Elective genetic and genomic testing

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Elective genetic and genomic testing are DNA tests performed for an individual who does not have an indication for testing. An elective genetic test analyzes selected sites in the human genome while an elective genomic test analyzes the entire human genome. Some elective genetic and genomic tests require a physician to order the test to ensure that individuals understand the risks and benefits of testing as well as the results. Other DNA-based tests, such as a genealogical DNA test do not require a physician's order. Elective testing is generally not paid for by health insurance companies. With the advent of personalized medicine, [1] also called precision medicine, an increasing number of individuals are undertaking elective genetic and genomic testing.

Contents

History

Genetic testing [2] for a variety of disorders has seen many advances starting with cytogenetics to evaluate human chromosomes for aneuploidy and other chromosome abnormalities. [3] The development of molecular cytogenetics involving techniques such as fluorescence in situ hybridization (FISH) followed, [4] permitting the detection of more subtle changes in the karyotype. [5] [6] Techniques to determine the precise sequence of nucleotides in DNA by DNA sequencing, notably Sanger sequencing was developed in the 1970s. [7] In the 1980s the DNA microarray appeared, permitting laboratories to find copy number variants associated with disease [8] that are below the level of detection of cytogenetics but too large to be detected by DNA sequencing. In recent years the development of high-throughput or next-generation sequencing has dramatically lowered the cost of DNA sequencing permitting laboratories to evaluate all 20,000 genes of the human genome at once through exome sequencing and whole genome sequencing. [9] A catalogue of the many uses of these techniques can be found in the section: genetic testing. Most elective genetic and genomic testing employs either a DNA microarray or next-generation sequencing.

Historically, all laboratory tests were initiated and ordered by a physician or mandated by a state. Increasingly, patients and families have become more involved in their own health care. One outcome has been the growing availability of elective genetic and genomic testing that are initiated by a patient but still ordered by a physician. [10] Additionally, elective genetic and genomic testing that does not require a physician's order called, direct-to-consumer genetic testing has recently entered the testing landscape. [11]

Testing categories

Genetic testing identifies changes in chromosomes, genes, or proteins; some are associated with human disease. There are many different clinical and non-clinical situations in which genetic testing is used. [12]

Diagnostic testing

Diagnostic testing is used to identify or rule out a specific genetic or chromosomal condition when a particular disorder is suspected based on signs and symptoms present in the patient. [13] Catalogues of more than 50,000 tests available worldwide can be found at GeneTests [14] and Genetic Testing Registry. [15]

Predictive and pre-symptomatic testing

Predictive and pre-symptomatic testing is carried out in individuals who do not have evidence of the disease under investigation. This testing includes Mendelian conditions and polygenic diseases. [16]

Carrier testing

Carrier testing is used to identify people who carry one copy of a gene change (also referred to as a variant or mutation) that, when present in two copies, causes a genetic disorder. Carrier testing is typically offered to individuals who are considering pregnancy or are already pregnant, have a family history of a specific genetic disorder and to people in ethnic backgrounds that have an increased risk of specific genetic conditions. [17]

Pre-implantation genetic diagnosis

Pre-implantation genetic diagnosis (PGD) [18] is used in conjunction with in-vitro fertilization. In-vitro fertilization is the process of combining an egg (oocyte) and sperm outside of the body with intent of fertilization. [19] PGD is the testing of individual oocytes or embryos for a known genetic condition prior to transferring the embryo to the uterus. Used together, IVF and PGD allow for selection of embryos or oocytes presumably unaffected with the condition. PGD can be utilized by individuals or couples who are affected by a condition of genetic origin, or if both individuals are found to be carriers of a recessive genetic condition.

