You have your genome or exome (the protein-encoding part) sequenced to help diagnose a puzzling set of symptoms, and something totally unrelated, and unexpected, turns up - a so-called "incidental finding."Surprises, of course, aren't new in medicine. The term "incidental finding" comes from "incidentaloma," coined in 1995 to describe an adrenal tumor found on a scan looking for something else. I had one -- a CT scan of my appendix revealed a polycystic liver. A friend had it much worse. She volunteered to be a control in an Alzheimer's imaging trial, and her scan revealed two brain aneurysms!Geneticists have long expected an avalanche of incidental findings from clinical (exome or genome) sequencing. Researchers from Baylor College of Medicine and NHGRI and elsewhere described several cases at the American Society of Human Genetics annual meeting last fall. My favorites:- A boy had his genome sequenced as part of a project to better diagnose syndromes of developmental delay, intellectual disability, and seizures. Researchers found the aorta weakening of Marfan syndrome, gave the boy a repurposed drug in clinical trials, and he's ok.- A family with several members having their genomes sequenced to evaluate heart disease discovered that their "writer's cramp" is myoclonus dystonia, a neuromuscular disease.- A man had his genome sequenced in a study to investigate atherosclerosis and learned he had a deafness mutation. Although he claimed he had normal hearing, further testing showed he didn't - he'd adapted so well for so long that he hadn't known he was missing a sense.To provide guidelines for clinicians having to disclose a medical surprise, the American College of Medical Genetics and Genomics released much-anticipated recommendations on March 21, to kick off the annual meeting.The most important points come near the end of the 27-page document, especially the table of conditions to be tested for. And while the report is very clear, the accompanying news release uses some fuzzy definitions that often crop up when genetics is simplified. I know from genetic counseling and writing textbooks that misuse of certain terms can confuse. ("Genetic code" for "DNA sequence," and "carrier" in for "pre-symptomatic," when it more traditionally refers to someone who has one recessive allele, and no corresponding illness or trait.) News aggregators that boil down news releases may miss such nuances.So here are 12 major points I've distilled from the report.1. Labs doing clinical sequencing should test for well-studied mutations in 57 genes that cause or can theoretically cause disease. The mutations are fairly common, albeit among the rare - I've seen 3 in patients just this week. Most are "actionable," some even life-saving. Certain heart conditions and malignant hyperthermia, for example, can cause a first (and last) symptom of sudden death when a person takes a certain drug. A good thing to know.2. The list of 57 doesn't really mean 57 illnesses, from a patient's point of view. Tumor/cancer syndromes account for 25 of the 57, cardiovascular problems 23, and mutations in seven genes cause Marfan and related syndromes. Add the two lone conditions (a type of Ehlers-Danlos syndrome and malignant hyperthermia) and the list collapses to 5 to a patient.3. Of people having clinical sequencing, 1-2% are expected to have one of the 57 mutations. Technically, these aren't incidental findings, because they aren't found by accident, like my cystic liver - labs are looking for them. But that's ok. Just semantics.4. We don't know if the 57 variants that may cause disease in families who are having clinical sequencing to evaluate symptoms may do so in others. Due to effects of other genes and the environment, a mutation that causes a disease in one person may not in another.5. Clinical sequencing is not the sort of testing that some direct-to-consumer (DTC) companies offer. At the present time, for example, 23andMe's $99 test for 247 illnesses and traits include carrier tests that would already be part of a diagnostic work-up based on symptoms, family history, or newborn screening; and risks based on genetic marker (SNP) patterns that may or may not predict anything about the person sending in spit, due to population differences between the spitter and the study on which the test is based. DTC tests in their current incarnation are informational, not