Summary: A new study reports on the potential life changing benefits of GWS for children with certain intellectual disabilities.
Source: Child and Family Research Institute.
A study published today in The New England Journal of Medicine is one of the first to show the life-changing benefits of genome-wide sequencing for children with certain kinds of intellectual disability. The work was led by researchers at BC Children’s Hospital, an agency of the Provincial Health Services Authority, and the University of British Columbia.
The researchers diagnosed 68 per cent of the 41 families in the study with the precise underlying genetic condition and, based on this, were able to offer targeted treatments to more than 40 per cent of cases. They also discovered 11 new disease genes and described new physical traits and symptoms associated with a number of known diseases.
“This research is very encouraging because for a subset of patients we can identify the genetic underpinning of their intellectual disability and then determine the right intervention,” says Dr. Clara van Karnebeek, the study’s lead author, a paediatrician and biochemical geneticist at BC Children’s Hospital, and principal investigator in the Centre for Molecular Medicine and Therapeutics at the University of British Columbia. “There’s a bright future ahead for personalized medicine informed by genetic diagnosis.”
Some people’s intellectual disability is due to rare genetic conditions that interfere with the processes the body uses to break down food. Because of these metabolic dysfunctions, there is an energy deficit and build-up of toxic substances in the brain and body leading to symptoms such as developmental and cognitive delays, epilepsy, and organ dysfunction. Some of these rare diseases respond to treatments targeting the metabolic dysfunction at the cellular level and range from simple interventions like dietary modifications, vitamin supplements and medications to more invasive procedures like bone marrow transplants. Because the right treatment can improve cognitive functioning or slow or stop irreversible brain damage, early intervention can improve lifelong outcomes for affected children and their families.
Dr. van Karnebeek’s work is changing the paradigm for diagnosing and treating these conditions. In previous research, her team developed a mobile app that helps clinicians review the intellectual disability patient’s symptoms and arrive at diagnosis as early as possible, based on the best available evidence.
The goal of the current study was to diagnose patients with genetic conditions and discover and describe new diseases with potential for treatment. The study included patients with neurodevelopmental conditions that doctors suspected were genetic or metabolic in origin but had not been diagnosed using conventional methods. All the children in the study were referred by clinicians at BC Children’s Hospital with the exception of three international patients.
Dr. van Karnebeek and her team tested the children and their parents using a combination of metabolomic (large scale chemical) analysis and a type of genomic sequencing called whole exome sequencing. With this state-of-the-art technique, experts analyze and interpret the portion of DNA that codes for proteins.
During the study, researchers discovered a new genetic disease called carbonic anhydrase VA deficiency that presents during early childhood with life-threatening sleepiness and coma due to hyperammonemia (the build-up of a toxin if the body’s cells cannot properly break down proteins into energy). Researchers found that a drug called carglumic acid can prevent brain damage in children with this condition.
The researchers also discovered a new metabolic disease called glutamic oxalo-acetic transaminase 2 deficiency that affects the brain and is characterized by small head size, seizures, and developmental delays. Treatment with an amino-acid called serine and vitamin B6 improved the symptoms.
The study also provides insights into brain development and functioning. For example, the importance sialic acid production for normal brain and bone development was demonstrated by the discovery of NANS deficiency in one of the TIDEX study patients. Detailed description of this disorder in nine individuals from B.C. and Europe with bone abnormalities and intellectual disability, along with a potential treatment target, will be published on May 23rd in Nature Genetics, by Dr. Superti-Furga (Lausanne, Switzerland) and an international group including Dr. van Karnebeek.
“Our findings open the door to life-changing treatments for a small yet meaningful percentage of patients,” says Dr. van Karnebeek. “We’re learning more about brain function and the mechanisms underlying intellectual disability. These results are meaningful to individuals around the world who suffer these rare conditions.”
Patient selection, characterization and interpretation of the whole exome sequencing data involved an international team of clinicians, scientists and bio-informaticians including 37 researchers at BC Children’s Hospital and the University of British Columbia. Study authors include senior author Dr. Maja Tarailo-Graovac and Dr. Wyeth Wasserman (Centre for Molecular Medicine and Therapeutics at the Child & Family Research Institute/BC Children’s Hospital).