Prenatal testing

Prenatal testing is diagnostic testing of a fetus before birth to detect abnormalities in the chromosomes or genes. Samples for this testing are obtained through invasive procedures such as amniocentesis or chorionic villus sampling. [20] Prenatal testing is different from prenatal screening. [21]

Newborn screening

Newborn screening screens infants a few days after birth to evaluate for evidence of treatable diseases. Most newborn screening uses tandem mass spectroscopy [22] to detect biochemical abnormalities that suggest specific disorders. DNA-based newborn testing complements existing newborn screening methods and may replace it. [23]

Pharmacogenomic testing

Pharmacogenomic tests (also called pharmacogenetics) provide information that can help predict how an individual will respond to a medication. [24] Changes in certain genes affect drug pharmacodynamics (effects on drug receptors) and pharmacokinetics (drug uptake, distribution, and metabolism). Identifying these changes makes it possible to identify patients who are at increased risk for adverse effects from drugs or who are likely to be non-responders. Pharmacogenomic testing allows healthcare providers to tailor therapies by adjusting the dose or drug for an individual patient. [25] [26]

Identity testing

Identity testing is used to establish whether individuals are related to one another. It is commonly used to establish paternity but can be used to establish relatedness in adoption and immigration cases. It is also used in forensics. [27]

Ancestry testing

Ancestry testing (also referred to as genetic genealogy) allows individuals to establish their country of origin and ethnic background and identify distant relatives and ancestors. [28]

Trait testing

Some phenotypic traits in humans have a well established genetic basis, while others involve many genes or are a complex mix of genes and environment. [29]

Technologies

There are many different types of genetic testing that exist. Each is designed to look at different types of genetic changes that can occur. At present, no single genetic test can detect all types of genetic changes.

DNA sequencing

DNA sequencing is a method of testing that looks for single letter changes (single-nucleotide polymorphisms) in the genetic code. It can also determine when a small number of letters are missing (deletions) or extra (duplications). Sequencing may be performed on a single gene, a group of genes (panel testing), most of the coding region or exons (whole exome sequencing), or most of the genome (whole genome sequencing). With time, this technology is expected to be able to detect any abnormality of the human genome. [30]

Genotyping

Genotyping is testing that looks at specific variants in a particular area of the genetic code. This technology is limited only to those specific variants that the test is designed to detect. SNP genotyping is a specific form of genotyping. [31]

Deletion/duplication testing

Deletion/duplication testing is a type of testing designed to detect larger areas of the genetic code that are missing or extra. [32] This technology does not detect single letter variants or very small deletions or duplications. [33]

Panel testing

Panel testing refers to testing for a specific subset of genes most often related to a particular condition. This usually involves sequencing and may also include deletion/duplication analysis. This is often referred to as multigene panel testing because testing simultaneously examines a number of different genes. For example, an individual may have panel testing for a group of genes known to be associated with a particular type of cancer such hereditary colon cancer or hereditary breast and ovarian cancer. [34]

Array or microarrays

Array or DNA microarrays look at copy number changes (missing or extra genetic material). [8] This testing looks across a large portion of the genome for larger deletions or duplications (also referred to as copy number variation). This technology can not detect single letter changes or very small deletions or duplications.

Chromosome analysis/karyotype

Chromosome analysis, also known as karyotyping refers to testing that assesses whether the expected number of chromosomes are present, whether there is any rearrangement of the chromosomes, and also whether there are any large deletions or duplications. This technology can not detect single letter changes (single nucleotide variants) or small deletions or duplications. [35]

Noninvasive prenatal screening (NIPT) using cell-free fetal DNA

Non-invasive prenatal screening screens for specific chromosomal abnormalities such as Down Syndrome in a fetus using cell-free DNA. [36] This screening can also provide information about fetal sex and rhesus (Rh) blood type. A blood sample is drawn from the pregnant mother. This sample contains DNA from the mother and fetus. The amount of fetal DNA is assessed to determine if there is extra fetal genetic material present that may indicate an increased risk that the fetus has Down Syndrome or other selected conditions. As this is a screening test, other diagnostic tests such as amniocentesis or chorionic villus sampling are needed to confirm a diagnosis.

Newborn screening

Newborn screening is a type of testing that assesses risk for certain genetic, endocrine, metabolic disorders, hearing loss and critical congenital heart defects. Each state determines the exact list of conditions that are screened. [37] Early detection, diagnosis, and intervention can prevent death or disability and enable children to reach their full potential. The testing is performed from a few drops of blood collected in the newborn period, often by a heel stick. [38] The exact method of testing may vary but often uses levels of specific analytes present in the blood of the baby. Because this is a screening test, additional testing is often necessary to confirm a diagnosis.

