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
Recently, REAN Cloud built a digital concierge for a North Carolina hospital that had observed that most patient call button questions were repetitive. In addition, the paper-based process used to measure patient health metrics was laborious, not in real-time and sometimes error-prone. In their session at 21st Cloud Expo, Sean Finnerty, Executive Director, Practice Lead, Health Care & Life Science at REAN Cloud, and Dr. S.P.T. Krishnan, Principal Architect at REAN Cloud, discussed how they built...
In his Opening Keynote at 21st Cloud Expo, John Considine, General Manager of IBM Cloud Infrastructure, led attendees through the exciting evolution of the cloud. He looked at this major disruption from the perspective of technology, business models, and what this means for enterprises of all sizes. John Considine is General Manager of Cloud Infrastructure Services at IBM. In that role he is responsible for leading IBM’s public cloud infrastructure including strategy, development, and offering m...
Mobile device usage has increased exponentially during the past several years, as consumers rely on handhelds for everything from news and weather to banking and purchases. What can we expect in the next few years? The way in which we interact with our devices will fundamentally change, as businesses leverage Artificial Intelligence. We already see this taking shape as businesses leverage AI for cost savings and customer responsiveness. This trend will continue, as AI is used for more sophistica...
The “Digital Era” is forcing us to engage with new methods to build, operate and maintain applications. This transformation also implies an evolution to more and more intelligent applications to better engage with the customers, while creating significant market differentiators. In both cases, the cloud has become a key enabler to embrace this digital revolution. So, moving to the cloud is no longer the question; the new questions are HOW and WHEN. To make this equation even more complex, most ...
In his session at 21st Cloud Expo, Raju Shreewastava, founder of Big Data Trunk, provided a fun and simple way to introduce Machine Leaning to anyone and everyone. He solved a machine learning problem and demonstrated an easy way to be able to do machine learning without even coding. Raju Shreewastava is the founder of Big Data Trunk (www.BigDataTrunk.com), a Big Data Training and consulting firm with offices in the United States. He previously led the data warehouse/business intelligence and B...
Blockchain is a shared, secure record of exchange that establishes trust, accountability and transparency across business networks. Supported by the Linux Foundation's open source, open-standards based Hyperledger Project, Blockchain has the potential to improve regulatory compliance, reduce cost as well as advance trade. Are you curious about how Blockchain is built for business? In her session at 21st Cloud Expo, René Bostic, Technical VP of the IBM Cloud Unit in North America, discussed the b...
The past few years have brought a sea change in the way applications are architected, developed, and consumed—increasing both the complexity of testing and the business impact of software failures. How can software testing professionals keep pace with modern application delivery, given the trends that impact both architectures (cloud, microservices, and APIs) and processes (DevOps, agile, and continuous delivery)? This is where continuous testing comes in. D
SYS-CON Events announced today that Synametrics Technologies will exhibit at SYS-CON's 22nd International Cloud Expo®, which will take place on June 5-7, 2018, at the Javits Center in New York, NY. Synametrics Technologies is a privately held company based in Plainsboro, New Jersey that has been providing solutions for the developer community since 1997. Based on the success of its initial product offerings such as WinSQL, Xeams, SynaMan and Syncrify, Synametrics continues to create and hone in...
With tough new regulations coming to Europe on data privacy in May 2018, Calligo will explain why in reality the effect is global and transforms how you consider critical data. EU GDPR fundamentally rewrites the rules for cloud, Big Data and IoT. In his session at 21st Cloud Expo, Adam Ryan, Vice President and General Manager EMEA at Calligo, examined the regulations and provided insight on how it affects technology, challenges the established rules and will usher in new levels of diligence arou...
As you move to the cloud, your network should be efficient, secure, and easy to manage. An enterprise adopting a hybrid or public cloud needs systems and tools that provide: Agility: ability to deliver applications and services faster, even in complex hybrid environments Easier manageability: enable reliable connectivity with complete oversight as the data center network evolves Greater efficiency: eliminate wasted effort while reducing errors and optimize asset utilization Security: imple...
Nordstrom is transforming the way that they do business and the cloud is the key to enabling speed and hyper personalized customer experiences. In his session at 21st Cloud Expo, Ken Schow, VP of Engineering at Nordstrom, discussed some of the key learnings and common pitfalls of large enterprises moving to the cloud. This includes strategies around choosing a cloud provider(s), architecture, and lessons learned. In addition, he covered some of the best practices for structured team migration an...
No hype cycles or predictions of a gazillion things here. IoT is here. 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, an Associate Partner of Analytics, IoT & Cybersecurity at M&S Consulting, presented a step-by-step plan to develop your technology implementation strategy. He also discussed the evaluation of communication standards and IoT messaging protocols, data...
Companies are harnessing data in ways we once associated with science fiction. Analysts have access to a plethora of visualization and reporting tools, but considering the vast amount of data businesses collect and limitations of CPUs, end users are forced to design their structures and systems with limitations. Until now. As the cloud toolkit to analyze data has evolved, GPUs have stepped in to massively parallel SQL, visualization and machine learning.
The 22nd International Cloud Expo | 1st DXWorld Expo has announced that its Call for Papers is open. Cloud Expo | DXWorld Expo, to be held June 5-7, 2018, at the Javits Center in New York, NY, brings together Cloud Computing, Digital Transformation, Big Data, Internet of Things, DevOps, Machine Learning and WebRTC to one location. With cloud computing driving a higher percentage of enterprise IT budgets every year, it becomes increasingly important to plant your flag in this fast-expanding busin...
Modern software design has fundamentally changed how we manage applications, causing many to turn to containers as the new virtual machine for resource management. As container adoption grows beyond stateless applications to stateful workloads, the need for persistent storage is foundational - something customers routinely cite as a top pain point. In his session at @DevOpsSummit at 21st Cloud Expo, Bill Borsari, Head of Systems Engineering at Datera, explored how organizations can reap the bene...