By Deborah Levenson
TESTING UPDATE WHOLE-EXOME SEQUENCING EMERGES AS CLINICAL DIAGNOSTIC TOOL Testing method proves useful for diagnosing wide range of genetic disorders
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Alice Young and Bob Blakesley, National Genome Research Institute
hole-exome sequencing (WES) can very rare,” says senior author Christine patients with a specific neurologic finding, be a useful diagnostic tool outside of M. Eng, MD, Senior Director of the such as a movement disorder. research settings, a recent study shows. Medical Genetics Laboratories and Using WES testing methods, Medical Director of the Whole Genome Making Use of Recent Findings researchers at the Baylor College of Laboratory at Baylor. “With whole-exome About 25% of the diagnoses made for Medicine in Houston, Texas, were sequencing, physicians can make earlier patients in the study were based on able to diagnose 25% of recently discovered associations 250 previously undiagnosed between genes and diseases, the patients with suspected genetic researchers note. For example, disorders, according to a recent seven patients with mutations in paper published in the New the ARID1A, ARID1B, KANSL1, England Journal of Medicine SMARCB1, SRCAP, and C5orf42 [Yang et al, 2013]. genes would not have received As many as 80% of the diagnoses prior to 2012 because patients were children with associations with the mutations neurologic symptoms. In all, had not been found until then. scientists identified 86 mutated Another patient was diagnosed genes that are known to cause with Noonan syndrome based on genetic diseases in 62 of the a mutation in CBL, a gene only 250 patients. recently linked with the disorder. The overall diagnostic A previous Noonan panel test did yield of 25% is higher than that not look for mutations in this gene. of more established genetic WES also allowed researchers tests, such as karyotype and to give four individual patients chromosomal microarray, which diagnoses for more than one The above chart represents a data sample well flowgram from a provide answers in 15% to 20% gene sequencing machine at the National Institutes of Health condition because the testing of cases, say researchers. method sequences all proteinIntramural Sequencing Center in Rockville, Maryland. Advances coding genes, whereas panel in gene sequencing testing methods have enabled scientists to What Was Revealed tests typically detect mutations diagnose a wider range of genetic disorders. associated with one disease or a Among the 62 patients who received a diagnosis, 33 had autosomal diagnoses when the etiology isn’t clear, or small group of conditions. “A search for one unifying diagnosis dominant disease, 16 had autosomal when they’re not even sure where to look. recessive disease, and 9 had X-linked This can shorten the diagnostic odyssey is one of the main reasons for seeking a genetics consultation, but sometimes this disorders. Four patients received two that some families experience.” distinct molecular diagnoses that Patients with intellectual disabilities, is not the case because the patient has challenged previous determinations of developmental delay, and specific multiple mutations working together to disease based on history and physical neurologic findings are good candidates cause a complex phenotype,” says Dr. Eng. The authors predict that the exam. A total of 83% of the autosomal for WES, the researchers maintain. dominant mutant alleles and 40% of Among subjects with phenotypes diagnostic yield of WES will rise as X-linked mutant alleles occurred de novo, involving developmental delay and improved technology enables better say researchers. intellectual disability with no evidence of detection of copy-number variation in “There are thousands of genetic a syndromic disorder, WES’s diagnostic genes—which causes many diseases— conditions, some of which are very, yield was 33%. The yield was 31% for and as more gene-disease associations are © 2014 Wiley Periodicals, Inc.
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RESEARCH UPDATE CONTINUED made. Data from WES can be re-examined as new disease-gene discoveries are made, Dr. Eng adds, while panel testing cannot.
Taking Another Look Such re-examination of genomic data is crucial, says David Goldstein, PhD, Director of the Center for Human Genome Variation at Duke University in Durham, North Carolina. In addition to returning data on known pathogenic mutations for each individual patient, his lab notes suspicious gene mutations not seen in the general population and puts them on a watch list. If new medical literature identifies a mutation on the list as pathogenic, the lab does a subsequent review of that patient’s exome data. “Under no circumstances should you review negative exome data only once,” Dr. Goldstein says. “The pace of discovery is too rapid for a single analysis at one point in time to be sufficient.” An editorial accompanying the Baylor paper also raises the issue of findings with uncertain meaning. Those types of findings can be a major limitation on making a diagnosis using WES, writes Howard J. Jacob, PhD, Director of
Human and Molecular Genetics Center at the Medical College of Wisconsin in Milwaukee, which was among the first centers to offer clinical WES. “Any clinician who has received a clinical laboratory report from an exomesequencing laboratory will have noted that variants of unknown significance constitute the largest category of variants in many reports,” he notes [Jacob, 2013]. Both Dr. Jacob and the study paper’s authors note that many questions remain regarding the effect of WES-identified gene variants on clinical outcomes and the test’s cost-effectiveness, accuracy, yield, and integration into routine medical care. Answering these questions definitively would require an extremely complex prospective study involving a million variants per person and long-term followup periods, Dr. Jacobs adds. But, Dr. Goldstein and Heidi Rehm, PhD, Director, Laboratory for Molecular Medicine Partners Healthcare Center for Personalized Genetic Medicine in Cambridge, Massachusetts, are satisfied that the Baylor study shows WES has clinical value right now.
