Frequently Asked Questions

Glossary

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.

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.

Introduction

The history of human 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.8 Publically-funded initiatives to sequence entire populations have commenced as a form of proactive screening to deliver benefits to the entire population.9

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.10  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.11

  1. Lander ES, et al. 2001. Initial sequencing and analysis of the human genome. Nature 409(6822): 860-921
  2. Venter JC, et al. 2001. The sequence of the human genome. Science 291(5507): 1304-51
  3. Margulies M, et al. 2005. Genome sequencing in microfabricated high-density picolitre reactors. Nature 437(7057): 376-80
  4. Wheeler DA, et al. 2008. The complete genome of an individual by massively parallel DNA sequencing. Nature 452(7189): 872-6
  5. http://www.ncbi.nlm.nih.gov/genbank/statistics
  6. Choi M, et al. 2009. Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc Natl Acad Sci U S A 106(45): 19096-101
  7. Worthey EA, et al. 2011. Making a definitive diagnosis: successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease. Genet Med 13(3): 255-62
  8. Ginsburg G 2014. Medical genomics: Gather and use genetic data in health care. Nature 508(7497): 451-3
  9. Gudbjartsson DF, et al. 2015. Large-scale whole-genome sequencing of the Icelandic population. Nat Genet 47(5): 435-44
  10. http://www.omim.org/statistics/geneMap
  11. http://www.hgmd.org

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

  1. 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
  2. https://rarediseases.info.nih.gov/research/pages/27/undiagnosed-diseases-program
  3. Frezzo TM, et al. 2003. The genetic family history as a risk assessment tool in internal medicine. Genet Med 5(2): 84-91
  4. http://www.who.int/genomics/public/geneticdiseases/en/

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 (Bloss et al., 2011). 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 

Consultation with a health care provider is not a prerequisite, however, it is highly recommended if use of genomic sequencing is for obtaining specific health related information. If the services are for diagnostic purposes, involvement of a health care provider will be required.
Genome sequencing clients are required to sign a Web-based Informed Consent and a User Agreement. Relevant personal information will be collected and client payment information is obtained. Access to genetic counsellors can be requested prior to a decision to proceed with the sequencing.

In the first step of genome sequencing a web-based psychological health assessment questionnaire is filled out. The questionnaire is used to assess the potential risk of emotional distress that the client might experience if serious health risk is determined by the sequencing. The client has the option to decide against obtaining such results or against the sequencing procedure entirely if the results of the questionnaire show that such a finding could harm the mental state of the client. In this case a refund will be issued.

In the second step a DNA Swab Kit is sent to the client to obtain a saliva sample which will be used for DNA isolation and sequencing. For prenatal genome sequencing, a sample of the mother’s blood is necessary as it contains DNA of both mother and child. The blood sample must be drawn and sealed in a sterile container by appropriately trained health care personnel.

The third step is DNA analysis of the obtained specimen. The DNA analysis comprises known and validated health risks and this information is delivered to the client along with the determined DNA sequence. Report information will be organized from most scientifically validated to least validated. Only information regarded to have sufficient scientific validation can be considered “clinically actionable". Access to genetic counsellors can be requested to aid the client in data interpretation. Any “clinically actionable” information can be delivered to the health care provider of choice. Additional information of potential medical impact but that has no clinical utility or validity can also be delivered with client’s clear understanding that such information could be of no relevance to their health.

The client has an option of storing their genome sequence at a secure and private biobank with an additional option for future genome reanalysis.

Follow-up psychological health assessment is administered three months after genomic sequencing to measure possible client anxiety. Such information can help us to gauge the risks of use of this technology and can suggest ways to modify information delivery for population benefit.

How many people have sequenced their genomes thus far?

Many thousands of individuals have sequenced their genomes. Francis de Souza, president of Illumina, the world’s biggest maker of DNA sequencing machines, has estimated this number at 228 000 individuals.1 Illumina estimates that 1.6 million genomes will be completely sequenced by end of 2017.1

  1. Regalado A 2014. EmTech: Illumina Says 228,000 Human Genomes Will Be Sequenced This Year. Available at: http://www.technologyreview.com/news/531091/emtech-illumina-says-228000-human-genomes-will-be-sequenced-this-year/ [Access date: March 30, 2015]

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.1

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.

