Genetically complex epilepsies, copy number variants and syndrome constellations

Mefford, Heather C; Mulley, John C.

doi:10.1186/gm192

Cited by 36 publications

(33 citation statements)

References 70 publications

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“…A similar picture is suggested for structural variants at 16p13.11 where we again see a range of neurobehavioral phenotypes including autism [42], epilepsy [34], and epilepsy with intellectual disability [43]. There is a suggestion that 16p13.11 variants are more likely to result in an epilepsy phenotype versus intellectual disability or autism [39,44].…”

Section: Common Neurodevelopmental Determinants: Anatomical and Molecsupporting

confidence: 76%

“…This hypothesis fits nicely with a model of disease that emphasizes disruption of key neurobiological pathways in which one could observe a range of possible phenotypes. Typically, the common disease-rare variant hypothesis focuses on a single common disease phenotype; in the study of autism and epilepsy it appears that there are a number of rare variants that confer multiple phenotypesmany of which co-occur in individuals [34]. Again, this is a novel way of conceptualizing the relationship among neurodevelopmental phenotypes.…”

Section: Common Neurodevelopmental Determinants: Anatomical and Molecmentioning

confidence: 99%

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Epilepsy and Autism: Neurodevelopmental Perspective

Tuchman

Cuccaro

2011

Curr Neurol Neurosci Rep

111

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Epilepsy and autism coexist in up to 20% of children with either disorder. Current studies suggest that a frequent co-occurring condition in epilepsy and autism is intellectual disability, which shows a very high prevalence in those with both autism and epilepsy. In addition, these recent studies suggest that early-onset seizures may index a group of infants at high risk for developing autism, usually with associated intellectual deficits. In this review we discuss recent advances in the conceptualization of shared anatomical and molecular mechanisms that may account for the coexistence of epilepsy, autism, and intellectual disability. A major contribution to our improved understanding of the relationship among these three phenotypes is the discovery of multiple genomic variants that cut across them as well as other neurobehavioral phenotypes. As these discoveries continue they are very likely to elucidate causal mechanisms for the various phenotypes and pinpoint biologic pathways that may be amenable to therapeutic interventions for this group of neurodevelopmental disorders.

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Section: Common Neurodevelopmental Determinants: Anatomical and Molecsupporting

confidence: 76%

Section: Common Neurodevelopmental Determinants: Anatomical and Molecmentioning

confidence: 99%

Epilepsy and Autism: Neurodevelopmental Perspective

Tuchman

Cuccaro

2011

Curr Neurol Neurosci Rep

111

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“…In recent genome-wide studies, rare recurrent copy number variants (CNVs) that are important risk factors for other neuropsychiatric disorders were present in about 4% of the generalized epilepsies. [6][7][8] Several single cases with non-recurrent deletions have also been reported in otherwise common epilepsies accounting for up to 5% of patients studied. The genes located within these CNVs deserve further study given that they are potential candidates for susceptibility to GGE.…”

Section: Introductionmentioning

confidence: 94%

Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy

et al. 2016

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Genetic generalized epilepsy (GGE), formerly known as idiopathic generalized epilepsy, is the most common form of epilepsy and is thought to have predominant genetic etiology. GGE are clinically characterized by absence, myoclonic, or generalized tonic-clonic seizures with electroencephalographic pattern of bilateral, synchronous, and symmetrical spike-and-wave discharges. Despite their strong heritability, the genetic basis of generalized epilepsies remains largely elusive. Nevertheless, recent advances in genetic technology have led to the identification of numerous genes and genomic defects in various types of epilepsies in the past few years. In the present study, we performed whole-exome sequencing in a family with GGE consistent with the diagnosis of eyelid myoclonia with absences. We found a nonsense variant (c.196C4T/p.(Arg66*)) in RORB, which encodes the beta retinoid-related orphan nuclear receptor (RORβ), in four affected family members. In addition, two de novo variants (c.218T4C/p.(Leu73Pro); c.1249_1251delACG/p.(Thr417del)) were identified in sporadic patients by trio-based exome sequencing. We also found two de novo deletions in patients with behavioral and cognitive impairment and epilepsy: a 52-kb microdeletion involving exons 5-10 of RORB and a larger 9q21-microdeletion. Furthermore, we identified a patient with intellectual disability and a balanced translocation where one breakpoint truncates RORB and refined the phenotype of a recently reported patient with RORB deletion. Our data support the role of RORB gene variants/CNVs in neurodevelopmental disorders including epilepsy, and especially in generalized epilepsies with predominant absence seizures.

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“…33 36 38 In fact, the combined frequency of this CNV along with 15q13.3del and 16p13.11del is approximately 3% in patients with genetic generalised epilepsy (GGE),66 and these CNVs are particularly enriched in patients with ID plus GGE when compared with individuals with GGE or ID alone 14 67…”

Section: Recurrent Cnvs Associated With Increased Risk For Ndsmentioning

confidence: 99%

Recurrent copy number variations as risk factors for neurodevelopmental disorders: critical overview and analysis of clinical implications

2015

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Neurodevelopmental disorders (NDs) encompass a spectrum of neuropsychiatric manifestations. Chromosomal regions 1q21.1, 3q29, 15q11.2, 15q13.3, 16p11.2, 16p13.1 and 22q11 harbour rare but recurrent CNVs that have been uncovered as being important risk factors for several of these disorders. These rearrangements may underlie a broad phenotypical spectrum, ranging from normal development, to learning problems, intellectual disability (ID), epilepsy and psychiatric diseases, such as autism spectrum disorders (ASDs) and schizophrenia (SZ). The highly increased risk of developing neurodevelopmental phenotypes associated with some of these CNVs makes them an unavoidable element in the clinical context in paediatrics, neurology and psychiatry. However, and although finding these risk loci has been the goal of neuropsychiatric genetics for many years, the translation of this recent knowledge into clinical practice has not been trivial. In this article, we will: (1) review the state of the art on recurrent CNVs associated with NDs, namely ASD, ID, epilepsy and SZ; (2) discuss the models used to dissect the underlying neurobiology of disease, (3) discuss how this knowledge can be used in clinical practice.

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Genetically complex epilepsies, copy number variants and syndrome constellations

Cited by 36 publications

References 70 publications

Epilepsy and Autism: Neurodevelopmental Perspective

Epilepsy and Autism: Neurodevelopmental Perspective

Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy

Recurrent copy number variations as risk factors for neurodevelopmental disorders: critical overview and analysis of clinical implications

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