This research was conducted as part of the Treatable Intellectual Disability Endeavour in British Columbia (TIDE-BC, www.tidebc.org). TIDE-BC is a Collaborative Area of Innovation Project based at BC Children’s Hospital that launched in 2011, the focus of which is improving early diagnosis and treatment of intellectual disability. A diagnosis ends the diagnostic odyssey for patients, provides information and improves genetic counselling along with access to community services and, in some cases, the opportunity to improve patient management.
Funding: The research was supported by BC Children’s Hospital Foundation, Genome British Columbia, BC Clinical Genomics Network, Rare Diseases Foundation, Canadian Institutes of Health Research, Michael Smith Foundation for Health Research, Genome Canada, the British Heart Foundation, The National Institute of General Medical Sciences, Leenaards Foundation, Rare Disease Initiative Zurich, and the Clinical Research Priority Program at the University of Zurich.
Source: Child and Family Research Institute
Image Source: This NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Exome Sequencing and the Management of Neurometabolic Disorders” by Maja Tarailo-Graovac, Ph.D., Casper Shyr, Ph.D., Colin J. Ross, Ph.D., Gabriella A. Horvath, M.D., Ph.D., Ramona Salvarinova, M.D., Xin C. Ye, M.Sc., Lin-Hua Zhang, Ph.D., Amit P. Bhavsar, Ph.D., Jessica J.Y. Lee, B.Sc., Britt I. Drögemöller, Ph.D., Mena Abdelsayed, Ph.D., Majid Alfadhel, M.D., Linlea Armstrong, M.D., Matthias R. Baumgartner, M.D., Ph.D., Patricie Burda, Ph.D., Mary B. Connolly, M.D., Jessie Cameron, Ph.D., Michelle Demos, M.D., Tammie Dewan, M.D., Janis Dionne, M.D., A. Mark Evans, Ph.D., Jan M. Friedman, M.D., Ph.D., Ian Garber, M.D., Suzanne Lewis, M.D., Ph.D., Jiqiang Ling, Ph.D., Rupasri Mandal, Ph.D., Andre Mattman, M.D., Margaret McKinnon, M.D., Aspasia Michoulas, M.D., Daniel Metzger, M.D., Oluseye A. Ogunbayo, Ph.D., Bojana Rakic, Ph.D., Jacob Rozmus, M.D., Peter Ruben, Ph.D., Bryan Sayson, B.Sc., Saikat Santra, M.D., Kirk R. Schultz, M.D., Kathryn Selby, M.D., Paul Shekel, Ph.D., Sandra Sirrs, M.D., Cristina Skrypnyk, M.D., Andrea Superti-Furga, M.D., Ph.D., Stuart E. Turvey, M.D., Ph.D., Margot I. Van Allen, M.D., David Wishart, Ph.D., Jiang Wu, Ph.D., John Wu, M.D., Dimitrios Zafeiriou, M.D., Ph.D., Leo Kluijtmans, Ph.D., Ron A. Wevers, Ph.D., Patrice Eydoux, Ph.D., Anna M. Lehman, M.D., Hilary Vallance, M.D., Sylvia Stockler-Ipsiroglu, M.D., Ph.D., Graham Sinclair, Ph.D., Wyeth W. Wasserman, Ph.D., and Clara D. van Karnebeek, M.D., Ph.D. in New England Journal of Medicine. Published online May 25 2016 doi:10.1056/NEJMoa1515792
[cbtabs][cbtab title=”MLA”]Child and Family Research Institute. “Genome Wide Sequencing Enables Treatment of Some Intellectual Disabilities.” NeuroscienceNews. NeuroscienceNews, 29 May 2016.
<https://neurosciencenews.com/gws-intellectual-disabilities-4341/>.[/cbtab][cbtab title=”APA”]Child and Family Research Institute. (2016, May 29). Genome Wide Sequencing Enables Treatment of Some Intellectual Disabilities. NeuroscienceNews. Retrieved May 29, 2016 from https://neurosciencenews.com/gws-intellectual-disabilities-4341/[/cbtab][cbtab title=”Chicago”]Child and Family Research Institute. “Genome Wide Sequencing Enables Treatment of Some Intellectual Disabilities.” https://neurosciencenews.com/gws-intellectual-disabilities-4341/ (accessed May 29, 2016).[/cbtab][/cbtabs]
Abstract
Exome Sequencing and the Management of Neurometabolic Disorders
BACKGROUND
Whole-exome sequencing has transformed gene discovery and diagnosis in rare diseases. Translation into disease-modifying treatments is challenging, particularly for intellectual developmental disorder. However, the exception is inborn errors of metabolism, since many of these disorders are responsive to therapy that targets pathophysiological features at the molecular or cellular level.