diagnostic.6. Patients and their families won't be able to "opt-out" of knowing about the big 57, unless they refuse clinical sequencing. "Duty to warn" trumps patient autonomy.7. Kids count, contrary to precedent. Huntington disease set the pattern here - people under age 18 with an affected parent are generally not tested to see if they will develop HD 20 years later, because there's no treatment. But for the clinical sequencing guidelines, informing parents and even children is okay, because so many of the conditions can be prevented, treated, or risk reduced with lifestyle choices, even if an illness such as cancer won't start for many years.8. A negative result doesn't assure health. I'm thinking of Bruce Springsteen's "57 Channels (And Nothin' On)." Finding nothing on the 57 tests doesn't mean you're healthy or will stay that way. A person who has normal BRCA genes, for example, can still develop breast cancer from other genes going haywire. And sequencing won't spot missing, extra, or moved DNA; unusual mutations; or those lurking in genome regions with light sequencing coverage. (See "The Battle of the Prenatal Tests")9. Genetic counseling. Clinicians should provide it or refer for it - before and after testing. To help, ACMG will soon release informed consent guidelines for clinical sequencing. But physicians-in-training still get woefully little training in genetics and genomics.10. Genetic testing and sequencing are on a collision course, with mutation databases from patients edging toward the rapidly-growing databases from healthy people sending samples to DTC companies. (23andMe expects a million submissions by year's end.) But this convergence will be to everyone's benefit, I think. With all of these data, in a few years we'll know what the variations in the human genome, point by point, actually mean.11. Price is driving clinical sequencing. It's already cheaper to do a whole exome than to sequence a "big chunky" gene and all of its known mutations.If Amazon offered you a dozen books for the price of one, wouldn't you take it?12. Finally, at the end of the recommendations come some interesting terms that capture the disconnect I've long noticed between those of us who are more hesitant about sequencing and its enthusiasts: the "genetic empiricist" versus the "genetic libertarian".I've been an empiricist, against genetic testing when the info may be ambiguous because we don't yet know enough. A report in this week's Proceedings of the National Academy of Sciences from Yuval Itan and colleagues at Rockefeller University takes a major step in providing this needed context. They introduce the human gene connectome, a computational way to sort out gene-gene interactions that will be vital for making sense of genome information. Does a mutation in one gene protect against another? Imagine finding out you have a 3-fold increased risk of Alzheimer's, before researchers discover a protective variant that you also have?I still fear that too casual an approach to testing - like urging people to give spit kits for Christmas -- could create a population of Woody Allen-like hypochondriacs who overtax the health care system and take too many not-without-risk tests. Others will be falsely reassured.We genetic empiricists want evidence that a testing outcome is beneficial, that it "does no harm." That's still not known for all genetic tests.In contrast, "genetic libertarians" believe that everyone has the right to know everything. From responses to my blog posts, testimonials at the 23andMe website, and the streams of popular articles and books by people having their exomes/genomes "done," the genetic libertarians seem to far outnumber the genetic empiricists. Or at least they're more vocal.The new guidelines on clinical DNA sequencing present a starting point for handling what our genomes are telling us, focusing first on revelations that we can do something with, under the care of trained medical professionals. So by the time that devices the size of a dorm fridge are sequencing patients' DNA and spitting out risks, diagnoses, and suggested courses of action in the average internist's office, we'll be able to make the most of the information in our genomes. Follow Scientific American on Twitter @SciAm and @SciamBlogs.Visit ScientificAmerican.com for the latest in science, health and technology news. 2013 ScientificAmerican.com. All rights reserved.