Pros and cons

People choose to have genetic testing for many reasons. [39] [40] Testing may be beneficial whether the test identifies a gene change or not. A negative result can eliminate the need for unnecessary checkups and screening tests in some cases. A positive result can direct a person toward available screening, management or treatment options. [41]

Pros

, [42] [43] [44]

Cons

, [42] [43] [44] [45]

Importance of family history

A patient's family history also known as genealogy, can provide important insight into medical conditions within the family. [46] Given that many conditions have a genetic component, gathering an accurate family history can provide important information about an individual's personal risk for many diseases. Healthcare providers can use family history information to assess a patient's risk for disease, recommend testing or screening, suggest diet or other lifestyle habits that may help reduce risk, as well as assess risk of passing conditions on to children. When obtaining a family history, it is helpful to gather health information for the following family members: grandparents, parents, siblings, aunts, uncles and first cousins, and children. In the genetic counseling community this is often referred to as a three generation family history. [47] [48] [49]

Important information to gather about the individuals in the family include:

Some families decide to work together to develop a family history, however, some family members may feel uncomfortable disclosing personal medical information. A number of tools are available to gather family history information. Patients should ask their healthcare provider if their institution has a specific form they prefer to have filled out. The U.S. Surgeon General has created a computerized tool called My Family Health Portrait to help patients create a family medical history.

Ethical issues

Prior to undergoing elective genetic testing, there are many factors that an individual should consider including the scope of testing and potential results in terms of changes to medical management, risk to family members, and impact on legal and financial matters. [50]

Family implications

Genetic discrimination

Many patients are concerned about the possibility of genetic discrimination, the idea that certain individuals or entities would use a patient's genetic information against him or her in order to make employment, insurance policies, or other activities and services difficult or impossible to obtain. In 2008, a new federal law known as the Genetic Information Nondiscrimination Act (GINA) went into effect to help prevent such discrimination. GINA prohibits the use of genetic information to discriminate in health insurance and employment. GINA does not prevent all types of discrimination, however. For companies with fewer than 15 employees, these employment protections do not apply. GINA's protections do not apply to the US military or to federal government employees. Additionally, life, disability, and long-term care insurance policies are not included among GINA's protections. These may still continue to use genetic information to determine one's eligibility for coverage and/or policy premiums. Because of these important exceptions, an individual considering elective genetic testing should discuss the possibility of genetic discrimination with his or her physician or genetic counselor. [53] Some individuals choose to have certain insurance policies in place before undergoing whole genome sequencing so as to prevent future discrimination.

Secondary findings

When undergoing elective genetic testing, patients may expect to receive a variety of different results. In addition to results that may explain a particular symptom or answer a specific question the patient may have had, the scope of elective testing may reveal additional information. These “secondary findings” may include information about increased risk for both treatable and untreatable genetic diseases, carrier status for recessive conditions, and pharmacogenetic information. Most laboratories permit patients and families to decide what types of secondary findings (if any), they would like to receive. [54] It is critical that patients understand the scope of potential results from elective testing and have the opportunity to opt in or out of various results. [55]

Limitations

When considering elective genetic testing, it is important to take into account the type and goals of testing. Providers and patients should be familiar with differing testing methodologies the potential results from each test. For many individuals, factors such as test cost, scope, and deliverables, in combination with their specific clinical questions, play into the decision to undergo elective testing. It is also important to recognize that potential results from elective genetic testing are constrained by the current limits of medical knowledge concerning the association between genetics and human disease. As knowledge of rare genetic factors that confer high risk, as well as common factors that confer lower risks, increases, we will have the ability to learn more about an individual's current and future health. [42] [43] [44] [45]

How do I find a geneticist or genetic counselor?

Due to their advanced training, genetic counselors have a unique set of skills. Their clinical and psychosocial skills are used to help patients understand their genetic risks, determine which tests are most appropriate for their needs, and explain what the possible test results could mean for both the patient and the family. [56] Clinical geneticists often work in tandem with a genetic counselor and play an important role in providing genetic testing, interpreting test results, and explaining the results. [57] Given the ever-increasing number of elective genetic and genomic tests offered and the wide variety of issues raised by these tests (see pros & cons above), discussion with a clinical geneticist or genetic counselor may be helpful. [56] Directories of genetics professionals can be found through the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors.

