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There is limited data on the utility, yield, and cost efficiency of genetic testing in adults with epilepsy. We aimed to describe the yield and utility of genetic panels in our adult epilepsy clinic.
We performed a retrospective, cross-sectional study of all patients followed by an epileptologist at a Canadian tertiary care centre’s epilepsy clinic between January 2016 and August 2021 for whom a genetic panel was ordered. A panel was generally ordered when the etiology was unknown or in the presence of a malformation of cortical development. We determined the yield of panel positivity and of confirmed genetic diagnoses. We also estimated the proportion of these diagnoses that were clinically actionable.
In total, 164 panels were ordered in 164 patients. Most had refractory epilepsy (80%), and few had comorbid intellectual disability (10%) or a positive family history of epilepsy (11%). The yield of panel positivity was 11%. Panel results were uncertain 49% of the time and negative 40% of the time. Genetic diagnoses were confirmed in 7 (4.3%) patients. These genetic conditions involved the following genes: SCARB2, DEPDC5, PCDH19, LGI1, SCN1A, MT-TL1, and CHRNA7. Of the seven genetic diagnoses, 5 (71%) were evaluated to be clinically actionable.
We report a lower diagnostic yield for genetic panels in adults with epilepsy than what has so far been reported. Although the field of the genetics of epilepsy is a fast-moving one and more data is required, our findings suggest that guidelines for genetic testing in adults are warranted.
When individuals sign on to a DNA ancestry test, they understand that the company will undertake an analysis of certain segments of their genome, called ancestry information markers (AIMs). These segments can, under proper analysis, reveal their genetic descent from certain regions of the world.
Over a period of 20 years, family genetic genealogy, through the purchase of consumer ancestry testing kits, has been one of the fastest growing family activities of this generation. Citing data from the International Society of Genetic Genealogy, the Washington Post reported in 2017 that eight million people worldwide were involved with recreational genomics. It is estimated that by 2019 about 25 million people had signed up for a DNA ancestry test offered by one of the dozens of companies that have entered this marketplace. The kits are sent to a person’s home with return packaging that includes a reservoir for depositing saliva or swabs for sampling cheek cells. The MITTechnology Review predicted that by 2021 there would be 100 million consumers of ancestry DNA services.
Most human genetic diversity is found within populations rather than between populations. Scientists have reported that any two individuals within a particular population are as different genetically as any two people selected from any two populations in the world. Given this finding, how can science use a small percentage of genetic diversity between populations as markers of ancestral origins?
Much of recreational DNA ancestry offers consumers a long reach into the history of their descent by discovering which biogeographical population most closely matches their DNA profiles. The science and DNA analytics provide probability estimates that their DNA markers (ancestry informative markers, or AIMs) are most likely from a particular continent or even a specific country. But DNA ancestry tests have applications that go well beyond recreational genealogy. Even prior to the growth of this sector of direct-to-consumer testing, DNA was used to determine paternity and to establish identity in criminal investigations. An important and largely unintended application of ancestry DNA testing has been the uncovering of family secrets: “Why does my father look so different from his parents?” or “Why are my mother’s skin tones so much darker than those of her parents?”
As we noted previously, the science behind DNA ancestry requires that one compares the unique genetic markers on the consumer’s DNA sample with the frequency of those markers in reference panels representing different regions of the world. When the field of DNA ancestry began, it was a scientific project that involved the search for biogeographical DNA. Scientists could use changes in the human genome to determine how ancient populations moved around the globe. The further populations moved across the globe and the more time elapsed (many thousands of years), the greater the number of mutations or genetic variants. Genetic ancestry began with a half-dozen distinct continental regions and with markers called hypervariable microsatellites, or short tandem repeats (STRs) of DNA, 2–6 base pairs in length. These microsatellites were considered ideal at the time because they had a high heterozygosity, which means two different alleles at a site. A site that has an AA is homozygous, whereas one that has AG is heterozygous. The more diverse the alleles, the greater the chance of distinguishing allele frequencies among populations. Initially, scientists used changes in the maternally inherited mitochondrial DNA (mtDNA) and the paternally inherited Y chromosome. That changed when autosomal markers were chosen for ancestry analysis.
In order to locate people’s ancestry to a region of the world through their DNA, the markers on their DNA sample have to be compared to population reference panels for the regions that form part of the comparison group. These ancestry inference methods have served medical research, forensic science, and commercial popular genealogical interests. According to Santo et al., the reliability of any ancestry inference depends on the existence of reliable population reference databases. Many researchers and ancestry DNA companies utilize different sources for population data on different countries. For example, ALFRED is an allele frequency database supported by the Yale Center for Medical Informatics, which has genomic data from population samples across the globe. You can enter the name of a country or population group, such as Siberian Yupik (the sample was collected from unrelated Siberian Yupiks from northeastern Siberia, Russia) and it will provide information on the number of people (29) and/or chromosomes sampled (58).