Visit link:
Incidental Findings from Genome Sequencing Nuances and Caveats
- The complete plastome sequences of invasive weed Parthenium hysterophorus: genome organization, evolutionary ... - Nature.com - February 18th, 2024 [February 18th, 2024]
- Multi-omic profiling reveals associations between the gut microbiome, host genome and transcriptome in patients with ... - Journal of Translational... - February 18th, 2024 [February 18th, 2024]
- Polymerase Chain Reaction (PCR) - National Human Genome Research Institute - February 18th, 2024 [February 18th, 2024]
- Genomic Time Machine Reveals Secrets of Human DNA - SciTechDaily - February 18th, 2024 [February 18th, 2024]
- 1 Million Unannotated Exons Discovered in the Human Genome - Technology Networks - February 18th, 2024 [February 18th, 2024]
- Hope for the night parrot: bird's full genome has been sequenced - Cosmos - February 18th, 2024 [February 18th, 2024]
- RevIT AAV Enhancer: Rev-up AAV genome production in upstream manufacturing - BioProcess Insider - February 18th, 2024 [February 18th, 2024]
- Multi-omics resources for the Australian southern stuttering frog (Mixophyes australis) reveal assorted antimicrobial ... - Nature.com - February 18th, 2024 [February 18th, 2024]
- Large-scale gene expression alterations introduced by structural variation drive morphotype diversification in Brassica ... - Nature.com - February 18th, 2024 [February 18th, 2024]
- Near-gapless and haplotype-resolved apple genomes provide insights into the genetic basis of rootstock-induced ... - Nature.com - February 18th, 2024 [February 18th, 2024]
- Secrets of Night Parrot unlocked after first genome sequenced - CSIRO - February 18th, 2024 [February 18th, 2024]
- CRISPR gene editing tool gets a revolutionary high-tech upgrade - Earth.com - February 18th, 2024 [February 18th, 2024]
- Ancient retroviruses played a key role in the evolution of vertebrate brains - EurekAlert - February 18th, 2024 [February 18th, 2024]
- Natural selection and genetic diversity maintenance in a parasitic wasp during continuous biological control application - Nature.com - February 18th, 2024 [February 18th, 2024]
- Hopes elusive parrots genome will provide answers - news.com.au - February 18th, 2024 [February 18th, 2024]
- MicroRNA is the master regulator of the genome researchers are learning how to treat disease by harnessing the ... - The Conversation - November 30th, 2023 [November 30th, 2023]
- "Ground-Breaking" Release of World's Largest Whole Genome Resource - Inside Precision Medicine - November 30th, 2023 [November 30th, 2023]
- Pangenome analysis reveals genomic variations associated with domestication traits in broomcorn millet - Nature.com - November 30th, 2023 [November 30th, 2023]
- Global genetic diversity, introgression, and evolutionary adaptation of indicine cattle revealed by whole genome ... - Nature.com - November 30th, 2023 [November 30th, 2023]
- Genome characteristics of atypical porcine pestivirus from abortion cases in Shandong Province, China - Virology Journal - Virology Journal - November 30th, 2023 [November 30th, 2023]
- Correcting modification-mediated errors in nanopore sequencing by nucleotide demodification and reference-based ... - Nature.com - November 30th, 2023 [November 30th, 2023]
- CRISPR-Based "Genome Shredding" Technique Shows Promise in Treating Glioblastoma - Inside Precision Medicine - November 30th, 2023 [November 30th, 2023]
- Genome wide analysis revealed conserved domains involved in the effector discrimination of bacterial type VI secretion ... - Nature.com - November 30th, 2023 [November 30th, 2023]
- TRISH to investigate the effects of spaceflight on the human genome, central nervous system - Odessa American - November 30th, 2023 [November 30th, 2023]