  1. Sivell S, et al. 2008. How risk is perceived, constructed and interpreted by clients in clinical genetics, and the effects on decision making: systematic review. J Genet Couns 17(1): 30-63

 

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.1-4

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%.5, 6 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.7 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.

  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. Pedersen NL, et al. 2004. How heritable is Alzheimer's disease late in life? Findings from Swedish twins. Ann Neurol 55(2): 180-5
  6. Wirdefeldt K, et al. 2011. Heritability of Parkinson disease in Swedish twins: a longitudinal study. Neurobiol Aging 32(10): 1923 e1-8
  7. http://www.cdc.gov/genomics/gtesting/tier.htm

How is client sequence analyzed?

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.1

Analysis of the sequencing results in asymptomatic clients of Merogenomics Inc. is performed outside of a clinical setting and therefore primarily relies on automated bioinformatic methodologies. 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 ACMG and the Association for Molecular Pathology guidelines, higher specificity thresholds are adopted, and more evidence is required to suggest that a variant is pathogenic.2, 3

  1. ACMG Board of Directors 2012. Points to consider in the clinical application of genomic sequencing. Genet Med 14(8): 759-61
  2. Rehm HL, et al. 2013. ACMG clinical laboratory standards for next-generation sequencing. Genet Med 15(9): 733-47
  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

What is the current genomic knowledge that is of medical value? 

Current genomic sequencing technology is still such a relatively new invention that no adequate pathogenic mutations database exists sufficient for clinical use. However, there are concerted efforts in the global scientific community to develop such a database, especially because new genomic information is gained at a very rapid pace.1 Deciphering which and how variants are pathogenic will require time.

In July 2013 the American College of Medical Genetics and Genomics (ACMG) published clinical guidelines for mandatory informing of patients of mutations that lead to a disease state in 56 genes for either children or adults.2 The list of 56 genes was selected based on diseases that could be verified by additional diagnostic methods, and for which preventative measures and/or treatments could be undertaken. This list did not address the conditions that are already part of routine newborn screening in the public health framework. Currently these guidelines stand as the most authoritative recommendations on the subject of treatment action based on genomic findings. In this case, “actionable” means that the health conditions threatened by gene variants listed in this database can be addressed by clinical methods. Later that year a committee of medical genetics experts expanded the list by adding 68 genes for adult conditions only where action can be taken for patient benefit based on genome sequence.3 Genomic sequencing is a continuously evolving field. One study listed 1423 genes associated with 1493 autosomal recessive disorders and 112 genes associated with 159 X-linked recessive disorders.4 The largest list of gene-associated disorders contained a total of 2016 genes, including 161 actionable genes.5

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. The committees that are currently assembling and devising the lists of genes of known pathogenic mutation with direct consequences to human health concede that such lists are a starting point only, and are expected to be refined and updated at least annually.2 The College of American Pathologists Personalized Healthcare Committee has also formed a workgroup to create a clinically actionable genomic database.6 The National Institutes of Health has set up a Clinical Genome Resource dedicated to building a database of variants for precise use in medicine, including evidence based summaries for actionable variants in more than 30 conditions.7 In addition, the U.S. Centers for Disease Control and Prevention lists genomic tests that are grouped by evidence that supports their use.8

  1. Rehm HL, et al. 2015. ClinGen--the Clinical Genome Resource. N Engl J Med 372(23): 2235-42
  2. Green RC, et al. 2013. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med 15(7): 565-74
  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. Berg JS, et al. 2013. An informatics approach to analyzing the incidentalome. Genet Med 15(1): 36-44
  6. Crawford JM, et al. 2014. The business of genomic testing: a survey of early adopters. Genet Med 16(12): 954-61
  7. http://www.clinicalgenome.org/
  8. http://www.cdc.gov/genomics/gtesting/tier.htm

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.1

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.1

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.

  1. Wilson BJ and Nicholls SG 2015. The Human Genome Project, and recent advances in personalized genomics. Risk Manag Healthc Policy 8: 9-20

 

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.1 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.

Currently, the early adopters of genome sequencing in the U.S. health system are in clinical laboratories predominantly involved in genomic testing for cancer. Institutions are also using the technology for medical genetics.2 Genome sequencing has become a standard tool in the diagnoses of rare diseases that otherwise have eluded physicians who use traditional approaches (including genetic testing).3 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.4 Future planned use also includes infectious disease diagnostics.2 The advantages cited for the benefit of patients are “(i) the ability to identify druggable targets, (ii) elimination of redundant testing [by eliminating the single gene test approach], and (iii) earlier diagnosis”.

