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Developmental Biology - Genetic Cerebral Palsy

Study Confirms Genetic Link in Cerebral Palsy

Rare gene mutations can cause cerebral palsy...

An international research team including the University of Adelaide has found further evidence that rare gene mutations can cause cerebral palsy. It is hoped these findings will lead to earlier diagnosis and new treatments for this devastating movement disorder.

In the study published in the journal Nature Genetics researchers employed gene sequencing to examine the DNA of 250 cerebral palsy families, and compared this to a control group of almost 1,800 unaffected families. They then demonstrated the impact rare gene mutations can have on movement control using a fruit fly model.
These findings have important clinical implications and will provide some answers for parents as well. They will act as a guide to healthcare and family planning such as counselling for recurrence risk. Currently, risk is often quoted as around 1 per cent but could be as high as 10 per cent when factoring in genetic inheritance.

Co-author of the research, Emeritus Professor Alastair MacLennan, AO, University of Adelaide, says the new study confirms the pioneering work of the Australian Collaborative Cerebral Palsy Research Group based at the Robinson Research Institute at the University of Adelaide.
"Cerebral palsy is a non-progressive developmental movement disorder impacting motor function, which affects approximately one in every 700 births in Australia and a similar number worldwide. Symptoms range from mild to severe and can include intellectual disability.

Historically, cerebral palsy was considered largely the result of perinatal asphyxia — decreased oxygen to the baby's brain at birth — however this has only been found in 8-10 per cent of cases.

Eliminating other known causes, including premature birth and trauma at birth, leaves a large number of cases — as many as 40 per cent in some studies — with an unknown origin."

Alastair MacLennan, AO, MB ChB, MD, FRCOG, FRANZCOG, Emeritus Professor and third Head of Obstetrics and Gynecology, University of Adelaide, Australia.

Researchers at the University of Adelaide over many years have advocated that cerebral palsy is often caused by rare genetic variations (or mutations) which disrupt a child's control of movement and posture.

"Where previous studies have indicated underlying genetic causes in cerebral palsy, this study is the largest to date and includes in-depth statistical modelling with new controls to overcome limitations of earlier research," explains Emeritus Professor MacLennan.

Co-author Professor Jozef Gecz, Channel 7 Children's Research Foundation Chair for the Prevention of Childhood Disability and Head of Neurogenetics at the University of Adelaide, believes at a conservative estimate, 14 per cent of cerebral palsy families in the study had an excess of damaging genetic mutations and inherited recessive gene variations.
"Genes don't like to change; as soon as a gene is altered in any way you disturb its programing, and it can no longer perfectly perform what it's designed to do.

Our USA collaborators were able to disturb the same genes in fruit fly as found in humans, and in three out of four instances it severely altered the movement of either fruit fly larvae or adults or both. Gene mutations were mostly spontaneous new variants occurring in the sperm or an egg of the parents, who are otherwise not affected."

Jozef Gecz PhD, Channel 7 Children's Research Foundation Chair for the Prevention of Childhood Disability, Head of Neurogenetics, the University of Adelaide, and co-author of the research.

In some cases, identification of specific gene variations in individuals in the study led to new recommendations for patient health management, including treatments that would not have been initiated otherwise. Other benefits of the study include a potential reduction in litigation, and evidence for further research to identify other damaging genetic variants in human DNA.
"As recently as 30 years ago we were very limited in treatments for cerebral palsy, and the outlook for anyone diagnosed was grim. The more we understand the role of genetics in cerebral palsy, the closer we get to learning how to prevent it. We've now opened the door for new treatments, earlier diagnosis and intervention, which could lead to greatly improved quality of life."

Jozef Gécz MD, Head, Neurogenetics, Adelaide Medical School, South Australia's Scientist of the Year 2019.

In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent–offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1A and CTNNB1) met genome-wide significance. We identified two novel monogenic etiologies, FBXO31 and RHOB, and showed that the RHOB mutation enhances active-state Rho effector binding while the FBXO31 mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in a Drosophila reverse genetics screen. We estimate that 14% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.