METHODS
To uncover the genetic basis of potentially treatable inborn errors of metabolism, we combined deep clinical phenotyping (the comprehensive characterization of the discrete components of a patient’s clinical and biochemical phenotype) with whole-exome sequencing analysis through a semiautomated bioinformatics pipeline in consecutively enrolled patients with intellectual developmental disorder and unexplained metabolic phenotypes.
RESULTS
We performed whole-exome sequencing on samples obtained from 47 probands. Of these patients, 6 were excluded, including 1 who withdrew from the study. The remaining 41 probands had been born to predominantly nonconsanguineous parents of European descent. In 37 probands, we identified variants in 2 genes newly implicated in disease, 9 candidate genes, 22 known genes with newly identified phenotypes, and 9 genes with expected phenotypes; in most of the genes, the variants were classified as either pathogenic or probably pathogenic. Complex phenotypes of patients in five families were explained by coexisting monogenic conditions. We obtained a diagnosis in 28 of 41 probands (68%) who were evaluated. A test of a targeted intervention was performed in 18 patients (44%).
CONCLUSIONS
Deep phenotyping and whole-exome sequencing in 41 probands with intellectual developmental disorder and unexplained metabolic abnormalities led to a diagnosis in 68%, the identification of 11 candidate genes newly implicated in neurometabolic disease, and a change in treatment beyond genetic counseling in 44%. (Funded by BC Children’s Hospital Foundation and others.)
“Exome Sequencing and the Management of Neurometabolic Disorders” by Maja Tarailo-Graovac, Ph.D., Casper Shyr, Ph.D., Colin J. Ross, Ph.D., Gabriella A. Horvath, M.D., Ph.D., Ramona Salvarinova, M.D., Xin C. Ye, M.Sc., Lin-Hua Zhang, Ph.D., Amit P. Bhavsar, Ph.D., Jessica J.Y. Lee, B.Sc., Britt I. Drögemöller, Ph.D., Mena Abdelsayed, Ph.D., Majid Alfadhel, M.D., Linlea Armstrong, M.D., Matthias R. Baumgartner, M.D., Ph.D., Patricie Burda, Ph.D., Mary B. Connolly, M.D., Jessie Cameron, Ph.D., Michelle Demos, M.D., Tammie Dewan, M.D., Janis Dionne, M.D., A. Mark Evans, Ph.D., Jan M. Friedman, M.D., Ph.D., Ian Garber, M.D., Suzanne Lewis, M.D., Ph.D., Jiqiang Ling, Ph.D., Rupasri Mandal, Ph.D., Andre Mattman, M.D., Margaret McKinnon, M.D., Aspasia Michoulas, M.D., Daniel Metzger, M.D., Oluseye A. Ogunbayo, Ph.D., Bojana Rakic, Ph.D., Jacob Rozmus, M.D., Peter Ruben, Ph.D., Bryan Sayson, B.Sc., Saikat Santra, M.D., Kirk R. Schultz, M.D., Kathryn Selby, M.D., Paul Shekel, Ph.D., Sandra Sirrs, M.D., Cristina Skrypnyk, M.D., Andrea Superti-Furga, M.D., Ph.D., Stuart E. Turvey, M.D., Ph.D., Margot I. Van Allen, M.D., David Wishart, Ph.D., Jiang Wu, Ph.D., John Wu, M.D., Dimitrios Zafeiriou, M.D., Ph.D., Leo Kluijtmans, Ph.D., Ron A. Wevers, Ph.D., Patrice Eydoux, Ph.D., Anna M. Lehman, M.D., Hilary Vallance, M.D., Sylvia Stockler-Ipsiroglu, M.D., Ph.D., Graham Sinclair, Ph.D., Wyeth W. Wasserman, Ph.D., and Clara D. van Karnebeek, M.D., Ph.D. in New England Journal of Medicine. Published online May 25 2016 doi:10.1056/NEJMoa1515792