“These early adopters uniformly view genomic analysis as an imperative for developing their expertise in the implementation and practice of genomic medicine.”2 In 2013, an Implementing GeNomics In PracTicE (IGNITE) consortium was set up in the United States to investigate effective methods of incorporating patient genomic information into clinical care.5 These recent trends demonstrate both the novelty of these technologies, as well as the increasing awareness of the medical potential that can be harnessed by genomic sequencing.

  1. Ginsburg G 2014. Medical genomics: Gather and use genetic data in health care. Nature 508(7497): 451-3
  2. Crawford JM, et al. 2014. The business of genomic testing: a survey of early adopters. Genet Med 16(12): 954-61
  3. Gilissen C, et al. 2014. Genome sequencing identifies major causes of severe intellectual disability. Nature 511(7509): 344-7
  4. http://undiagnosed.hms.harvard.edu/
  5. http://rt5.cceb.med.upenn.edu/public/IGNITE_HOME.html

How is client sequence analyzed?

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.1

Analysis of the sequencing results in asymptomatic clients of Merogenomics Inc. is performed outside of a clinical setting and therefore primarily relies on automated bioinformatic methodologies. 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 ACMG and the Association for Molecular Pathology guidelines, higher specificity thresholds are adopted, and more evidence is required to suggest that a variant is pathogenic.2, 3

  1. ACMG Board of Directors 2012. Points to consider in the clinical application of genomic sequencing. Genet Med 14(8): 759-61
  2. Rehm HL, et al. 2013. ACMG clinical laboratory standards for next-generation sequencing. Genet Med 15(9): 733-47
  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

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 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 his or her 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:

1) 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.

2) 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.

3) 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 his or her 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%.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.2

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.3 Such discovery can have profound emotional implications for an individual, such as feelings of guilt and anxiety of potentially affecting the offspring.2, 4

  1. Gambin T, et al. 2015. Secondary findings and carrier test frequencies in a large multiethnic sample. Genome Med 7(1): 54
  2. Francke U, et al. 2013. Dealing with the unexpected: consumer responses to direct-access BRCA mutation testing. PeerJ 1: e8
  3. Sivell S, et al. 2008. How risk is perceived, constructed and interpreted by clients in clinical genetics, and the effects on decision making: systematic review. J Genet Couns 17(1): 30-63
  4. Maat-Kievit A, et al. 2001. New problems in testing for Huntington's disease: the issue of intermediate and reduced penetrance alleles. J Med Genet 38(4): E12

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 recent study showed that one or more variants were implicated in the patient response to five common prescription drugs in 91% of all patients.

  1. Van Driest SL, et al. 2014. Clinically actionable genotypes among 10,000 patients with preemptive pharmacogenomic testing. Clin Pharmacol Ther 95(4): 423-31

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. However, verification of genetic variants that can be used clinically has been a slow process. Stanford University manages a public database of variants that influence drug response (PharmGKB).1 As of 2015, 197 entries have been collected from different international medical agencies (U.S., Canada, Europe, and Japan), including 169 drugs with pharmacogenomics labeling for safety or efficacy listed by the U.S. Food and Drug Administration.2, 3 Multiple medical centers have commenced using personal genomic information to guide prescription choice in a clinical setting. In one such project, during a patient attitude survey, 84% percent of respondents found the use of genotyping acceptable as means of gaining additional information of medical value.4 The authors of the study predicted that improved efforts to obtain personal pharmacogenomic information will reduce treatment costs by enhanced monitoring against 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.5

  1. http://www.pharmgkb.org
  2. PharmGKB 2015. Drug Labels. Available at: https://www.pharmgkb.org/view/drug-labels.do [Access date: August 26, 2015]
  3. US Food and Drug Administration 2015. Table of Pharmacogenomic Biomarkers in Drug Labeling. Available at: http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm [Access date: August 26, 2015]
  4. Pulley JM, et al. 2012. Operational implementation of prospective genotyping for personalized medicine: the design of the Vanderbilt PREDICT project. Clin Pharmacol Ther 92(1): 87-95
  5. Stanek EJ, et al. 2012. Adoption of pharmacogenomic testing by US physicians: results of a nationwide survey. Clin Pharmacol Ther 91(3): 450-8

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.1 As European-decent groups have been studied the most, the available understanding of pathogenic mutations is of highest benefit to this racial group.2 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.