Future

Elective genetic and genomic testing will continue to evolve as the cost of genetic testing technology falls and patients become increasingly involved in their own health care. The rapid drop in cost of whole exome sequencing and whole genome sequencing in the last five years has resulted in the initiation of several large scale sequencing studies that are systematically evaluating the benefits and limitations of elective genetic and genomic testing. [58] [59] [60] Many of these studies have specifically focused on healthy individuals pursuing elective WES or WGS.

Other driving forces in the adoption of this type of testing include continued social empowerment of patients regarding their own health care and increasing private and government funded sequencing projects focused on better understanding the biological, environment, and behavioral factors that drive common disease with the hope of developing more effective ways to treat and manage disease. The Million Veteran Program is one example of a government funded project aimed at collecting data from veterans using questionnaires, health record information, and blood samples for testing, including genetic testing. [61] Aimed at recruiting 1 million or more Americans to participate in the research cohort, The Precision Medicine Initiative will have a large impact on public awareness of precision medicine and the importance of using genetic information to treat and manage disease as well as optimize health. [62] While elective testing is typically not paid for by health insurance companies, this may change as clinical utility continues to be demonstrated.

Future applications for elective genetic and genomic testing may include:

See also

Related Research Articles

<span class="mw-page-title-main">Human genome</span> Complete set of nucleic acid sequences for humans

The human genome is a complete set of nucleic acid sequences for humans, encoded as DNA within the 23 chromosome pairs in cell nuclei and in a small DNA molecule found within individual mitochondria. These are usually treated separately as the nuclear genome and the mitochondrial genome. Human genomes include both protein-coding DNA sequences and various types of DNA that does not encode proteins. The latter is a diverse category that includes DNA coding for non-translated RNA, such as that for ribosomal RNA, transfer RNA, ribozymes, small nuclear RNAs, and several types of regulatory RNAs. It also includes promoters and their associated gene-regulatory elements, DNA playing structural and replicatory roles, such as scaffolding regions, telomeres, centromeres, and origins of replication, plus large numbers of transposable elements, inserted viral DNA, non-functional pseudogenes and simple, highly repetitive sequences. Introns make up a large percentage of non-coding DNA. Some of this non-coding DNA is non-functional junk DNA, such as pseudogenes, but there is no firm consensus on the total amount of junk DNA.

<span class="mw-page-title-main">Genetic counseling</span> Advising those affected by or at risk of genetic disorders

Genetic counseling is the process of investigating individuals and families affected by or at risk of genetic disorders to help them understand and adapt to the medical, psychological and familial implications of genetic contributions to disease. This field is considered necessary for the implementation of genomic medicine. The process integrates:

<span class="mw-page-title-main">Genetic testing</span> Medical test

Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or through biochemical analysis to measure specific protein output. In a medical setting, genetic testing can be used to diagnose or rule out suspected genetic disorders, predict risks for specific conditions, or gain information that can be used to customize medical treatments based on an individual's genetic makeup. Genetic testing can also be used to determine biological relatives, such as a child's biological parentage through DNA paternity testing, or be used to broadly predict an individual's ancestry. Genetic testing of plants and animals can be used for similar reasons as in humans, to gain information used for selective breeding, or for efforts to boost genetic diversity in endangered populations.

<span class="mw-page-title-main">Prenatal testing</span> Testing for diseases or conditions in a fetus

Prenatal testing is a tool that can be used to detect some birth defects at various stages prior to birth. Prenatal testing consists of prenatal screening and prenatal diagnosis, which are aspects of prenatal care that focus on detecting problems with the pregnancy as early as possible. These may be anatomic and physiologic problems with the health of the zygote, embryo, or fetus, either before gestation even starts or as early in gestation as practicable. Screening can detect problems such as neural tube defects, chromosome abnormalities, and gene mutations that would lead to genetic disorders and birth defects, such as spina bifida, cleft palate, Down syndrome, trisomy 18, Tay–Sachs disease, sickle cell anemia, thalassemia, cystic fibrosis, muscular dystrophy, and fragile X syndrome. Some tests are designed to discover problems which primarily affect the health of the mother, such as PAPP-A to detect pre-eclampsia or glucose tolerance tests to diagnose gestational diabetes. Screening can also detect anatomical defects such as hydrocephalus, anencephaly, heart defects, and amniotic band syndrome.