The criminal justice system began using DNA to solve crimes in the 1980s, after a geneticist from the University of Leicester in the UK developed a method for sequencing certain segments of chromosomal DNA. Those segments, called short tandem repeats (STRs), were expressed differently in different people, in contrast to the 99.9 percent of our DNA that is the same, and thus could be used to establish an indicator of personal identity (see Chapter 1).
As a recreational activity, with no serious consequences at stake, it barely matters whether the results consumers receive from their DNA ancestry tests accurately represent the percentages of their ancestry from different geographical regions. Given that there are no international standards for such testing, unlike genetic disease tests, it is not surprising that the results from different ancestry testing companies vary. As noted in Chapter 4, there are several stages in the analysis of a person’s saliva or cheek swabs where the criteria, reference frames, or analytics can vary among companies, yielding different outcomes.
When you purchase a DNA ancestry service you are sent a kit containing instructions for submitting a DNA sample. Most companies provide a plastic tube, which they ask the test-taker to fill with saliva or cheek swabs, seal, and return. When the company receives your DNA test sample it is processed for analysis. As noted previously, the vast amount of your genome does not distinguish you from other individuals. Therefore, your genome is broken down into segments of DNA that contain the alleles of interest, rather than it being fully sequenced. Here is how AncestryDNA describes the processing of the DNA samples it receives from customers:
[T]o obtain a customer’s ethnicity estimate, we divide the customer’s genome into small windows. For each window we assign a single population to the DNA within that window inherited from each parent, one population for each parental haplotype. Each window gets a population assignment based on how well it matches genomes in the reference panel.
We do not know the exact haplotype boundaries, which differ between people, but we can achieve a good approximation by dividing the genome into 1,001 small windows. Each window covers one section of a single chromosome and is small enough (e.g., 3–10 centimorgans) that both the maternal and paternal haplotype, the DNA from Mom and the DNA from Dad, in a given window are likely to each come from a single, though not necessarily the same, population.
By this point in the book, we have explored multiple perspectives of DNA ancestry testing, beginning with its commercial success as a consumer recreational activity, its serious scientific foundations in population genetics, its applications in criminal investigations, and its social and ethical consequences in searching for one’s identity.
If human populations in different geographical regions can be identified by DNA, while the vast amount of human DNA is identical, then, in the regions or places on the genome that are variable, there must be markers that reveal biogeographical regions of origin. DNA polymorphisms (letter changes in the nucleotides) are currently the choice markers because most human polymorphisms are characterized by alleles that are unevenly distributed among the world’s distinct populations.
Stories of family deceits and deceptions have become commonplace in a media receptive to personal tales of triumph and tragedy. A distinguished geneticist learns in his mature years that his mother, while married to his legal father, had a secret affair that begat him. A best-selling author discovers that her paternal DNA was from a medical student serving as a sperm donor and not her legal father, who traced her ancestry deep into Eastern Europe. A woman who, as a newborn, was left in a bag abandoned in the foyer of a Brooklyn apartment building searches for her biological parents 23 years later. These revelations are the result of the millennial DNA ancestry revolution.
DNA ancestry companies generate revenues in the region of $1bn a year, and the company 23andMe is said to have sold 10 million DNA ancestry kits to date. Although evidently popular, the science behind how DNA ancestry tests work is mystifying and difficult for the general public to interpret and understand. In this accessible and engaging book, Sheldon Krimsky, a leading researcher, investigates the methods that different companies use for DNA ancestry testing. He also discusses what the tests are used for, from their application in criminal investigations to discovering missing relatives. With a lack of transparency from companies in sharing their data, absent validation of methods by independent scientists, and currently no agreed-upon standards of accuracy, this book also examines the ethical issues behind genetic genealogy testing, including concerns surrounding data privacy and security. It demystifies the art and science of DNA ancestry testing for the general reader.
The purpose of DNA ancestry genealogy is to determine what the geographical origins are of an individual’s ancestry, regardless of where he or she is currently living. The scientific premise behind this exercise is that people’s DNA contains sequences of their ancestors’ DNA, which can be traced back hundreds or even thousands of years, and that their ancestors were settled in a region of the world that remained relatively isolated. This isolation allowed ancient populations to remain inbred within certain geographical parameters. Inbreeding is the mating of humans closely related by ancestry. It is more likely to occur in isolated, non-migrating populations, resulting in a loss of genetic diversity and a high incidence of birth defects. Mutations in the DNA circulating within these inbred populations can provide a genetic fingerprint of the geographical region in which they were located.
In 2017, personal genetics company 23andMe announced that it had received FDA approval to provide people with their apolipoprotein E (APOE) genotype and nine other genes linked with health risks. The APOE gene is associated with late-onset Alzheimer’s disease (AD), the leading cause of dementia. In this chapter, I argue that APOE testing is of limited clinical significance given the present lack of disease-modifying therapies for AD and the fact that preventive measures are the same regardless of an individual’s APOE status. Nevertheless, an APOE result can have great personal and legal significance to individuals–for instance, influencing decision-making around insurance, employment, end-of-life care. One way to reconcile the obvious tension between paternalism and the individual’s right to know their genetic risk for late-onset AD is to provide genetic information in the context of robust information about the personal and legal ramifications of the result. This, I argue, is an area were 23andMe and other DTC genetic testing companies fall short.
