Mutations disrupting neuritogenesis genes confer risk for cerebral palsy

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Abstract

<p class="first" id="d5478125e981">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. </p>

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DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants

Janet Piñero, Àlex Bravo, Núria Queralt-Rosinach … (2016)

The information about the genetic basis of human diseases lies at the heart of precision medicine and drug discovery. However, to realize its full potential to support these goals, several problems, such as fragmentation, heterogeneity, availability and different conceptualization of the data must be overcome. To provide the community with a resource free of these hurdles, we have developed DisGeNET (http://www.disgenet.org), one of the largest available collections of genes and variants involved in human diseases. DisGeNET integrates data from expert curated repositories, GWAS catalogues, animal models and the scientific literature. DisGeNET data are homogeneously annotated with controlled vocabularies and community-driven ontologies. Additionally, several original metrics are provided to assist the prioritization of genotype–phenotype relationships. The information is accessible through a web interface, a Cytoscape App, an RDF SPARQL endpoint, scripts in several programming languages and an R package. DisGeNET is a versatile platform that can be used for different research purposes including the investigation of the molecular underpinnings of specific human diseases and their comorbidities, the analysis of the properties of disease genes, the generation of hypothesis on drug therapeutic action and drug adverse effects, the validation of computationally predicted disease genes and the evaluation of text-mining methods performance.

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An update on the prevalence of cerebral palsy: a systematic review and meta-analysis.

Maryam Oskoui, Franzina Coutinho, Jonathan Dykeman … (2013)

The aim of this study was to provide a comprehensive update on (1) the overall prevalence of cerebral palsy (CP); (2) the prevalence of CP in relation to birthweight; and (3) the prevalence of CP in relation to gestational age. A systematic review and meta-analysis was conducted and reported, based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement. Population-based studies on the prevalence of CP in children born in 1985 or after were selected. Statistical analysis was carried out using computer package R, version 2.14. A total of 49 studies were selected for this review. The pooled overall prevalence of CP was 2.11 per 1000 live births (95% confidence interval [CI] 1.98-2.25). The prevalence of CP stratified by gestational age group showed the highest pooled prevalence to be in children weighing 1000 to 1499g at birth (59.18 per 1000 live births; 95% CI 53.06-66.01), although there was no significant difference on pairwise meta-regression with children weighing less than 1000g. The prevalence of CP expressed by gestational age was highest in children born before 28 weeks' gestation (111.80 per 1000 live births; 95% CI 69.53-179.78; p<0.0327). The overall prevalence of CP has remained constant in recent years despite increased survival of at-risk preterm infants. © The Authors. Developmental Medicine & Child Neurology © 2013 Mac Keith Press.

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Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands

Sheng Jin, Jason Homsy, Samir Zaidi … (2017)

Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Exome sequencing of a single cohort of 2,871 CHD probands including 2,645 parent-offspring trios implicated rare inherited mutations in 1.8%, including a recessive founder mutation in GDF1 accounting for ~5% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for ~11% of Shone complex, and dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot. De novo mutations (DNMs) accounted for 8% of cases, including ~3% of isolated CHD patients and ~28% with both neurodevelopmental and extra-cardiac congenital anomalies. Seven genes surpassed thresholds for genome-wide significance and 12 genes not previously implicated in CHD had > 70% probability of being disease-related; DNMs in ~440 genes are inferred to contribute to CHD. There was striking overlap between genes with damaging DNMs in probands with CHD and autism.