Canadian study identifies genetic link to cause of cerebral palsy

New, groundbreaking evidence suggests a much stronger underlying genetic link in children with hemiplegic CP – the most common type of CP – than previously thought.

The Hospital for Sick Children (SickKids) August 3, 2017

A Canadian study published today in Genetics in Medicine has identified a genetic link that may explain how cerebral palsy (CP) develops in-utero. CP is the most common cause of physical disability in children, and considered to be caused by factors such as birth asphyxia, stroke, and infection in the developing brain of a child.

However, new groundbreaking evidence suggests a much stronger underlying genetic link in children with hemiplegic CP – the most common type of CP – than previously thought. This research was led by scientists at Holland Bloorview Kids Rehabilitation Hospital and The Hospital for Sick Children (SickKids), and funded by CP-NET (Childhood Cerebral Palsy Integrated Neuroscience Discovery Network) Integrated Discovery Program of the Ontario Brain Institute (OBI). The research was a collaborative effort involving clinicians and scientists across numerous Ontario institutions working with individuals with CP and their families.

“We are getting closer to understanding the complex biology of CP and the potential ‘brain development’ genes that impact a child’s risk of developing it, including the importance of considering genetic testing for kids and youth with symptoms or signs,” says Dr. Darcy Fehlings, senior clinician scientist at Holland Bloorview Kids Rehabilitation Hospital and principal investigator at CP-NET. “Findings support a strong genetic link to the cause of hemiplegic CP, which affects 35 per cent of kids with CP. Clinically this supports the use of genomic testing as part of forming the work-up for a child with hemiplegic CP. In the future, understanding the genetic basis of CP may lead to the development of new treatment approaches.”

The research team performed DNA analysis on nearly 100 children with hemiplegic CP (where only one side of their body is affected) and their biological parents to identify rare copy-number variations (CNVs) – or structural alterations to the DNA of a genome – compared to those of over 10,000 population controls. Rare CNVs that impacted genes critical for brain development and function were found in more than 20 per cent of children with hemiplegic CP, while in 5 per cent of these children, the CNV was likely the major factor causing CP. These findings are significant in that they support the results of an earlier study in 2015, and point to an even stronger association between CNVs, CP, and related medical complications.

“This study reflects our previous findings that CNVs are involved in a significant proportion of individuals with the hemiplegic form of cerebral palsy,” says Dr. Stephen Scherer, director of TCAG and senior scientist at SickKids, director of the McLaughlin Centre and professor in the Department of Molecular Genetics at the University of Toronto. “In 2015, we found that CNVs were a significant contributor in unselected cerebral palsy; mimicking the results of this study and showing an even greater connection. We anticipate finding an even greater role for genetics in CP when we use newer technologies like whole genome sequencing.”

Tom Mikkelsen, president and scientific director at the Ontario Brain Institute added that, “The discovery of a genetic link to CP not only demonstrates progress in understanding the condition better but also highlights the benefit and need for increased research collaboration. To find definite answers and effective treatments, we need to come together as a neuroscience community in order to maximize impact and improve the lives of people living with brain disorders.”

Microarray analysis, a first-tier clinical diagnostic test for individuals with developmental disabilities and birth defects, was used to analyze genes to further understand the biology of hemiplegic CP. While microarray analysis is not currently used in CP, its use in this study raises the question of whether genomic testing should be part of a clinical assessment for a child with CP. Such testing shows strong promise for helping to provide parents and families with information on why their child developed CP, and helping scientists develop new and better ways to prevent, treat, and manage symptoms in children with CP.

In Canada, three in every 1000 children are diagnosed each year with CP. Signs and symptoms range – while some children are mildly affected – others can experience challenges in motor development or muscle control, or being unable to walk or communicate.

About Holland Bloorview Kids Rehabilitation Hospital

Holland Bloorview Kids Rehabilitation Hospital is Canada’s largest children’s rehabilitation hospital and cares for kids with disabilities and medical complexity, and provides rehabilitation after illness or trauma. Fully affiliated with the University of Toronto, Holland Bloorview serves nearly 7,500 children and youth annually accounting for over 1,000 unique diagnoses. Holland Bloorview is a global leader in disability research, teaching, and client- and family-centered care. Holland Bloorview pioneers treatments, technologies, therapies and real-world programs that give kids with disabilities the tools to participate fully in life.

About The Hospital for Sick Children

The Hospital for Sick Children (SickKids) is recognized as one of the world’s foremost paediatric health-care institutions and is Canada’s leading centre dedicated to advancing children’s health through the integration of patient care, research and education. Founded in 1875 and affiliated with the University of Toronto, SickKids is one of Canada’s most research-intensive hospitals and has generated discoveries that have helped children globally. Its mission is to provide the best in complex and specialized child and family-centred care; pioneer scientific and clinical advancements; share expertise; foster an academic environment that nurtures health-care professionals; and champion an accessible, comprehensive and sustainable child health system. SickKids is proud of its vision for Healthier Children. A Better World. Follow us on Twitter @SickKidsNews and Instagram @SickKidsToronto

About Ontario Brain Institute

The Ontario Brain Institute is a provincially-funded, not-for-profit research centre seeking to maximize the impact of neuroscience and establish Ontario as a world leader in brain research, commercialization and care. We create convergent partnerships between researchers, clinicians, industry, patients, and their advocates to foster discovery and deliver innovative products and services that improve the lives of those living with brain disorders.

For more information

Michelle Stegnar Holland Bloorview Kids Rehabilitation Hospital mstegnar@hollandbloorview.ca 416-425-6220 ext. 3497

Matet Nebres The Hospital for Sick Children matet.nebres@sickkids.ca 416-813-6380

Source The Hospital for Sick Children (SickKids)

References

De novo and rare inherited copy-number variations in the hemiplegic form of cerebral palsy, Zarrei M, Fehlings DL, Mawjee K, Switzer L, Thiruvahindrapuram B, Walker S, Merico D, Casallo G, Uddin M, MacDonald JR, Gazzellone MJ, Higginbotham EJ, Campbell C, deVeber G, Frid P, Gorter JW, Hunt C, Kawamura A, Kim M, McCormick A, Mesterman R, Samdup D, Marshall CR, Stavropoulos DJ, Wintle RF, Scherer SW. Genet Med. 2017 Aug 3. doi: 10.1038/gim.2017.83.   PDF in Nature

Clinically relevant copy number variations detected in cerebral palsy, Oskoui M, Gazzellone MJ, Thiruvahindrapuram B, Zarrei M, Andersen J, Wei J, Wang, Wintle RF, Marshall CR, Cohn RD, Weksberg R, Stavropoulos DJ, Fehlings D, Shevell MI, Scherer SW. Nat Commun. 2015 Aug 3;6:7949. doi: 10.1038/ncomms8949. PDF in Nature