As genetic sequencing technologies become faster, cheaper, and more informative, they are making their way into many different facets of our lives. We are becoming accustomed to using and sharing our own genetic information, whether it be to investigate ancestry, further medical research, detect diseases, establish paternity, or to inform our reproductive choices. It will not be long before the genetic information of others, public figures in particular, becomes a subject of public discussion. The media will be there to capitalize on this interest, and it might well be only a matter of time before genetic disclosures are published alongside candid photographs of celebrities on tabloid pages. Should such predictions come to pass, genetic paparazzi with swabs and sterile tubes in hand will seek out and analyze discarded genetic materials from the celebrities they pursue, publishing the results, and lawsuits will follow. This chapter provides a current overview of the legal landscape in which genetic paparazzi lawsuits will unfold, including a detailed look at how the proliferation of state genetic privacy laws will intersect with traditional protections afforded to the press.
Genetic testing is well established in many areas of clinical medicine, is increasingly used in clinical psychiatry and it becomes increasingly important to understand the scope and limitations of the different genetic tests applied. The recommended genetic work-up of patients with neurodevelopmental disorders (such as intellectual disability or autism spectrum disorders) includes conventional karyotyping (low resolution) able to detect chromosomal rearrangement and structural variants (>5Mb, 5 million-bp), testing for fragile X-Syndrome, screening for deletions and duplications down to 20 Kb by Comparative Genomic Hybridisation (CGH), able to detect Copy Number Variation (CNVs; gain or loss of genetic material compared to the reference genome). Sanger sequencing is used for mapping of single base pair genetic variants in single genes but unable to identify deletions or duplications. The more advanced Next Generation Sequencing (NGS) have enabled to detect variants in panels of 10-100 (or more) genes, or in all coding regions using Whole Exome Sequencing (WES; 23.000 genes). Whole Genome Sequencing (WGS) analysis enables also the detection of all size range and types of genetic variation including CNVs, trinucleotide repeats and translocations. All this led to an impressive change in interpreting genomic variants that need to be strictly linked to clinical information before it can be used by clinicians to improve diagnosis or care. Bioinformatic tools to annotate variants, predict their effects and select the genes and genomic regions of interest are needed to guide the clinical work followed with careful evaluation of the prioritized variants based on the clinical knowledge (https://www.cost.eu/actions/CA17130/#tabs|Name:overview).
Assuming that all patients are created equal may lead many to suffer prolonged, frustrating, and expensive trial-and-error therapy, in which one treatment after another is attempted in an effort to remedy patients’ maladies. Critics of this traditional kind of care champion a new approach – personalized or precision medicine – in which genomic testing might help us understand and remedy the ravages of rare genetic illnesses as well as energize efforts to treat more common afflictions. After three decades of well-funded research, has personalized medicine measured up to the hype of its ushering in a fresh paradigm for delivering unsurpassed health care? Has it displaced trial-and-error treatment? Or is personalized medicine itself undergoing a trial-and-error process of development and testing? These and other questions must be answered if we are to best deploy limited resources to combat a wide variety of diseases – from individual genetic disorders to devastating pandemics.
To compare the genetic testing results of neonates with CHD by chromosomal microarray to karyotyping and fluorescence in situ hybridisation analysis.
This was a single-centre retrospective comparative study of patients with CHD and available genetic testing results admitted to the cardiac ICU between January, 2004 and December, 2017. Patients from 2004 to 2010 were tested by karyotyping and fluorescence in situ hybridisation analysis, while patients from 2012 to 2017 were analysed by chromosomal microarray.
Eight-hundred and forty-nine neonates with CHD underwent genetic testing, 482 by karyotyping and fluorescence in situ hybridization, and 367 by chromosomal microarray. In the karyotyping and fluorescence in situ hybridisation analysis group, 86/482 (17.8%) had genetic abnormalities detected, while in the chromosomal microarray group, 135/367 (36.8%) had genetic abnormalities detected (p < 0.00001). Of patients with abnormal chromosomal microarray results, 41/135 (30.4%) had genetic abnormality associated with neurodevelopmental disorders that were exclusively identified by chromosomal microarray. Conotruncal abnormalities were the most common diagnosis in both groups, with karyotyping and fluorescence in situ hybridisation analysis detecting genetic abnormalities in 26/160 (16.3%) patients and chromosomal microarray detecting abnormalities in 41/135 (30.4%) patients (p = 0.004). In patients with d-transposition of the great arteries, 0/68 (0%) were found to have genetic abnormalities by karyotyping and fluorescence in situ hybridisation compared to 7/54 (13.0%) by chromosomal microarray.
Chromosomal microarray identified patients with CHD at genetic risk of neurodevelopmental disorders, allowing earlier intervention with multidisciplinary care and more accurate pre-surgical prognostic counselling.