“Whole-exome sequencing has an impressive yield and can be a useful diagnostic tool that leads to improved understanding of disease and management of patients,” says Dr. Rehm. “As a geneticist, you see families who want to know what comes next. That’s easier to do with a diagnosis. For many patients, this test may get you there.” “Whole-exome sequencing is ready for deployment,” adds Dr. Goldstein. “There will be a whole lot more of it in the future, and it’s likely [that] most sequence data will be from clinical cases, not research.”
References Yang Y, Muzny DM, Reid JG, Bainbridge MN, Willis A, Ward PA, Braxton A, Beuten J, Xia F, Niu Z, Hardison M, Person R, Bekheirnia MR, Leduc MS, Kirby A, Pham P, Scull J, Wang M, Ding Y, Plon SE, Lupski JR, Beaudet AL, Gibbs RA, Eng CM. Clinical whole-exome sequencing for the diagnosis of Mendelian disorders. N Engl J Med 2013; 369:1502-1511. Jacob HJ. Next-generation sequencing for clinical diagnostics. N Engl J Med 2013; 369:1557-1558. DOI: 10.1002/ajmg.a.36385 2014 Wiley Periodicals, Inc.
SCREENING UPDATE WHO SHOULD CONTROL GENOMIC DATA? Researchers advocate putting patients in charge of their own results
I
ndividuals should select which genomic test results they want and change their preferences as they see fit, say genetic researchers at the University of Washington in Seattle. In a paper published in Genetics in Medicine, the authors advocate a major shift in how patients, research subjects, and healthcare providers think about data from genomic sequencing, and who should manage it. Rather than viewing data as test results to be returned and dispensed by healthcare providers and researchers, data should be regarded as a trove of information that patients can
x
access anytime, the researchers contend [Yu et al, 2013]. The authors view geneticists not as gatekeepers, but as professionals who translate and interpret genomic results patients may want to know at various times in their lives. For example, someone who has a risk variant for cystic fibrosis or breast cancer may not want this information as a teenager or young adult, but may feel differently as they get older, the paper points out. “It’s important to give people a choice,” says Holly Tabor, PhD, a coauthor of the paper and Assistant
Professor, Department of Pediatrics at the University of Washington. “They should be able to decide what they want according to values they hold at different points in time.”
Testing the Proposal The authors are testing their proposal with the website my46.org, developed at the University of Washington and named in reference to the 46 chromosomes in most human cells. The website, which is currently being used only for research purposes, allows patients and their families to indicate the particular genetic
TESTING UPDATE WHOLE-EXOME SEQUENCING EMERGES AS CLINICAL DIAGNOSTIC TOOL Testing method proves useful for diagnosing wide range of genetic disorders
W
Alice Young and Bob Blakesley, National Genome Research Institute
hole-exome sequencing (WES) can very rare,” says senior author Christine patients with a specific neurologic finding, be a useful diagnostic tool outside of M. Eng, MD, Senior Director of the such as a movement disorder. research settings, a recent study shows. Medical Genetics Laboratories and Using WES testing methods, Medical Director of the Whole Genome Making Use of Recent Findings researchers at the Baylor College of Laboratory at Baylor. “With whole-exome About 25% of the diagnoses made for Medicine in Houston, Texas, were sequencing, physicians can make earlier patients in the study were based on able to diagnose 25% of recently discovered associations 250 previously undiagnosed between genes and diseases, the patients with suspected genetic researchers note. For example, disorders, according to a recent seven patients with mutations in paper published in the New the ARID1A, ARID1B, KANSL1, England Journal of Medicine SMARCB1, SRCAP, and C5orf42 [Yang et al, 2013]. genes would not have received As many as 80% of the diagnoses prior to 2012 because patients were children with associations with the mutations neurologic symptoms. In all, had not been found until then. scientists identified 86 mutated Another patient was diagnosed genes that are known to cause with Noonan syndrome based on genetic diseases in 62 of the a mutation in CBL, a gene only 250 patients. recently linked with the disorder. The overall diagnostic A previous Noonan panel test did yield of 25% is higher than that not look for mutations in this gene. of more established genetic WES also allowed researchers tests, such as karyotype and to give four individual patients chromosomal microarray, which diagnoses for more than one The above chart represents a data sample well flowgram from a provide answers in 15% to 20% gene sequencing machine at the National Institutes of Health condition because the testing of cases, say researchers. method sequences all proteinIntramural Sequencing Center in Rockville, Maryland. Advances coding genes, whereas panel in gene sequencing testing methods have enabled scientists to What Was Revealed tests typically detect mutations diagnose a wider range of genetic disorders. associated with one disease or a Among the 62 patients who received a diagnosis, 33 had autosomal diagnoses when the etiology isn’t clear, or small group of conditions. “A search for one unifying diagnosis dominant disease, 16 had autosomal when they’re not even sure where to look. recessive disease, and 9 had X-linked This can shorten the diagnostic odyssey is one of the main reasons for seeking a genetics consultation, but sometimes this disorders. Four patients received two that some families experience.” distinct molecular diagnoses that Patients with intellectual disabilities, is not the case because the patient has challenged previous determinations of developmental delay, and specific multiple mutations working together to disease based on history and physical neurologic findings are good candidates cause a complex phenotype,” says Dr. Eng. The authors predict that the exam. A total of 83% of the autosomal for WES, the researchers maintain. dominant mutant alleles and 40% of Among subjects with phenotypes diagnostic yield of WES will rise as X-linked mutant alleles occurred de novo, involving developmental delay and improved technology enables better say researchers. intellectual disability with no evidence of detection of copy-number variation in “There are thousands of genetic a syndromic disorder, WES’s diagnostic genes—which causes many diseases— conditions, some of which are very, yield was 33%. The yield was 31% for and as more gene-disease associations are © 2014 Wiley Periodicals, Inc.
