(1): 68-70

Risk for multifactorial common diseases conditions [e.g., diabetes]

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.1-4 As these variants currently have either no clinical validity or unclear validity, testing for them is not typically offered in a clinical setting.5

This information can be presented to the client for future reference while recognizing the limitations of such information.

  1. Meigs JB, et al. 2008. Genotype score in addition to common risk factors for prediction of type 2 diabetes. N Engl J Med 359(21): 2208-19
  2. Paynter NP, et al. 2010. Association between a literature-based genetic risk score and cardiovascular events in women. JAMA 303(7): 631-7
  3. Richards S, et al. 2015. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17(5): 405-24
  4. Voight BF, et al. 2010. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet 42(7): 579-89
  5. Weaver M and Pollin TI 2012. Direct-to-Consumer genetic testing: what are we talking about? J Genet Couns 21(3): 361-6

Nonmedically related traits and information [e.g., ancestry, hair loss]

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.

The client’s decision to omit specific types of information in the Analysis Report is subject to change if such decision takes place prior to data being destroyed.

 

 

The information the client receives in the Analysis Report interpreting the DNA sequence data, is not meant to be construed as medical advice or a diagnosis but only as auxiliary information for the client’s educational use. Data and information received from Merogenomics Inc. or third party service providers are not intended to replace professional medical advice, diagnosis, or treatment. Information or data should be analyzed and confirmed by a licensed healthcare professional before being used for a medical purpose.

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. While the information presented is meant for private education only, 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 Inc. at extra cost) to answer health related questions.

Merogenomics Inc. will not share client information, DNA sequence data, or the Analysis Report with a health care provider unless specifically requested to do so by the client. There is an exception to this rule if the client is undergoing a procedure that requires the oversight of a clinical geneticist who must have access to the whole genome sequence to perform his or her service (as in the case of a diagnostic procedure).

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)

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

Genomic location

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 will 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.

  • 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 will not be 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); instead, the risk for each variant will 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.

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.

Special Considerations for an Analysis Report Based on a Cancer Sample

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 Mutations

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.

Prognosis

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

Analysis of the sequencing results in asymptomatic clients of Merogenomics Inc. is performed outside of a clinical setting and relies on automated bioinformatic methodologies. In a clinical setting, an additional manual oversight of generated data can be expected (software generated data is inspected by medical genetics doctors). When appropriate, Merogenomics Inc. will aid client access to clinical management, such as in the case of genome sequencing for disease diagnosis, or cancer treatment.

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. 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 should be considered only as a guide for the assessment of a qualified medical geneticist who could establish correlating evidence.

The results the client receives have not been interpreted or analyzed by a clinical geneticist, nor are the results confirmed by additional methods. 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.1, 2

  1. Rehm HL, et al. 2013. ACMG clinical laboratory standards for next-generation sequencing. Genet Med 15(9): 733-47
  2. Richards S, et al. 2015. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17(5): 405-24

 

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 Inc. recommends storing personal genome DNA sequence data in a digital repository for future reanalysis as new scientific data emerges.

Analysis Report Limitations

Merogenomics Inc. cannot guarantee 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. Merogenomics Inc. 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, Merogenomics Inc. cannot guarantee that the Analysis Report is accurate or complete. All information will be supplemented with citations of key studies providing current evidence for the disclosed information.

Receipt of Data

Genomic information generated from sequencing and data analysis is for private (client) use, will be kept confidential until delivered to the client, 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.

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.

Once it is confirmed that the subject's genome sequence and the Analysis Report based on it has been downloaded by the client, these data will be deleted within two weeks (14 days) by Merogenomics Inc. and by associated third parties involved in the data generation. Long term storage can be achieved by storage at a secure digital genome repository.

For security reasons the client has a period of 30 days to accept the return of genome sequencing data and the Analysis Report from the moment of first contact informing the client that the data are available for upload. If no communication with the client is achieved, the next of kin for which contact has been afforded will be contacted. If the client or the next of kin does not accept the test results within 30 days of the first communication, the data and contact details will be permanently destroyed. In such case no refund will be dispensed for the services performed.

Only one Analysis Report is provided per client. Merogenomics Inc. will not update or supplement the Analysis Report unless the client agrees to purchase a new one.

 

Additional Products

  • genomic counseling
  • genome sequencing
  • pathogenic variants verification
  • digital biobank storage

 

Related Information:

Advantages and Limitations of Genome Sequencing 

Procedure Overview

Considerations Before the Purchase 

Action After Procedure Completion

Genomic Education


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