<span class="mw-page-title-main">Personalized medicine</span> Medical model that tailors medical practices to the individual patient

Personalized medicine, also referred to as precision medicine, is a medical model that separates people into different groups—with medical decisions, practices, interventions and/or products being tailored to the individual patient based on their predicted response or risk of disease. The terms personalized medicine, precision medicine, stratified medicine and P4 medicine are used interchangeably to describe this concept though some authors and organisations use these expressions separately to indicate particular nuances.

<span class="mw-page-title-main">Medical genetics</span> Medicine focused on hereditary disorders

Medical genetics is the branch of medicine that involves the diagnosis and management of hereditary disorders. Medical genetics differs from human genetics in that human genetics is a field of scientific research that may or may not apply to medicine, while medical genetics refers to the application of genetics to medical care. For example, research on the causes and inheritance of genetic disorders would be considered within both human genetics and medical genetics, while the diagnosis, management, and counselling people with genetic disorders would be considered part of medical genetics.

Predictive medicine is a field of medicine that entails predicting the probability of disease and instituting preventive measures in order to either prevent the disease altogether or significantly decrease its impact upon the patient.

Public health genomics is the use of genomics information to benefit public health. This is visualized as more effective preventive care and disease treatments with better specificity, tailored to the genetic makeup of each patient. According to the Centers for Disease Control and Prevention (U.S.), Public Health genomics is an emerging field of study that assesses the impact of genes and their interaction with behavior, diet and the environment on the population's health.

Personal genomics or consumer genetics is the branch of genomics concerned with the sequencing, analysis and interpretation of the genome of an individual. The genotyping stage employs different techniques, including single-nucleotide polymorphism (SNP) analysis chips, or partial or full genome sequencing. Once the genotypes are known, the individual's variations can be compared with the published literature to determine likelihood of trait expression, ancestry inference and disease risk.

<span class="mw-page-title-main">Whole genome sequencing</span> Determining nearly the entirety of the DNA sequence of an organisms genome at a single time

Whole genome sequencing (WGS), also known as full genome sequencing, complete genome sequencing, or entire genome sequencing, is the process of determining the entirety, or nearly the entirety, of the DNA sequence of an organism's genome at a single time. This entails sequencing all of an organism's chromosomal DNA as well as DNA contained in the mitochondria and, for plants, in the chloroplast.

The exome is composed of all of the exons within the genome, the sequences which, when transcribed, remain within the mature RNA after introns are removed by RNA splicing. This includes untranslated regions of messenger RNA (mRNA), and coding regions. Exome sequencing has proven to be an efficient method of determining the genetic basis of more than two dozen Mendelian or single gene disorders.

Genomic counseling is the process by which a person gets informed about his or her genome often in the setting of elective genetic and genomic testing. In contrast to genetic counseling, which focuses on Mendelian diseases and typically involves person-to-person communication with a genetic counselor or other medical genetics expert, genomic counseling is not limited to currently clinically relevant information. It is often based on genomic information that is of interest for the informed person, such as increased risk for common complex disease that has actionable components, genetically determined non-disease related traits, or recreational forms of information and genetic genealogy data. An individual's response to certain medications/drugs based on their pharmacogenomic profile may be provided.

<span class="mw-page-title-main">Exome sequencing</span> Sequencing of all the exons of a genome

Exome sequencing, also known as whole exome sequencing (WES), is a genomic technique for sequencing all of the protein-coding regions of genes in a genome. It consists of two steps: the first step is to select only the subset of DNA that encodes proteins. These regions are known as exons—humans have about 180,000 exons, constituting about 1% of the human genome, or approximately 30 million base pairs. The second step is to sequence the exonic DNA using any high-throughput DNA sequencing technology.