- The venom preceded the stinger: Genomic studies shed light on the origins of bee venom - EurekAlert - November 30th, 2023 [November 30th, 2023]
- Integrating genomic and multiomic data for Angelica sinensis provides insights into the evolution and biosynthesis of ... - Nature.com - November 30th, 2023 [November 30th, 2023]
- Genetic diversity and ancestry of the Khmuic-speaking ethnic groups ... - Nature.com - September 21st, 2023 [September 21st, 2023]
- Researchers to Apply Genome Analysis to Childhood Cancers; Goal ... - The Japan News - September 21st, 2023 [September 21st, 2023]
- How Bats' Genomes May Help Them Avoid Cancer and Survive ... - Technology Networks - September 21st, 2023 [September 21st, 2023]
- Longitudinal genomic surveillance of carriage and transmission of ... - Nature.com - September 21st, 2023 [September 21st, 2023]
- Whole genomes from bacteria collected at diagnostic units around ... - Nature.com - September 21st, 2023 [September 21st, 2023]
- Genome-wide identification of lncRNA & mRNA for T2DM | PGPM - Dove Medical Press - September 21st, 2023 [September 21st, 2023]
- Tasmanian tiger RNA is first to be recovered from an extinct animal - Nature.com - September 21st, 2023 [September 21st, 2023]
- Loneliness and depression: bidirectional mendelian randomization ... - Nature.com - September 21st, 2023 [September 21st, 2023]
- Rome Therapeutics adds $72 million to Series B round to harness ... - OutSourcing-Pharma.com - September 21st, 2023 [September 21st, 2023]
- Mystery of 'living fossil' tree frozen in time for 66 million years finally ... - Livescience.com - September 21st, 2023 [September 21st, 2023]
- Why the human genome could be healthcares holy grail - Yahoo Finance - May 4th, 2023 [May 4th, 2023]
- Scientists Compare Genomes of 240 Mammals to Understand Human DNA - The New York Times - May 4th, 2023 [May 4th, 2023]
- Genomes From 240 Mammalian Species Help Explain 100 Years Of Evolution And Human Disease - ABP Live - May 4th, 2023 [May 4th, 2023]
- 'Deletions' from the human genome may be what made us human - Yale News - May 4th, 2023 [May 4th, 2023]
- GeneDx Adds Buccal Swab as Non-Invasive Whole Genome ... - GlobeNewswire - May 4th, 2023 [May 4th, 2023]
- Whole-genome sequencing used to track down genes behind familial glioma - Medical Xpress - May 4th, 2023 [May 4th, 2023]
- Wiggly proteins guard the genome: Dynamic network in the pores of ... - Science Daily - May 4th, 2023 [May 4th, 2023]
- Genome-Wide Splicing Quantitative Expression Locus Analysis ... - Cancer Discovery - May 4th, 2023 [May 4th, 2023]
- Digital Genome Market is expand at a CAGR of 8.6% to reach USD ... - Digital Journal - May 4th, 2023 [May 4th, 2023]
- High School Students Learn the Basics of Base Editing to Cure GFP ... - University of California San Diego - May 4th, 2023 [May 4th, 2023]
- Genomic researchers gain access to CSIRO's AI-powered data ... - Microsoft - May 4th, 2023 [May 4th, 2023]
- Archaic hominin traits through the splicing lens - Nature.com - May 4th, 2023 [May 4th, 2023]
- Critical bug in genome sequencing device scores '10' on CVSS ratings - SC Media - May 4th, 2023 [May 4th, 2023]
- Novel Genomic Approach Ensures Better Diagnosis of Hereditary ... - Technology Networks - May 4th, 2023 [May 4th, 2023]
- Intellia Therapeutics: Leading the Way in Revolutionary Genome ... - Best Stocks - May 4th, 2023 [May 4th, 2023]
- Visual tracking of viral infection dynamics reveals the synergistic ... - Nature.com - May 4th, 2023 [May 4th, 2023]
- Genome | Genome LLC | United States - March 31st, 2023 [March 31st, 2023]
- Belarus: EU and WHO deliver equipment for research of genomes of infectious disease agents - EIN News - February 24th, 2023 [February 24th, 2023]
- Gene vs. genome: Definition, function, and impact - January 30th, 2023 [January 30th, 2023]