  1. Chanock SJ, et al. 2007. Replicating genotype-phenotype associations. Nature 447(7145): 655-60
  2. Dorschner MO, et al. 2013. Actionable, pathogenic incidental findings in 1,000 participants' exomes. Am J Hum Genet 93(4): 631-40

Should children have their genomes sequenced? 

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.1 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.1 For these reasons, as well as “the long turnaround times and interpretive complexities currently associated with this technology,” ACMG recommends that genome sequencing should not be used for prenatal screening or newborn screening, but ought to be considered in preconception carrier screening.2

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.3 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

  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. ACMG Board of Directors 2012. Points to consider in the clinical application of genomic sequencing. Genet Med 14(8): 759-61
  3. Dickens BM 2014. Ethical and legal aspects of noninvasive prenatal genetic diagnosis. Int J Gynaecol Obstet 124(2): 181-4
  4. 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

Prenatal screening considerations

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.1 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.1 For these reasons, as well as “the long turnaround times and interpretive complexities currently associated with this technology,” ACMG recommends that genome sequencing should not be used for prenatal screening or newborn screening, but ought to be considered in preconception carrier screening.2

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.3 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

  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. ACMG Board of Directors 2012. Points to consider in the clinical application of genomic sequencing. Genet Med 14(8): 759-61
  3. Dickens BM 2014. Ethical and legal aspects of noninvasive prenatal genetic diagnosis. Int J Gynaecol Obstet 124(2): 181-4
  4. 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

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. For example, if a mutation that leads to a disease is mistaken for a normal gene (a false negative), the person could think they have been successfully tested for a condition and found to be “negative” for it, whereas that might not be the case. Conversely, a gene could be misread as a mutation that is expected to lead to an adverse condition, whereas in reality, the person is not harbouring such a mutation in their genome (a false positive).

For these reasons, whole genome sequencing platforms are currently used only for research purposes (including population research that Merogenomics Inc. propagates) and not for clinical diagnostics. It is therefore important to remember that information obtained from genome sequencing is not to be used for medical interpretation unless it is validated by additional means. It is the first step only in unravelling biological information from personal DNA.

For example, recent data analysis of two different competing sequencing platforms indicated that a median of 10–19% (depending on the platform) of genes associated with inherited diseases (including genes recommended for pathogenic variant (mutants) discovery by the American College of Medical Genetics and Genomics contained segments that were not read at the minimum threshold required to confidently determine a variant.1 These areas of the genome, albeit small, would not be of sufficient quality to use for clinical diagnostic purposes.
However, due to the lag time in the scientific publication process, the equipment used for the above research was available in 2011 and early 2012. The technical performance of sequencing platforms has continuously improved since, but the example described above indicates the potential limitations of genomic sequencing in the context of diagnostics. There are already next generation sequencing platforms that are cleared for clinical use by the U.S. Food and Drug Administration for certain gene panels of clinical interest (MiSeq Dx by Illumina and PGM Dx by Ion Torrent), and generation sequencing platforms that are cleared for whole genome sequencing are eagerly anticipated. In summary, genome depth coverage varies throughout, and the lower the depth, the lower the probability that base was measured correctly. Conversely, the higher the coverage, the higher the probability of accurate base calling.

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 interpretable for the benefit of a client. Instead, current genome sequencing allows for analysis of potential impact of individual base changes. The American College of Medical Genetics and Genomics guidelines for mandatory returns of incidental findings have also been set up with this limitation in mind, and the guidelines do not recommend a search for structural variants in the list of genes they recommend.2
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.3 Simply put, currently there is no gold standard against which the performance of population genomic screening can be judged.4 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. The Personalized Health Care Committee of the College of American Pathologists, a seven-person workgroup tasked with examining the role of genome sequencing for clinical use is the first step undertaken in this direction. Their analysis of 13 academic medical centers performing genome sequencing for human diagnostics under a Clinical Laboratory Improvement Amendments license highlights the expanding role of genomics in medical practice.3 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.3

  1. Dewey FE, Grove ME, Pan C et al. (2014) Clinical interpretation and implications of whole-genome sequencing. JAMA 311(10): 1035-1045
  2. Green RC, Berg JS, Grody WW et al. (2013) ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med 15(7): 565-574
  3. Crawford JM, Bry L, Pfeifer J et al. (2014) The business of genomic testing: a survey of early adopters. Genet Med 16(12): 954-961
  4. Wilson BJ and Nicholls SG 2015. The Human Genome Project, and recent advances in personalized genomics. Risk Manag Healthc Policy 8: 9-20

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

  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

What are the chances that genome sequencing results will provide important incidental findings?