<span class="mw-page-title-main">Robert C. Green</span> American geneticist

Robert C. Green is an American medical geneticist, physician, and public health researcher. He directs the Genomes2People Research Program in translational genomics and health outcomes in the Division of Genetics at Brigham and Women's Hospital and the Broad Institute, and is Director of the Preventive Genomics Clinic at Brigham and Women's Hospital. Research led by Green includes clinical and research aspects of genomic and precision medicine, including the development and disclosure of Alzheimer's disease risk estimates and one of the first prospective studies of direct-to-consumer genetic testing services. He has studied the implementation of medical sequencing in healthy adults, newborns, and active duty military personnel. As of 2020, he is leading the first research collaboration to explore return of genomic results and better understand penetrance in a population-based cohort of underrepresented minorities. He has led the Preventive Genomics Clinic at Brigham and Women's Hospital since its creation in 2019.

Cell-free fetal DNA (cffDNA) is fetal DNA that circulates freely in the maternal blood. Maternal blood is sampled by venipuncture. Analysis of cffDNA is a method of non-invasive prenatal diagnosis frequently ordered for pregnant women of advanced maternal age. Two hours after delivery, cffDNA is no longer detectable in maternal blood.

<span class="mw-page-title-main">Molecular diagnostics</span> Collection of techniques used to analyze biological markers in the genome and proteome

Molecular diagnostics is a collection of techniques used to analyze biological markers in the genome and proteome, and how their cells express their genes as proteins, applying molecular biology to medical testing. In medicine the technique is used to diagnose and monitor disease, detect risk, and decide which therapies will work best for individual patients, and in agricultural biosecurity similarly to monitor crop- and livestock disease, estimate risk, and decide what quarantine measures must be taken.

A variant of uncertainsignificance (VUS) is a genetic variant that has been identified through genetic testing but whose significance to the function or health of an organism is not known. Two related terms are "gene of uncertain significance" (GUS), which refers to a gene that has been identified through genome sequencing but whose connection to a human disease has not been established, and "insignificant mutation", referring to a gene variant that has no impact on the health or function of an organism. The term "variant' is favored in clinical practice over "mutation" because it can be used to describe an allele more precisely. When the variant has no impact on health, it is called a "benign variant". When it is associated with a disease, it is called a "pathogenic variant". A "pharmacogenomic variant" has an effect only when an individual takes a particular drug and therefore is neither benign nor pathogenic.

Personalized onco-genomics (POG) is the field of oncology and genomics that is focused on using whole genome analysis to make personalized clinical treatment decisions. The program was devised at British Columbia's BC Cancer Agency and is currently being led by Marco Marra and Janessa Laskin. Genome instability has been identified as one of the underlying hallmarks of cancer. The genetic diversity of cancer cells promotes multiple other cancer hallmark functions that help them survive in their microenvironment and eventually metastasise. The pronounced genomic heterogeneity of tumours has led researchers to develop an approach that assesses each individual's cancer to identify targeted therapies that can halt cancer growth. Identification of these "drivers" and corresponding medications used to possibly halt these pathways are important in cancer treatment.

Personalized genomics is the human genetics-derived study of analyzing and interpreting individualized genetic information by genome sequencing to identify genetic variations compared to the library of known sequences. International genetics communities have spared no effort from the past and have gradually cooperated to prosecute research projects to determine DNA sequences of the human genome using DNA sequencing techniques. The methods that are the most commonly used are whole exome sequencing and whole genome sequencing. Both approaches are used to identify genetic variations. Genome sequencing became more cost-effective over time, and made it applicable in the medical field, allowing scientists to understand which genes are attributed to specific diseases.

Dame Lyn Susan Chitty is a British physician and Professor of Genetics and Fetal Medicine at University College London. She is the deputy director of the National Institute for Health and Care Research Great Ormond Street Hospital Biomedical Research Centre. She is the 2022 president of the International Society for Prenatal Diagnosis. Her research considers non-invasive prenatal diagnostics. She was made a Dame in the 2022 New Year Honours.

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