Insights From Genetic Studies of Cerebral Palsy.
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ABSTRACT:
SUBMITTER: Lewis SA
PROVIDER: S-EPMC7859255 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:AIM To determine which patients with cerebral palsy (CP) should undergo genetic testing, we compared the rate of likely causative genetic variants from whole-exome sequencing in individuals with and without environmental risk factors. METHOD Patients were part of a convenience and physician-referred cohort recruited from a single medical center, and research whole-exome sequencing was completed. Participants were evaluated for the following risk factors: extreme preterm birth, brain bleed or stroke, birth asphyxia, brain malformations, and intrauterine infection. RESULTS A total of 151 unrelated individuals with CP (81 females, 70 males; mean age 25y 7mo [SD 17y 5mo], range 3wks-72y) participated. Causative genetic variants were identified in 14 participants (9.3%). There was no significant difference in diagnostic rate between individuals with risk factors (10 out of 123; 8.1%) and those without (4 out of 28; 14.3%) (Fisher's exact p=0.3). INTERPRETATION While the rate of genetic diagnoses among individuals without risk factors was higher than those with risk factors, the difference was not statistically significant at this sample size. The identification of genetic diagnoses in over 8% of cases with risk factors suggests that these might confer susceptibility to environmental factors, and that further research should include individuals with risk factors. What this paper adds There is no significant difference in diagnostic rate between individuals with and without risk factors. Genetic variants may confer susceptibility to environmental risk factors. Six causative variants were identified in genes not previously associated with cerebral palsy. Global developmental delay/intellectual disability is positively associated with a genetic etiology. Extreme preterm birth, stroke/brain hemorrhage, and older age are negatively associated with a genetic etiology.
| S-EPMC9277698 | biostudies-literature
Project description:AimTo define clinical common data elements (CDEs) and a mandatory minimum data set (MDS) for genomic studies of cerebral palsy (CP).MethodCandidate data elements were collated following a review of the literature and existing CDEs. An online, three-round Delphi survey was used to rate each data element as either 'core', 'recommended', 'exploratory', or 'not required'. Members of the International Cerebral Palsy Genomics Consortium (ICPGC) rated the core CDEs as either mandatory or not, to form the MDS. For both the CDEs and the MDS, a data element was considered to have reached consensus if more than 75% of respondents agreed.ResultsForty-six individuals from around the world formed the Delphi panel: consumers (n=2), scientists/researchers (n=17), medical (n=19), and allied health professionals (n=8). The CDEs include 107 data elements across six categories: demographics, diagnostics, family history, antenatal and neonatal details, clinical traits, and CP-specific assessments. Of these, 10 are mandatory, 42 core, 41 recommended, and 14 are exploratory.InterpretationThe ICPGC CDEs provide a foundation for the standardization of phenotype data captured in CP genomic studies and will benefit international collaborations and pooling of data, particularly in rare conditions.What this paper addsA set of 107 common data elements (CDEs) for genomics studies in cerebral palsy is provided. The CDEs include standard definitions and data values domains. The CDEs will facilitate international data sharing, collaboration, and improved clinical interpretation of findings.
| S-EPMC9790418 | biostudies-literature
Project description:BackgroundAlthough many clinical risk factors of spastic cerebral palsy (CP) have been identified, the genetic basis of spastic CP is largely unknown. Here, using whole-genome genetic information linked to a deidentified electronic health record (BioVU) with replication in the UK Biobank and FinnGen, we perform the first genome-wide association study (GWAS) for spastic CP.ObjectiveTo define the genetic basis of spastic CP.MethodsWhole-genome data were obtained using the multi-ethnic genotyping array (MEGA) genotyping array capturing single-nucleotide polymorphisms (SNPs), minor allele frequency (MAF) > 0.01, and imputation quality score (r2) > 0.3, imputed based on the 1000 genomes phase 3 reference panel. Threshold for genome-wide significance was defined after Bonferroni correction for the total number of SNPs tested (P < 5.0 × 10-8). Replication analysis (defined as P < .05) was performed in the UK Biobank and FinnGen.ResultsWe identify 1 SNP (rs78686911) reaching genome-wide significance with spastic CP. Expression quantitative trait loci (eQTL) analysis suggests that rs78686911 decreases expression of GRIK4, a gene that encodes a high-affinity kainate glutamatergic receptor of largely unknown function. Replication analysis in the UK Biobank and FinnGen reveals additional SNPs in the GRIK4 loci associated with CP.ConclusionTo our knowledge, we perform the first GWAS of spastic CP. Our study indicates that genetic variation contributes to CP risk.
| S-EPMC8364821 | biostudies-literature
Project description:Cerebral palsy (CP) represents a group of non-progressive clinically heterogeneous disorders that are characterized by motor impairment and early age-of-onset, frequently accompanied by co-morbidities. The cause of CP has historically been attributed to environmental stressors resulting in brain damage. While genetic risk factors are also implicated, guidelines for diagnostic assessment of CP do not recommend for routine genetic testing. Given numerous reports of etiologic copy number variations (CNVs) in other neurodevelopmental disorders, we used microarrays to genotype a population-based prospective cohort of children with CP and their parents. Here we identify de novo CNVs in 8/115 (7.0%) CP patients (~1% rate in controls). In four children, large chromosomal abnormalities deemed pathogenic were found, and they were significantly more likely to have severe neuro-motor impairments than those CP subjects without such alterations. Overall the CNV data would have impacted our diagnosis or classification of CP in 11/115 (9.6%) families. Dr. Maryam Oskoui* , Mr. Matthew Gazzellone* , Ms. Bhooma Thiruvahindrapuram , Dr. Mehdi Zarrei , Dr. John Andersen , Dr. John Wei , Dr. Zhouzhi Wang , Dr. Richard Wintle , Dr. Christian Marshall , Dr. Ronald Cohn , Dr. Rosanna Weksberg , Dr. James Stavropoulos , Dr. Darcy Fehlings , Dr. Michael Shevell, Dr. Stephen Scherer. Clinically Relevant Copy Number Variations Detected in Cerebral Palsy. Nature Communications, 2015. Following our rigorous quality control procedure, we successfully genotyped 147 proband samples from individuals with cerebral palsy (81 males and 66 females) and 282 samples obtained from parents (134 males and 148 females). This facilitated the identification of de novo and rare inherited copy number variations of clinical interest.