Scientific data are beginning 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 would could expect at least similar levels of incidental findings as observed in other populations.2

Another genome sequencing study of individuals afflicted with pancreatic cancer showed that in 4.2% of cases medical action was taken based on the data return.3  

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.4 In another analysis of 1092 individuals who had their genomes sequenced, a 1% rate of incidental findings was observed.5 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.

  1. Dorschner MO, et al. 2013. Actionable, pathogenic incidental findings in 1,000 participants' exomes. Am J Hum Genet 93(4): 631-40
  2. Abecasis GR, et al. 2012. An integrated map of genetic variation from 1,092 human genomes. Nature 491(7422): 56-65
  3. Johns AL, et al. 2014. Returning individual research results for genome sequences of pancreatic cancer. Genome Med 6(5): 42
  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

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.

 

  1. Francke U, et al. 2013. Dealing with the unexpected: consumer responses to direct-access BRCA mutation testing. PeerJ 1: e8
  2. Hamilton JG, et al. 2009. Emotional distress following genetic testing for hereditary breast and ovarian cancer: a meta-analytic review. Health Psychol 28(4): 510-8
  3. Maat-Kievit A, et al. 2001. New problems in testing for Huntington's disease: the issue of intermediate and reduced penetrance alleles. J Med Genet 38(4): E12
  4. Green RC, et al. 2009. Disclosure of APOE genotype for risk of Alzheimer's disease. N Engl J Med 361(3): 245-54
  5. Bloss CS, et al. 2011. Effect of direct-to-consumer genomewide profiling to assess disease risk. N Engl J Med 364(6): 524-34
  6. 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
  7. 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

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

  1. Semaka A, et al. 2013. "Grasping the grey": patient understanding and interpretation of an intermediate allele predictive test result for Huntington disease. J Genet Couns 22(2): 200-17
  2. Sivell S, et al. 2008. How risk is perceived, constructed and interpreted by clients in clinical genetics, and the effects on decision making: systematic review. J Genet Couns 17(1): 30-63
  3. Bloss CS, et al. 2011. Effect of direct-to-consumer genomewide profiling to assess disease risk. N Engl J Med 364(6): 524-34

What behavioural changes are observed from genomic disclosure?

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.1 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.2 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.

Another worthy observation in the same study was the potential influence of genomic test results on smoking. The authors noticed that nearly half of the participants in the study who were smokers (~ 6% of the studied population) reduced or quit smoking post-testing, and that those who ceased smoking comprised the majority.2 This finding is in contrast to past data that showed that genetic testing was not associated with smoking cessation.3-5 In addition, 14% of the Bloss et al. (2011) study subjects reported a change in their use of alcohol, the majority reporting a decreased use or an end to the use of alcohol.

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.2

  1. Sivell S, et al. 2008. How risk is perceived, constructed and interpreted by clients in clinical genetics, and the effects on decision making: systematic review. J Genet Couns 17(1): 30-63
  2. Bloss CS, et al. 2011. Effect of direct-to-consumer genomewide profiling to assess disease risk. N Engl J Med 364(6): 524-34
  3. Lerman C, et al. 1997. Incorporating biomarkers of exposure and genetic susceptibility into smoking cessation treatment: effects on smoking-related cognitions, emotions, and behavior change. Health Psychol 16(1): 87-99
  4. Marteau TM, et al. 2010. Effects of communicating DNA-based disease risk estimates on risk-reducing behaviours. Cochrane Database Syst Rev (10): CD007275
  5. McBride CM, et al. 2002. Incorporating genetic susceptibility feedback into a smoking cessation program for African-American smokers with low income. Cancer Epidemiol Biomarkers Prev 11(6): 521-8

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 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.3-6 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.7

 

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.8 Thus claims that personal risk information can be provided for common complex diseases are not supported by current science.7

 

Merogenomics Inc. 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.