Sheng Chih Jin, Sara A. Lewis, Somayeh Bakhtiari, Xue Zeng, Michael C. Sierant, Sheetal Shetty, Sandra M. Nordlie, Aureliane Elie, Mark A. Corbett, Bethany Y. Norton, Clare L. van Eyk, Shozeb Haider, Brandon S. Guida, Helen Magee, James Liu, Stephen Pastore, John B. Vincent, Janice Brunstrom-Hernandez, Antigone Papavasileiou, Michael C. Fahey, Jesia G. Berry, Kelly Harper, Chongchen Zhou, Junhui Zhang, Boyang Li, Jennifer Heim, Dani L. Webber, Mahalia S. B. Frank, Lei Xia, Yiran Xu, Dengna Zhu, Bohao Zhang, Amar H. Sheth, James R. Knight, Christopher Castaldi, Irina R. Tikhonova, Francesc López-Giráldez, Boris Keren, Sandra Whalen, Julien Buratti, Diane Doummar, Megan Cho, Kyle Retterer, Francisca Millan, Yangong Wang, Jeff L. Waugh, Lance Rodan, Julie S. Cohen, Ali Fatemi, Angela E. Lin, John P. Phillips, Timothy Feyma, Suzanna C. MacLennan, Spencer Vaughan, Kylie E. Crompton, Susan M. Reid, Dinah S. Reddihough, Qing Shang, Chao Gao, Iona Novak, Nadia Badawi, Yana A. Wilson, Sarah J. McIntyre, Shrikant M. Mane, Xiaoyang Wang, David J. Amor, Daniela C. Zarnescu, Qiongshi Lu, Qinghe Xing, Changlian Zhu, Kaya Bilguvar, Sergio Padilla-Lopez, Richard P. Lifton, Jozef Gecz, Alastair H. MacLennan and Michael C. Kruer.

The authors gratefully acknowledge the support of the patients and families who have graciously and patiently supported this work from its inception. Without their partnership, these studies would not have been possible. We acknowledge the support of the clinicians who generously provided their expertise in support of this study, including M.-C. Waugh, M. Axt and V. Roberts of the Children’s Hospital Westmead; K. Lowe of Sydney Children’s Hospital; R. Russo, J. Rice and A. Tidemann of the Women’s and Children’s Hospital, Adelaide; T. Carroll and L. Copeland of the Lady Cilento Children’s Hospital, Brisbane; and J. Valentine of Perth Children’s Hospital. We appreciate the collaboration of S. Knoblach and E. Hoffman (Children’s National Medical Center). This work was supported in part by the Cerebral Palsy Alliance Research Foundation (M.C.K.), the Yale-NIH Center for Mendelian Genomics (U54 HG006504-01), Doris Duke Charitable Foundation CSDA 2014112 (M.C.K.), the Scott Family Foundation (M.C.K.), Cure CP (M.C.K.), NHMRC grant 1099163 (A.H.M., C.L.v.E., J.G. and M.A.C.), NHMRC Senior Principal Research Fellowship 1155224 (J.G.), Channel 7 Children’s Research Foundation (J.G.), a Cerebral Palsy Alliance Research Foundation Career Development Award (M.A.C.), the Tenix Foundation (A.H.M., J.G., C.L.v.E. and M.A.C.), the National Natural Science Foundation of China (U1604165, X.W.), Henan Key Research Program of China (171100310200, C. Zhu), VINNOVA (2015-04780, C. Zhu), the James Hudson Brown–Alexander Brown Coxe Postdoctoral Fellowship at the Yale University School of Medicine (S.C.J.), an American Heart Association Postdoctoral Fellowship (18POST34060008 to S.C.J.), the NIH K99/R00 Pathway to Independence Award (R00HL143036-02 to S.C.J.) and NIH grants R01NS091299 (D.C.Z.) and NIH R01NS106298 (M.C.K.).

Researchers across four countries co-authored this study. Authoring institutions include — USA: Yale University School of Medicine, Rockefeller University, Phoenix Children's Hospital and University of Arizona College of Medicine; and in China, the Children's Hospital of Zhengzhou and Shanghai Institute of Planned Parenthood Research.

The Australian Collaborative Cerebral Palsy Research Group at the University of Adelaide's Robinson Research Institute studies the causes of cerebral palsy, with particular focus on genetic pathways. The group has been a leader in its field for more than 20 years. The authors declare no competing interests.

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Oct 9 2020   Fetal Timeline   Maternal Timeline   News

Emeritus Professor Alastair MacLennan beside Mathew Reinersten, Adelaide, who is an ambassador for the group's cerebral palsy research. CREDIT University of Adelaide

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