Summary: Researchers have identified mutations in single genes that appear to explain some cases of cerebral palsy that are not the result of birth injury.
Source: WUSTL
Cerebral palsy has traditionally been attributed to factors such as in utero infection, premature birth or brain injury around the time of delivery—often linked to oxygen deprivation. Yet many children diagnosed with cerebral palsy show no history of those events, prompting researchers to investigate other causes.
A new international study led by teams at Washington University School of Medicine in St. Louis, the University of Arizona College of Medicine in Phoenix, and Yale University shows that single-gene mutations can account for at least some cerebral palsy cases. The results indicate that many of these mutations arise de novo—that is, they occur by chance in the affected child and are not inherited from the parents.
This work is part of the International Cerebral Palsy Genomics Consortium, a global effort to map genetic contributions to cerebral palsy. Better genetic understanding may improve diagnosis, counseling and ultimately open paths to targeted therapies.
The study was published Sept. 28 in Nature Genetics.
To test the biological relevance of the genetic findings, researchers recreated mutations in fruit flies. Flies carrying mutations in the same genes displayed striking movement problems that mirror the neuromotor deficits seen in many people with cerebral palsy.
Cerebral palsy affects gait, balance and posture and is a lifelong neurodevelopmental disorder. Its severity ranges widely: some people walk independently while others require walkers or wheelchairs. According to public health estimates, cerebral palsy affects approximately two to four children per 1,000 worldwide.
“This international collaboration enabled the largest genetic analysis of cerebral palsy patients and their parents to date,” said Sheng Chih (Peter) Jin, PhD, assistant professor of genetics at Washington University. “Identifying new genetic causes creates opportunities to develop treatments tailored to these underlying mechanisms.”
Although genetic factors have long been suspected to influence cerebral palsy risk, specific causative gene mutations were rarely pinpointed. To explore this, the team performed whole-exome sequencing on 250 trios—children with cerebral palsy and both parents—searching for damaging mutations that could explain the disorder.
The analysis highlighted two genes in particular—FBXO31 and RHOB—where mutations alone were sufficient to cause cerebral palsy. Many other implicated variants were de novo, present only in the affected child; some were inherited from parents who themselves did not have cerebral palsy. Overall, the identified genes tend to play key roles in early brain wiring and neuronal connectivity.
“When we introduced these mutations into fruit flies, the animals’ walking ability was severely impaired,” said senior author Michael Kruer, MD, of the University of Arizona College of Medicine. “We assessed nearly two dozen genes in the fly model and confirmed their importance for neuromotor function and the biology underlying cerebral palsy.”
The study also found overlap between genes implicated in cerebral palsy and genes previously associated with autism, intellectual disability and epilepsy—consistent with clinical observations that many individuals with cerebral palsy experience additional neurodevelopmental challenges.
“Some people with cerebral palsy only have motor difficulties, but there is substantial overlap among neurodevelopmental disorders,” Kruer noted. “More than half of cerebral palsy patients have some degree of learning or intellectual disability, around 40% have epilepsy, and a smaller percentage meet criteria for autism. The genetic results mirror these clinical patterns.”
In the cohort studied, about 12% of cerebral palsy cases could be explained by random de novo mutations, while roughly 2% were due to inherited mutations present in both parents who themselves did not have the disorder. The remaining 86% of cases may arise from environmental factors, other genetic variants that require larger samples to detect, or combinations of genetic and environmental influences that remain under investigation.
“This research can reassure families who were told their child’s condition must have resulted from a pregnancy or delivery problem,” Kruer said. “It also provides important information for genetic counseling, helping families understand recurrence risk for future children.”
Jin added: “We are expanding our studies of cerebral palsy patients and their parents. As sample sizes grow, we expect to quantify contributions from rarer inherited dominant and recessive mutations. This study marks an early but important step toward designing treatments based on genetic insights. Our understanding of cerebral palsy genetics is only beginning, and continued research is essential to uncover causes and find ways to prevent or treat the disorder.”
Funding: This work was supported in part by the Cerebral Palsy Alliance Research Foundation; the Yale-NIH Center for Mendelian Genomics (grant U54 HG006504-01); the Doris Duke Charitable Foundation (CSDA 2014112); the Scott Family Foundation; Cure Cerebral Palsy; the NHMRC (grant 1099163); the Cerebral Palsy Alliance Research Foundation Career Development Award; the Tenix Foundation; the National Natural Science Foundation of China (grant U1604165); the Henan Key Research Program of China (grant 171100310200); VINNOVA (grant 2015-04780); the James Hudson Brown–Alexander Brown Coxe Postdoctoral Fellowship at Yale University School of Medicine; an American Heart Association Postdoctoral Fellowship (18POST34060008); the NIH K99/R00 Pathway to Independence Award (K99HL143036 and R00HL143036); and NIH grants R01NS091299, R01NS106298 and 5R24HD050846-08.
About this genetics research article
Source:
Garvan Institute of Medical Research
Contacts:
Diane Duke Williams – WUSTL
Image Source:
The image is credited to Kruer Lab.
Original Research:
“Mutations disrupting neuritogenesis genes confer risk for cerebral palsy” by Jin SC, et al., published in Nature Genetics. (Closed access)
Abstract
Mutations disrupting neuritogenesis genes confer risk for cerebral palsy
In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. The authors 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) reached genome-wide significance. Two novel monogenic etiologies, FBXO31 and RHOB, were identified. The RHOB mutation enhances active-state Rho effector binding while the FBXO31 mutation reduces cyclin D levels. Candidate cerebral palsy risk genes overlap with neurodevelopmental disorder genes. Network analyses revealed enrichment in Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Risk genes in these pathways regulated neuromotor function in a Drosophila reverse genetics screen. The authors estimate that 14% of cases could be attributed to an excess of damaging de novo or recessive variants, supporting genetically mediated disruption of early neuronal connectivity in cerebral palsy.