ix
RESEARCH UPDATE CONTINUED made. Data from WES can be re-examined as new disease-gene discoveries are made, Dr. Eng adds, while panel testing cannot.
Taking Another Look Such re-examination of genomic data is crucial, says David Goldstein, PhD, Director of the Center for Human Genome Variation at Duke University in Durham, North Carolina. In addition to returning data on known pathogenic mutations for each individual patient, his lab notes suspicious gene mutations not seen in the general population and puts them on a watch list. If new medical literature identifies a mutation on the list as pathogenic, the lab does a subsequent review of that patient’s exome data. “Under no circumstances should you review negative exome data only once,” Dr. Goldstein says. “The pace of discovery is too rapid for a single analysis at one point in time to be sufficient.” An editorial accompanying the Baylor paper also raises the issue of findings with uncertain meaning. Those types of findings can be a major limitation on making a diagnosis using WES, writes Howard J. Jacob, PhD, Director of
Human and Molecular Genetics Center at the Medical College of Wisconsin in Milwaukee, which was among the first centers to offer clinical WES. “Any clinician who has received a clinical laboratory report from an exomesequencing laboratory will have noted that variants of unknown significance constitute the largest category of variants in many reports,” he notes [Jacob, 2013]. Both Dr. Jacob and the study paper’s authors note that many questions remain regarding the effect of WES-identified gene variants on clinical outcomes and the test’s cost-effectiveness, accuracy, yield, and integration into routine medical care. Answering these questions definitively would require an extremely complex prospective study involving a million variants per person and long-term followup periods, Dr. Jacobs adds. But, Dr. Goldstein and Heidi Rehm, PhD, Director, Laboratory for Molecular Medicine Partners Healthcare Center for Personalized Genetic Medicine in Cambridge, Massachusetts, are satisfied that the Baylor study shows WES has clinical value right now.
“Whole-exome sequencing has an impressive yield and can be a useful diagnostic tool that leads to improved understanding of disease and management of patients,” says Dr. Rehm. “As a geneticist, you see families who want to know what comes next. That’s easier to do with a diagnosis. For many patients, this test may get you there.” “Whole-exome sequencing is ready for deployment,” adds Dr. Goldstein. “There will be a whole lot more of it in the future, and it’s likely [that] most sequence data will be from clinical cases, not research.”
References Yang Y, Muzny DM, Reid JG, Bainbridge MN, Willis A, Ward PA, Braxton A, Beuten J, Xia F, Niu Z, Hardison M, Person R, Bekheirnia MR, Leduc MS, Kirby A, Pham P, Scull J, Wang M, Ding Y, Plon SE, Lupski JR, Beaudet AL, Gibbs RA, Eng CM. Clinical whole-exome sequencing for the diagnosis of Mendelian disorders. N Engl J Med 2013; 369:1502-1511. Jacob HJ. Next-generation sequencing for clinical diagnostics. N Engl J Med 2013; 369:1557-1558. DOI: 10.1002/ajmg.a.36385 2014 Wiley Periodicals, Inc.
SCREENING UPDATE WHO SHOULD CONTROL GENOMIC DATA? Researchers advocate putting patients in charge of their own results
I
ndividuals should select which genomic test results they want and change their preferences as they see fit, say genetic researchers at the University of Washington in Seattle. In a paper published in Genetics in Medicine, the authors advocate a major shift in how patients, research subjects, and healthcare providers think about data from genomic sequencing, and who should manage it. Rather than viewing data as test results to be returned and dispensed by healthcare providers and researchers, data should be regarded as a trove of information that patients can
x
access anytime, the researchers contend [Yu et al, 2013]. The authors view geneticists not as gatekeepers, but as professionals who translate and interpret genomic results patients may want to know at various times in their lives. For example, someone who has a risk variant for cystic fibrosis or breast cancer may not want this information as a teenager or young adult, but may feel differently as they get older, the paper points out. “It’s important to give people a choice,” says Holly Tabor, PhD, a coauthor of the paper and Assistant
Professor, Department of Pediatrics at the University of Washington. “They should be able to decide what they want according to values they hold at different points in time.”
Testing the Proposal The authors are testing their proposal with the website my46.org, developed at the University of Washington and named in reference to the 46 chromosomes in most human cells. The website, which is currently being used only for research purposes, allows patients and their families to indicate the particular genetic
