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
Business professionals no longer wonder if they'll migrate to the cloud; it's now a matter of when. The cloud environment has proved to be a major force in transitioning to an agile business model that enables quick decisions and fast implementation that solidify customer relationships. And when the cloud is combined with the power of cognitive computing, it drives innovation and transformation that achieves astounding competitive advantage.
IoT is rapidly becoming mainstream as more and more investments are made into the platforms and technology. As this movement continues to expand and gain momentum it creates a massive wall of noise that can be difficult to sift through. Unfortunately, this inevitably makes IoT less approachable for people to get started with and can hamper efforts to integrate this key technology into your own portfolio. There are so many connected products already in place today with many hundreds more on the h...
In his session at Cloud Expo, Alan Winters, U.S. Head of Business Development at MobiDev, presented a success story of an entrepreneur who has both suffered through and benefited from offshore development across multiple businesses: The smart choice, or how to select the right offshore development partner Warning signs, or how to minimize chances of making the wrong choice Collaboration, or how to establish the most effective work processes Budget control, or how to maximize project result...
"Software-defined storage is a big problem in this industry because so many people have different definitions as they see fit to use it," stated Peter McCallum, VP of Datacenter Solutions at FalconStor Software, in this SYS-CON.tv interview at 18th Cloud Expo, held June 7-9, 2016, at the Javits Center in New York City, NY.
"Our strategy is to focus on the hyperscale providers - AWS, Azure, and Google. Over the last year we saw that a lot of developers need to learn how to do their job in the cloud and we see this DevOps movement that we are catering to with our content," stated Alessandro Fasan, Head of Global Sales at Cloud Academy, in this SYS-CON.tv interview at 20th Cloud Expo, held June 6-8, 2017, at the Javits Center in New York City, NY.
Personalization has long been the holy grail of marketing. Simply stated, communicate the most relevant offer to the right person and you will increase sales. To achieve this, you must understand the individual. Consequently, digital marketers developed many ways to gather and leverage customer information to deliver targeted experiences. In his session at @ThingsExpo, Lou Casal, Founder and Principal Consultant at Practicala, discussed how the Internet of Things (IoT) has accelerated our abilit...
Data is the fuel that drives the machine learning algorithmic engines and ultimately provides the business value. In his session at Cloud Expo, Ed Featherston, a director and senior enterprise architect at Collaborative Consulting, discussed the key considerations around quality, volume, timeliness, and pedigree that must be dealt with in order to properly fuel that engine.
In his keynote at 19th Cloud Expo, Sheng Liang, co-founder and CEO of Rancher Labs, discussed the technological advances and new business opportunities created by the rapid adoption of containers. With the success of Amazon Web Services (AWS) and various open source technologies used to build private clouds, cloud computing has become an essential component of IT strategy. However, users continue to face challenges in implementing clouds, as older technologies evolve and newer ones like Docker c...
As organizations shift towards IT-as-a-service models, the need for managing and protecting data residing across physical, virtual, and now cloud environments grows with it. Commvault can ensure protection, access and E-Discovery of your data – whether in a private cloud, a Service Provider delivered public cloud, or a hybrid cloud environment – across the heterogeneous enterprise. In his general session at 18th Cloud Expo, Randy De Meno, Chief Technologist - Windows Products and Microsoft Part...
Andi Mann, Chief Technology Advocate at Splunk, is an accomplished digital business executive with extensive global expertise as a strategist, technologist, innovator, marketer, and communicator. For over 30 years across five continents, he has built success with Fortune 500 corporations, vendors, governments, and as a leading research analyst and consultant.
"Cloud computing is certainly changing how people consume storage, how they use it, and what they use it for. It's also making people rethink how they architect their environment," stated Brad Winett, Senior Technologist for DDN Storage, in this SYS-CON.tv interview at 20th Cloud Expo, held June 6-8, 2017, at the Javits Center in New York City, NY.
In his session at 20th Cloud Expo, Brad Winett, Senior Technologist for DDN Storage, will present several current, end-user environments that are using object storage at scale for cloud deployments including private cloud and cloud providers. Details on the top considerations of features and functions for selecting object storage will be included. Brad will also touch on recent developments in tiering technologies that deliver single solution and an end-user view of data across files and objects...
In his keynote at 18th Cloud Expo, Andrew Keys, Co-Founder of ConsenSys Enterprise, provided an overview of the evolution of the Internet and the Database and the future of their combination – the Blockchain. Andrew Keys is Co-Founder of ConsenSys Enterprise. He comes to ConsenSys Enterprise with capital markets, technology and entrepreneurial experience. Previously, he worked for UBS investment bank in equities analysis. Later, he was responsible for the creation and distribution of life settl...
No hype cycles or predictions of zillions of things here. IoT is big. You get it. You know your business and have great ideas for a business transformation strategy. What comes next? Time to make it happen. In his session at @ThingsExpo, Jay Mason, Associate Partner at M&S Consulting, presented a step-by-step plan to develop your technology implementation strategy. He discussed the evaluation of communication standards and IoT messaging protocols, data analytics considerations, edge-to-cloud tec...
In his session at @ThingsExpo, Dr. Robert Cohen, an economist and senior fellow at the Economic Strategy Institute, presented the findings of a series of six detailed case studies of how large corporations are implementing IoT. The session explored how IoT has improved their economic performance, had major impacts on business models and resulted in impressive ROIs. The companies covered span manufacturing and services firms. He also explored servicification, how manufacturing firms shift from se...