Welcome!

News Feed Item

"Deep sequencing" picks up hidden causes of brain disorders

New approach complements whole-genome and whole-exome sequencing

BOSTON, Aug. 20, 2014 /PRNewswire-USNewswire/ -- Not every cell in the body is the same genetically, and disease-causing mutations don't necessarily affect every cell—making these mutations easy to miss even with next-generation genomic sequencing. A study from Boston Children's Hospital used a "deep sequencing" technique and was able to identify subtle somatic mutations—those affecting just a percentage of cells—in patients with brain disorders. The approach, described in the August 21st issue of The New England Journal of Medicine, opens up new possibilities for finding genetic causes for previously mysterious neurologic and psychiatric conditions.

"There are two kinds of somatic mutations that get missed," explains Christopher Walsh, MD, PhD, chief of Genetics and Genomics at Boston Children's Hospital and principal investigator on Boston Children's portion of the Undiagnosed Disease Network.  "One is mutations that are limited to specific tissues: If we do a blood test, but the mutation is only in the brain, we won't find it. Other somatic mutations may be in all tissues, but occur in only a fraction of the cells—a mosaic pattern. These could be detectable through a blood test in the clinic but aren't common enough to be easily detectable."

Walsh and postdoctoral fellow Saumya Jamuar, MD, now a clinical geneticist at the KK Women's and Children's Hospital in Singapore, used a technique called "targeted high-coverage sequencing" to search for mutations in 158 patients with brain malformations of unknown genetic cause, who had symptoms such as seizures, intellectual disability and speech and language impairments.

Rather than analyzing the whole genome or exome (protein-coding regions of genes), the investigators focused on a panel of known or suspected genes, but drilled deeper than the traditional genomic sequencing technique. Whole genome or exome sequencing typically breaks the DNA into little fragments, each of which is read multiple times—typically 30—to find the disease-causing mutation. But 30 reads aren't enough to reliably catch mutations that only occur in 15 to 20 percent of our cells—especially given that mutations may affect just one of our two copies of a gene.

So Walsh, Jamuar and colleagues scaled up the number of reads, sequencing each candidate gene not 30 times but 200 times or more. This enabled them to find mutations in 27 of the 158 patients (17 percent). Of these, eight mutations (30 percent) occurred in only a proportion of the blood cells (so-called mosaic mutations). Five of the eight were missed by traditional Sanger genomic sequencing. One of the eight had also undergone prior whole-exome sequencing that missed the diagnosis.

"Our findings suggest that serious neuropsychiatric disorders can result from mutations that are detectable in as few as 10 percent of patients' blood cells," says Walsh. "By limiting ourselves to selected genes, but covering them more deeply, we may be able to find more answers for families and better understand these disorders."

Walsh, who is part of Boston Children's Brain Development and Genetics Clinic, which sees patients with brain malformations, thinks the results may possibly help explain other brain-based disorders such as autism, intellectual disability and epilepsy that don't have an inherited cause but occur as a result of de novo mutations—those occurring spontaneously and sometimes, as in these cases, after conception.

"Traditionally, our genes are considered to be the same across all cells of our body, and disease-causing mutations are either inherited from one or both parents or occur in the parent's sperm or egg before conception," Jamuar explains. "Our study creates a paradigm shift, providing evidence that a significant proportion of mutations causing brain disorders occur after conception and would be missed by routine testing. Finding the mutation ends the patient's diagnostic odyssey and allows us to provide more accurate genetic counseling to the family."

"The range of possibilities caused by somatic mutations is vast," says Timothy Yu, MD, PhD, a co-author on the study and a researcher in the Division of Genetics and Genomics at Boston Children's. "The challenge remains in developing technologies to study these mutations in other conditions."

The NEJM study was funded by the National Institute of Neurological Disorders and Stroke (R01NS079277, R01NS035129, K23NS069784), the National Institute of Mental Health (1RC2MH089952), the University of Washington Centers for Mendelian Genomics (HG006493), the Manton Center for Orphan Disease Research, the National Institute of General Medical Sciences (T32GM07753), the Allen Foundation and the Howard Hughes Medical Institute.

Boston Children's Hospital is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 1,100 scientists, including seven members of the National Academy of Sciences, 14 members of the Institute of Medicine and 14 members of the Howard Hughes Medical Institute comprise Boston Children's research community. Founded as a 20-bed hospital for children, Boston Children's today is a 395-bed comprehensive center for pediatric and adolescent health care. Boston Children's is also the primary pediatric teaching affiliate of Harvard Medical School.

For more information about research and clinical innovation at Boston Children's, visit: http://vectorblog.org.
Join the social discussion and tweet us @BostonChildrens @BCH_Innovation.
Follow Boston Children's on Facebook: http://on.bchil.org/1mJ9fxf. 
Follow Boston Children's on YouTube: http://on.bchil.org/1oJib5B.    

CONTACT: 
Keri Stedman
Boston Children's Hospital
[email protected] 
617-919-3110

SOURCE Boston Children's Hospital

More Stories By PR Newswire

Copyright © 2007 PR Newswire. All rights reserved. Republication or redistribution of PRNewswire content is expressly prohibited without the prior written consent of PRNewswire. PRNewswire shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon.