2015-07-28 | E-GEOD-70374 | biostudies-arrayexpress
Project description:Cerebral palsy is a chronic childhood disorder that can have diverse etiologies. Injury to the developing brain that occurs either in utero or soon after birth can result in the motor, sensory, and cognitive deficits seen in cerebral palsy. Although the etiologies for cerebral palsy are variable, neuroinflammation plays a key role in the pathophysiology of the brain injury irrespective of the etiology. Currently, there is no effective cure for cerebral palsy. Nanomedicine offers a new frontier in the development of therapies for prevention and treatment of brain injury resulting in cerebral palsy. Nanomaterials such as dendrimers provide opportunities for the targeted delivery of multiple drugs that can mitigate several pathways involved in injury and can be delivered specifically to the cells that are responsible for neuroinflammation and injury. These materials also offer the opportunity to deliver agents that would promote repair and regeneration in the brain, resulting not only in attenuation of injury, but also enabling normal growth. In this review, the current advances in nanotechnology for treatment of brain injury are discussed with specific relevance to cerebral palsy. Future directions that would facilitate clinical translation in neonates and children are also addressed.
| S-EPMC3818020 | biostudies-other
Project description:Data Access Committee EGAC00001003068
| EGAC00001003068 | EGA
Project description:ObjectiveTo introduce the Korean Database of Cerebral Palsy (KDCP) and to provide the first report on characteristics of subjects with cerebral palsy (CP).MethodsThe KDCP is a nationwide database of subjects with CP, which includes a total of 773 subjects. Characteristics such as demography, birth history, onset and type of CP, brain magnetic resonance imaging (MRI) findings, functional ability and accompanying impairments, were extracted and analyzed.ResultsPreterm delivery and low birth weight were found in 59.51% and 60.28% of subjects, respectively. Postnatally acquired CP was 15.3%. The distribution of CP was 87.32%, 5.17%, and 1.81% for spastic, dyskinetic, and ataxic types, respectively. Functional ability was the worst in dyskinetic CP, as compared to other types of CP. Speech-language disorder (43.9%), ophthalmologic impairment (32.9%), and intellectual disability (30.3%) were the three most common accompanying impairments. The number of accompanying impairments was elevated in subjects with preterm birth and low birth weight. Brain MRI showed normal findings, malformations, and non-malformations in 10.62%, 9.56%, and 77.35% of subjects, respectively. Subjects with normal MRI findings had better functional ability than subjects with other MRI findings. MRI findings of a non-malformation origin, such as periventricular leukomalacia, were more common in subjects with preterm birth and low birth weight.ConclusionThe KDCP and its first report are introduced in this report, wherein the KDCP established agreement on terminologies of CP. This study added information on the characteristics of subjects with CP in South Korea, which can now be compared to those of other countries and ethnicities.
| S-EPMC5608672 | biostudies-literature
Project description: Not available
| S-EPMC1420759 | biostudies-literature
Project description: Not available
| S-EPMC6481791 | biostudies-literature
Project description:ObjectiveThe objective of this study was to assess the rehabilitation status and factors associated with rehabilitation service utilisation among children with cerebral palsy (CP) in Bangladesh.Materials and methodsThis is a population-based surveillance study conducted among children with CP registered in the Bangladesh CP Register (BCPR), the first population-based register of children with CP aged <18 years (y) in Bangladesh. Children with CP were identified from the community using the key informant method and underwent a detailed neurodevelopmental assessment. Socio-demographic, clinical and rehabilitation status were documented. Unadjusted and adjusted analyses with a 95% confidence interval (CI) were used to identify potential predictors of rehabilitation service uptake.ResultsBetween January 2015 and December 2019, 2852 children with CP were registered in the BCPR (mean (standard deviation, SD) age: 7 y 8 months (mo) (4 y 7 mo), 38.5% female). Of these, 50.2% had received rehabilitation services; physiotherapy was the most common type of service (90.0%). The mean (SD) age at commencement of rehabilitation services was 3 y 10 mo (3 y 1 mo). The odds of not receiving rehabilitation was significantly higher among female children (adjusted odds ratio (aOR) 1.3 [95% CI: 1.0-1.7], children whose mothers were illiterate and primary level completed (aOR 2.1 [95% CI: 1.4-3.1] and aOR 1.5 [95% CI: 1.1-2.1], respectively), fathers were illiterate (aOR 1.9 [95% CI: 1.3-2.8]), had a monthly family income ~US$ 59-118 (aOR: 1.8 [95% CI: 1.2-2.6]), had hearing impairment (aOR: 2.3 [95% CI: 1.5-3.5]) and motor severity (i.e. Gross Motor Function Classification System level III (aOR: 0.6 [95% CI: 0.3-0.9]) and level V (aOR: 0.4 [95% CI: 0.2-0.7])).ConclusionsRehabilitation status was poor among the majority of the children with CP in the BCPR cohort, limiting their opportunities for functional improvement. A community-based rehabilitation model focusing on socio-demographic and clinical characteristics should be a public health priority in Bangladesh.
| S-EPMC8092763 | biostudies-literature