Benefits of genomic sequencing evident in pediatric diagnoses: recent study finds testing method less costly, more effective than other medical, genetic tests.

Abstract

American Journal of Medical Genetics Part AVolume 167, Issue 3 p. vii-viii the AJMG SEQUENCE: Decoding News and Trends for the Medical Genetics Community by Deborah LevensonFree Access Benefits of genomic sequencing evident in pediatric diagnoses Recent study finds testing method less costly, more effective than other medical, genetic tests First published: 18 February 2015 https://doi.org/10.1002/ajmg.a.37019AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Genomic sequencing appears to be an effective, time-saving, and cost efficient method of identifying pediatric neurodevelopmental disorders that earlier genetic tests have failed to diagnose. In a recent study involving a total of 119 children (and their parents) who had whole-exome sequencing (WES) or expedited whole-genome sequencing (WGS) to detect previously undiagnosed neurodevelopmental conditions, 45% of patients were found to have disease causing genetic mutations (Soden et al., 2014). Likewise, results of genomic sequencing tests initiated a change in diagnosis, either working or actual, and in medical care for 49% of the children, the study reports. If these children, whose average age was seven, had received genomic sequencing early when symptoms first appeared, researchers contend that they would have had diagnoses an average of six years earlier. Researchers also included infants in intensive care units and their parents in the study, testing them with a rapid WGS platform and accelerated data analysis strategy known as Stat-Seq. Almost 75% of these acutely affected infants received diagnoses through WGS and Stat-Seq compared with 40% of infant patients and their parents diagnosed at outpatient clinics by WES. That percentage is consistent with diagnostic yields for neurodevelopmental disorders found in other recent studies (Yang et al., 2014, and Lee et al., 2014). “Genomic sequencing is effective and can bring about etiologic diagnosis more quickly and, we believe, more effectively than serial gene sequencing,” says study lead author Sarah E. Soden, MD, a developmental pediatrician and Medical Director of the Center for Pediatric Genomic Medicine at Children's Mercy Kansas City in Missouri. Her study shows that “genomic sequencing is a good strategy if you don't have a strong hypothesis [about a genetic cause] up front,” she adds. Bertrand Might (right), diagnosed with deficiency of a protein expressed by the NGLY1 gene, with siblings Victoria (left) and Winston. Advantages of Genomic Sequencing In their paper, Dr. Soden and colleagues give examples of how genomic sequencing ended lengthy diagnostic odysseys for patients and parents and how genetic diagnoses changed patients' medical care. In one example, the researchers describe how genomic sequencing diagnosed two siblings, one of whom was 10 years old, by showing that the same genetic mutation caused both of their developmental delays, autistic behavior, and poor muscle tone. The researchers also describe how diagnoses drove changes in medication, relieving respiratory symptoms and seizures and improving muscle tone and alertness in other patients. Obtaining diagnoses quicker can allow determinations of recurrence risk that can aid family planning, the researchers point out. This information may have been important to the families with multiple affected children and the families of 23 patients who did not inherit disease-causing mutations from their parents, researchers say. The researchers estimate that to be competitive with the total cost of other diagnostic tests, genomic sequencing should cost $7,640 per family. That figure, which is similar to what many labs currently charge, is based on a diagnostic yield of 40% and the total cost of previous uninformative diagnostic testing, which averaged $19,100 per family in the study. Sequencing Usage Expands Christian Schaaf, MD, PhD, still relies on chromosome microarray analysis and single-gene tests if he suspects a specific condition. “When these tests come back normal, I order exome or genome sequencing. I do not accept a child with neurodevelopmental disorder as an ‘unsolved case’ until I order exome or genome sequencing,” says Dr. Schaaf, Assistant Professor at Baylor College of Medicine in Houston. Genomic sequencing “should be considered routine in our diagnostic approach to all children with congenital malformations, severe and acute disorders of unknown etiology, and those involving significant developmental delay or intellectual disability, and autism spectrum disorder,” Dr. Schaaf adds. But he emphasizes the need for appropriate genetic counseling that includes a discussion of ethical issues, such as the return of possible secondary findings indicating that a child will likely suffer an adult-onset disease. The American College of Medical Genetics and Genomics (ACMG) will eventually recommend genomic testing to determine causes of autism, says Bradley Schaefer, MD, senior author of ACMG guidelines on autism testing and Section Chief of Genetics and Metabolism at Arkansas Children's Hospital in Little Rock. A growing number of papers suggests genomic sequencing is “the way to go” for diagnosing genetic disorders with neurologic symptoms, he points out. “The question isn't if it's going to happen, it's when,” says Dr. Schaefer. ACMG's Professional Practice Guidelines Committee is expected to start reviewing evidence related to genomic sequencing later this year as part of its usual triennial update to guidelines, he says. A Case in Point One family's experience supports many of the study's findings regarding cost and postdiagnosis treatment changes. Cristina Casanova Might and Matthew Might's seven-year-old son, Bertrand, was the first patient to be diagnosed with deficiency of a protein expressed by the NGLY1gene, causing seizures, abnormalities in movement, developmental delays, and liver problems. When Bertrand was diagnosed at age four, the cost of his care totaled more than $450,000. This figure included charges for multiple magnetic resonance imaging tests; computed tomography scans; lumbar punctures; skeletal surveys; electromyographies; nerve-conduction studies; ultrasounds; eye exams; blood tests; and biopsies of the liver, skin, and muscles. Many of these diagnostic tests required pediatric general anesthesia. The single-gene tests alone accounted for $22,000, says Mrs. Might. At the time, the $100,000 expense for WGS for Bertrand was far less than all of these tests combined. The Mights could not afford to pay, so they got the test as research participants. “It's easy to put a figure on the financial cost, but the greatest cost of all is human,” emphasizes Mrs. Might, who says that very young children with undiagnosed diseases endure many painful blood draws and biopsies that ultimately yield no useful information. “It's more humane to avoid them. The human cost alone justifies doing [genomic sequencing] earlier,” she maintains. After the diagnosis, a change in Bertrand's dietary supplements reduced seizures within a few days, and the Mights were able to find physicians to better manage his care and medications. With a diagnosis and the Mights' use of social media, the couple and researchers quickly found other affected families, allowing researchers, including Dr. Schaaf, to describe NGLY1 deficiency in detail (Enns et al., 2014). Connections with these families also create a supportive community and allow the Mights to swap information regarding helpful therapies and technology. Mrs. Might says she knows five families with multiple children affected by NGLY1 deficiency, some of whom have died. But with Bertrand's diagnosis and recurrence risk information, she and her husband were able to make family planning decisions that led to the birth of Bertrand's healthy younger brother, Winston. “Winston is here, thanks to whole-genome sequencing,” she says. References Enns GM, Shashi V, Bainbridge M, Gambello MJ, Zahir FR, Bast T, Crimian R, Schoch K, Platt J, Cox R, Bernstein JA, Scavina M, Walter RS, Bibb A, Jones M, Hegde M, Graham BH, Need AC, Oviedo A, Schaaf CP, Boyle S, Butte AJ, Chen R, Clark MJ, Haraksingh R. FORGE Canada Consortium Cowan TM, He P, Langlois S, Zoghbi HY, Snyder M, Gibbs RA, Freeze HH, Goldsein DB, 2014. 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