The Diverse Genetic Landscape of Neurodevelopmental Disorders

Hu, Wentao; Chahrour, Maria H.; Walsh, Christopher A.

doi:10.1146/annurev-genom-090413-025600

Cited by 156 publications

(130 citation statements)

References 143 publications

(161 reference statements)

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“…[55][56][57][58][59] However, in vivo modeling of somatic mutations in the developing brain has been challenging given the limitations of genome-editing tools 60 and the size constraints of viral vectors. 61 In the present study, we combined in utero electroporation with the CRISPR-Cas9 system to introduce somatic genome modifications in a small fraction of neurons in the developing brain.…”

Section: Discussionmentioning

confidence: 99%

Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia

Lim

Gopalappa

Kim

et al. 2017

The American Journal of Human Genetics

174

159

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Focal cortical dysplasia (FCD) is a major cause of the sporadic form of intractable focal epilepsies that require surgical treatment. It has recently been reported that brain somatic mutations in MTOR account for 15%-25% of FCD type II (FCDII), characterized by cortical dyslamination and dysmorphic neurons. However, the genetic etiologies of FCDII-affected individuals who lack the MTOR mutation remain unclear. Here, we performed deep hybrid capture and amplicon sequencing (read depth of 1003-20,0123) of five important mTOR pathway genes-PIK3CA, PIK3R2, AKT3, TSC1, and TSC2-by using paired brain and saliva samples from 40 FCDII individuals negative for MTOR mutations. We found that 5 of 40 individuals (12.5%) had brain somatic mutations in TSC1 (c.64C>T [p.Arg22Trp] and c.610C>T [p.Arg204Cys]) and TSC2 (c.4639G>A [p.Val1547Ile]), and these results were reproducible on two different sequencing platforms. All identified mutations induced hyperactivation of the mTOR pathway by disrupting the formation or function of the TSC1-TSC2 complex. Furthermore, in utero CRISPR-Cas9-mediated genome editing of Tsc1 or Tsc2 induced the development of spontaneous behavioral seizures, as well as cytomegalic neurons and cortical dyslamination. These results show that brain somatic mutations in TSC1 and TSC2 cause FCD and that in utero application of the CRISPR-Cas9 system is useful for generating neurodevelopmental disease models of somatic mutations in the brain.

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Section: Discussionmentioning

confidence: 99%

Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia

Lim

Gopalappa

Kim

et al. 2017

The American Journal of Human Genetics

174

159

View full text Add to dashboard Cite

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“…Further, mutations in KDM5B have been reported in individuals with non-syndromic intellectual disability and autism spectrum disorders (Athanasakis et al, 2014;De Rubeis et al, 2014;Iossifov et al, 2014) and mutations in KDM5A have been linked to an autosomal recessive form of intellectual disability (Najmabadi et al, 2011). Similarly, several genes implicated in cytoskeleton dynamics are mutated in intellectual disability and autism spectrum disorders (Nadif Kasri and Van Aelst, 2008;Ba et al, 2013;Hu et al, 2014;Srivastava and Schwartz, 2014). Thus, our results help to establish a functional link between chromatin regulators and the actin-remodeling genes required for axon/dendrite formation and synaptic plasticity, which are processes compromised in neurodevelopmental and psychiatric disorders.…”

Section: Discussionmentioning

confidence: 99%

The H3K4me3/2 histone demethylase RBR-2 controls axon guidance by repressing the actin-remodeling gene wsp-1

Mariani

Lussi

Vandamme

et al. 2016

Journal of Cell Science

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The dynamic regulation of histone modifications is important for modulating transcriptional programs during development. Aberrant H3K4 methylation is associated with neurological disorders, but how the levels and the recognition of this modification affect specific neuronal processes is unclear. Here, we show that RBR-2, the sole homolog of the KDM5 family of H3K4me3/2 demethylases in Caenorhabditis elegans, ensures correct axon guidance by controlling the expression of the actin regulator wsp-1. Loss of rbr-2 results in increased levels of H3K4me3 at the transcriptional start site of wsp-1, with concomitant higher wsp-1 expression responsible for defective axon guidance. In agreement, overexpression of WSP-1 mimics rbr-2 loss, and its depletion restores normal axon guidance in rbr-2 mutants. NURF-1, an H3K4me3-binding protein and member of the chromatin-remodeling complex NURF, is required for promoting aberrant wsp-1 transcription in rbr-2 mutants and its ablation restores wild-type expression of wsp-1 and axon guidance. Thus, our results establish a precise role for epigenetic regulation in neuronal development by demonstrating a functional link between RBR-2 activity, H3K4me3 levels, the NURF complex and the expression of WSP-1.

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“…These studies indicate that many phenotypically different disorders may share identical underlying genetic risk factors, 8,9 and conversely, different genetic factors may lead to phenotypically similar clinical syndromes. 10 Such discoveries challenge traditional diagnostic categories, suggesting that many neurodevelopmental disorders may be part of a continuum of clinical expression rather than distinct conditions. CP is not yet considered among them, even though many children with CP also experience epilepsy, cognitive impairment, autism spectrum disorders, or attention-deficit/hyperactivity disorder (ADHD).…”

mentioning

confidence: 99%

Neurodevelopmental Disorders or Early Death in Siblings of Children With Cerebral Palsy

et al. 2016

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To explore the presence of shared underlying causes of cerebral palsy (CP) and other neurodevelopmental disorders, by examining risks of other disorders in siblings of children with CP. METHODS:We used Norwegian national registries to identify 1.4 million pairs of full siblings (singletons) and 28 000 sets of twins born from 1967 to 2006, identify stillbirths and neonatal deaths, and find individuals with CP, epilepsy, intellectual disability, autism spectrum disorders, attention-deficit/hyperactivity disorder, blindness, deafness, schizophrenia, and bipolar disorder. Associations between CP in 1 sibling and neurodevelopmental disorders or early death in other siblings were estimated using logistic regression models.RESULTS: There were 5707 neonatal survivors (beyond 28 days) with CP (2.5/1000). These children had substantial comorbidity (eg, 29% had epilepsy). Singleton siblings of (singleton) children with CP had increased risks of neurodevelopmental problems, including epilepsy (odds ratio CONCLUSIONS: Siblings of a child with CP were at increased risk for a variety of other neurodevelopmental morbidities, as well as early death, indicating the presence of shared underlying causes.[

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The Diverse Genetic Landscape of Neurodevelopmental Disorders

Cited by 156 publications

References 143 publications

Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia

Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia

The H3K4me3/2 histone demethylase RBR-2 controls axon guidance by repressing the actin-remodeling gene wsp-1

Neurodevelopmental Disorders or Early Death in Siblings of Children With Cerebral Palsy

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