- Big cog in the wheel: As Covid worries reappear, Insacogs genome sequencing ability must be aided by govts - Times of India - December 25th, 2022 [December 25th, 2022]
- CapitalGainsReport Sector Spotlight: Healthcare Penny Stocks On The Move (ARDX, WHSI, BNGO) - Marketscreener.com - November 25th, 2022 [November 25th, 2022]
- Genome Insight and Kun-hee Lee Child Cancer & Rare Disease Project Team of SNUH (Seoul National University Hospital) Made an Agreement About a... - November 23rd, 2022 [November 23rd, 2022]
- Genome-wide association study reveals distinct genetic associations related to leaf hair density in two lineages of wheat-wild relative Aegilops... - October 19th, 2022 [October 19th, 2022]
- The Global Genomics Market to Exhibit Growth at a CAGR of 16.90% During the Forecast Period (20222027) | DelveInsight - Yahoo Finance - October 19th, 2022 [October 19th, 2022]
- Illumina and GenoScreen Partner to Expand Access to Genomic Testing for Multidrug-Resistant Tuberculosis - PR Newswire - October 19th, 2022 [October 19th, 2022]
- Superresolution Method Poised to Better Gene Function Understanding - Photonics.com - October 19th, 2022 [October 19th, 2022]
- Genome-centric analysis of short and long read metagenomes reveals uncharacterized microbiome diversity in Southeast Asians - Nature.com - October 15th, 2022 [October 15th, 2022]
- How a New Battery Data Genome Project Will Use Vast Amounts of Information to Build Better EVs - InsideClimate News - October 15th, 2022 [October 15th, 2022]
- Scientists Reconstruct the Genome of the 180-Million-Year-Old Common Ancestor of All Mammals - SciTechDaily - October 15th, 2022 [October 15th, 2022]
- Combining OSMAC, metabolomic and genomic methods for the production and annotation of halogenated azaphilones and ilicicolins in termite symbiotic... - October 15th, 2022 [October 15th, 2022]
- Concerted expansion and contraction of immune receptor gene repertoires in plant genomes - Nature.com - October 15th, 2022 [October 15th, 2022]
- Uncovering the Full Variant Continuum with Pioneering Solutions from Bionano - Inside Precision Medicine - October 15th, 2022 [October 15th, 2022]
- Metagenomic analysis of viromes in tissues of wild Qinghai vole from the eastern Tibetan Plateau | Scientific Reports - Nature.com - October 15th, 2022 [October 15th, 2022]
- Research Assistant in Molecular and Genome Editing Therapeutics job with KINGS COLLEGE LONDON | 311876 - Times Higher Education - October 15th, 2022 [October 15th, 2022]
- Lessons learnt from COVID-19 shed light on future pandemic preparedness - The Peter Doherty Institute for Infection and Immunity - October 15th, 2022 [October 15th, 2022]
- From Neanderthal genome to Nobel prize: meet geneticist Svante Pbo - Nature.com - October 8th, 2022 [October 8th, 2022]
- Revealing the genome organization of the earliest common ancestor of all mammals - Tech Explorist - October 8th, 2022 [October 8th, 2022]
- Mitochondrial DNA Is Working Its Way Into the Human Genome - Technology Networks - October 8th, 2022 [October 8th, 2022]
- Animated Map: Where to Find Water on Mars - Visual Capitalist - October 8th, 2022 [October 8th, 2022]
- Reconstruction of The First Mammal's Genome Suggests It Had 38 Chromosomes - ScienceAlert - October 6th, 2022 [October 6th, 2022]
- Genomic Science Breakthroughs Are Happening Faster Than Ever Thanks to HPC - CIO - October 6th, 2022 [October 6th, 2022]
- Genome Of Ancient Humans Is The Winning Field Of 2022's Nobel Prize in Medicine - IFLScience - October 6th, 2022 [October 6th, 2022]
- ASU professor to study new genome editing tools with NIH Innovator Award - ASU News Now - October 6th, 2022 [October 6th, 2022]
- New R&D norms to fast-track research on genome-edited crops - The Financial Express - October 6th, 2022 [October 6th, 2022]