 

  1. Francke U, et al. 2013. Dealing with the unexpected: consumer responses to direct-access BRCA mutation testing. PeerJ 1: e8
  2. Yang Y, et al. 2013. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med 369(16): 1502-11
  3. 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
  4. Paynter NP, et al. 2010. Association between a literature-based genetic risk score and cardiovascular events in women. JAMA 303(7): 631-7
  5. 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
  6. Voight BF, et al. 2010. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet 42(7): 579-89
  7. Weaver M and Pollin TI 2012. Direct-to-Consumer genetic testing: what are we talking about? J Genet Couns 21(3): 361-6
  8. Ng PC, et al. 2009. An agenda for personalized medicine. Nature 461(7265): 724-6

Action taken after genome sequencing results

After receiving genome sequence information, the client should 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.

Insurance for genome sequencing: availability and discrimination

Two issues associated with genome sequencing involve health insurance: (i) is insurance coverage available for genome sequencing? (ii) 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

 

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.1,3

 

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. For example, if a relevant pathogenic mutation is discovered in an individual and such information is communicated within the family, relatives of the tested individual will be obliged to disclose their own genetic risk for a particular condition when applying for insurance. Therefore, risk assessments must be made with appropriate actuarial modeling to avoid potential antidiscrimination charges. 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.4

 

Merogenomics Inc. recommends open dialogue between an interested client and his or her insurance provider prior to genomic sequencing.

 

In the United States, the Centers for Medicare & Medicaid Services (CMS) covers multiple genomic tests; others can be covered if supporting evidence is provided.5 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.

 

  1. Keogh LA and Otlowski MF 2013. Life insurance and genetic test results: a mutation carrier's fight to achieve full cover. Med J Aust 199(5): 363-6
  2. Wilson BJ and Nicholls SG 2015. The Human Genome Project, and recent advances in personalized genomics. Risk Manag Healthc Policy 8: 9-20
  3. Watson M, et al. 2004. Psychosocial impact of breast/ovarian (BRCA1/2) cancer-predictive genetic testing in a UK multi-centre clinical cohort. Br J Cancer 91(10): 1787-94
  4. Barlow-Stewart K, et al. 2009. Verification of consumers' experiences and perceptions of genetic discrimination and its impact on utilization of genetic testing. Genet Med 11(3): 193-201
  5. http://www.cdc.gov/genomics/gtesting/tier.htm

 

 

The role of genetic counseling in genome sequencing

Two issues associated with genome sequencing involve health insurance: (i) is insurance coverage available for genome sequencing? (ii) 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

 

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, 3

 

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. For example, if a relevant pathogenic mutation is discovered in an individual and such information is communicated within the family, relatives of the tested individual will be obliged to disclose their own genetic risk for a particular condition when applying for insurance. Therefore, risk assessments must be made with appropriate actuarial modeling to avoid potential antidiscrimination charges. 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.4

 

Merogenomics Inc. recommends open dialogue between an interested client and his or her insurance provider prior to genomic sequencing.

 

In the United States, the Centers for Medicare & Medicaid Services (CMS) covers multiple genomic tests; others can be covered if supporting evidence is provided.5 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.

 

  1. Keogh LA and Otlowski MF 2013. Life insurance and genetic test results: a mutation carrier's fight to achieve full cover. Med J Aust 199(5): 363-6
  2. Wilson BJ and Nicholls SG 2015. The Human Genome Project, and recent advances in personalized genomics. Risk Manag Healthc Policy 8: 9-20
  3. Watson M, et al. 2004. Psychosocial impact of breast/ovarian (BRCA1/2) cancer-predictive genetic testing in a UK multi-centre clinical cohort. Br J Cancer 91(10): 1787-94
  4. Barlow-Stewart K, et al. 2009. Verification of consumers' experiences and perceptions of genetic discrimination and its impact on utilization of genetic testing. Genet Med 11(3): 193-201
  5. http://www.cdc.gov/genomics/gtesting/tier.htm

The role of genetic counseling in genome sequencing

Merogenomics Inc. 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 a licensed healthcare practitioner authorized by the client to use the information for client’s benefit. Merogenomics Inc. recommends that only the pertinent information contained in the Analysis Report be shared with a doctor. The exception to this rule is if the client seeks a procedure that requires the oversight of a clinical geneticist with access to the whole genome sequence, as in the case of a diagnostic quest.

  

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 will be required to sign a consent form in order to receive the results.