Latest Stories
"Matrix is an ambitious open standard and implementation that's set up to break down the fragmentation problems that exist in IP messaging and VoIP communication," explained John Woolf, Technical Evangelist at Matrix, in this SYS-CON.tv interview at @ThingsExpo, held Nov 4–6, 2014, at the Santa Clara Convention Center in Santa Clara, CA.
"A lot of times people will come to us and have a very diverse set of requirements or very customized need and we'll help them to implement it in a fashion that you can't just buy off of the shelf," explained Nick Rose, CTO of Enzu, in this SYS-CON.tv interview at 18th Cloud Expo, held June 7-9, 2016, at the Javits Center in New York City, NY.
As software becomes more and more complex, we, as software developers, have been splitting up our code into smaller and smaller components. This is also true for the environment in which we run our code: going from bare metal, to VMs to the modern-day Cloud Native world of containers, schedulers and micro services. While we have figured out how to run containerized applications in the cloud using schedulers, we've yet to come up with a good solution to bridge the gap between getting your contain...
Web Real-Time Communication APIs have quickly revolutionized what browsers are capable of. In addition to video and audio streams, we can now bi-directionally send arbitrary data over WebRTC's PeerConnection Data Channels. With the advent of Progressive Web Apps and new hardware APIs such as WebBluetooh and WebUSB, we can finally enable users to stitch together the Internet of Things directly from their browsers while communicating privately and securely in a decentralized way.
"We host and fully manage cloud data services, whether we store, the data, move the data, or run analytics on the data," stated Kamal Shannak, Senior Development Manager, Cloud Data Services, IBM, in this SYS-CON.tv interview at 18th Cloud Expo, held June 7-9, 2016, at the Javits Center in New York City, NY.
Information technology (IT) advances are transforming the way we innovate in business, thereby disrupting the old guard and their predictable status-quo. It’s creating global market turbulence. Industries are converging, and new opportunities and threats are emerging, like never before. So, how are savvy chief information officers (CIOs) leading this transition? Back in 2015, the IBM Institute for Business Value conducted a market study that included the findings from over 1,800 CIO interviews ...
Who are you? How do you introduce yourself? Do you use a name, or do you greet a friend by the last four digits of his social security number? Assuming you don’t, why are we content to associate our identity with 10 random digits assigned by our phone company? Identity is an issue that affects everyone, but as individuals we don’t spend a lot of time thinking about it. In his session at @ThingsExpo, Ben Klang, Founder & President of Mojo Lingo, discussed the impact of technology on identity. Sho...
"Operations is sort of the maturation of cloud utilization and the move to the cloud," explained Steve Anderson, Product Manager for BMC’s Cloud Lifecycle Management, in this SYS-CON.tv interview at 18th Cloud Expo, held June 7-9, 2016, at the Javits Center in New York City, NY.
Due of the rise of Hadoop, many enterprises are now deploying their first small clusters of 10 to 20 servers. At this small scale, the complexity of operating the cluster looks and feels like general data center servers. It is not until the clusters scale, as they inevitably do, when the pain caused by the exponential complexity becomes apparent. We've seen this problem occur time and time again. In his session at Big Data Expo, Greg Bruno, Vice President of Engineering and co-founder of StackIQ...
"I think that everyone recognizes that for IoT to really realize its full potential and value that it is about creating ecosystems and marketplaces and that no single vendor is able to support what is required," explained Esmeralda Swartz, VP, Marketing Enterprise and Cloud at Ericsson, in this SYS-CON.tv interview at @ThingsExpo, held June 7-9, 2016, at the Javits Center in New York City, NY.
The buzz continues for cloud, data analytics and the Internet of Things (IoT) and their collective impact across all industries. But a new conversation is emerging - how do companies use industry disruption and technology enablers to lead in markets undergoing change, uncertainty and ambiguity? Organizations of all sizes need to evolve and transform, often under massive pressure, as industry lines blur and merge and traditional business models are assaulted and turned upside down. In this new da...
Bert Loomis was a visionary. This general session will highlight how Bert Loomis and people like him inspire us to build great things with small inventions. In their general session at 19th Cloud Expo, Harold Hannon, Architect at IBM Bluemix, and Michael O'Neill, Strategic Business Development at Nvidia, discussed the accelerating pace of AI development and how IBM Cloud and NVIDIA are partnering to bring AI capabilities to "every day," on-demand. They also reviewed two "free infrastructure" pr...
"We got started as search consultants. On the services side of the business we have help organizations save time and save money when they hit issues that everyone more or less hits when their data grows," noted Otis Gospodnetić, Founder of Sematext, in this SYS-CON.tv interview at @DevOpsSummit, held June 9-11, 2015, at the Javits Center in New York City.
With major technology companies and startups seriously embracing IoT strategies, now is the perfect time to attend @ThingsExpo 2016 in New York. Learn what is going on, contribute to the discussions, and ensure that your enterprise is as "IoT-Ready" as it can be! Internet of @ThingsExpo, taking place June 6-8, 2017, at the Javits Center in New York City, New York, is co-located with 20th Cloud Expo and will feature technical sessions from a rock star conference faculty and the leading industry p...
It is one thing to build single industrial IoT applications, but what will it take to build the Smart Cities and truly society changing applications of the future? The technology won’t be the problem, it will be the number of parties that need to work together and be aligned in their motivation to succeed. In his Day 2 Keynote at @ThingsExpo, Henrik Kenani Dahlgren, Portfolio Marketing Manager at Ericsson, discussed how to plan to cooperate, partner, and form lasting all-star teams to change the...