<i>WWOX</i>-related encephalopathies: delineation of the phenotypical spectrum and emerging genotype-phenotype correlation

Mignot, Cyril; Lambert, Laëtitia; Pasquier, Laurent; Bienvenu, Thierry; Delahaye‐Duriez, Andrée; Keren, Boris; Lefranc, Jérémie; Saunier, Aline; Allou, Lila; Roth, Virginie; Valduga, Mylène; Moustaïne, Aissa; Auvin, Stéphane; Barrey, Catherine; Chantot‐Bastaraud, Sandra; Lebrun, Nicolas; Moutard, Marie‐Laure; Nouguès, Marie‐Christine; Vermersch, Anne-Isabelle; Héron, Bénédicte; Pipiras, Eva; Héron, Delphine; Olivier-Faivre, Laurence; Guéant, Jean‐Louis; Jonveaux, Philippe; Philippe, Christophe

doi:10.1136/jmedgenet-2014-102748

Cited by 69 publications

(100 citation statements)

References 32 publications

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“…2). WWOX has previously been implicated in intellectual disability (Tabarki et al 2015;Mignot et al 2015;Ben-Salem et al 2015). Only one variant remained after filtering the data from family II, and was found within a homozygous interval in chromosome 6; p.H530Y (c.1588C > T) in RARS2 gene.…”

Section: Resultsmentioning

confidence: 89%

“…A critical role of WWOX in central nervous system (CNS) homeostasis has been suggested by the pattern of its increased expression in the CNS (Nunez et al 2006). Several WWOX mutations have been reported in patients characterized as having intellectual disability, epilepsy, developmental delay, and/or neurological manifestations of ataxia (AbdelSalam et al 2014;Mallaret et al 2014;Mignot et al 2015;Ben-Salem et al 2015;Valduga et al 2015;Tabarki et al 2015). The WWOX-associated phenotype displays a wide range of phenotypic abnormalities which might be related to the nature of mutations; point mutations (such as p.P47T, p.P47R, p.G372R) are usually associated with milder phenotypes than those associated with nonsense mutations (such as p.R54*, p.K297*, p.W335*) or partial/complete deletions (Abu-Remaileh et al 2015).…”

Section: Discussionmentioning

confidence: 99%

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Novel mutations in WWOX, RARS2, and C10orf2 genes in consanguineous Arab families with intellectual disability

et al. 2016

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Intellectual disability is a heterogeneous disease with many genes and mutations influencing the phenotype. Consanguineous families constitute a rich resource for the identification of rare variants causing autosomal recessive disease, due to the effects of inbreeding. Here, we examine three consanguineous Arab families, recruited in a quest to identify novel genes/mutations. All the families had multiple offspring with non-specific intellectual disability. We identified homozygosity (autozygosity) intervals in those families through SNP genotyping and whole exome sequencing, with variants filtered using Ingenuity Variant Analysis (IVA) software. The families showed heterogeneity and novel mutations in three different genes known to be associated with intellectual disability. These mutations were not found in 514 ethnically matched control chromosomes. p.G410C in WWOX, p.H530Y in RARS2, and p.I69F in C10orf2 are novel changes that affect protein function and could give new insights into the development and function of the central nervous system.

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Section: Resultsmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Novel mutations in WWOX, RARS2, and C10orf2 genes in consanguineous Arab families with intellectual disability

et al. 2016

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“…Loss of WWOX in animal models is associated with epilepsy and ataxia [106, 107]. In agreement with these observations, several recent reports have described homozygous mutation of WWOX in epileptic patients [108–110]. Some of these reports described early onset death of patients, as shown in the Wwox null mice [17, 90, 91], precluding adult tumor analysis.…”

Section: Cfs Gene Products With Roles In the Ddrmentioning

confidence: 80%

Tumor Suppressor Genes within Common Fragile Sites Are Active Players in the DNA Damage Response

2016

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The role of common fragile sites (CFSs) in cancer remains controversial. Two main views dominate the discussion: one suggests that CFS loci are hotspots of genomic instability leading to inactivation of genes encoded within them, while the other view proposes that CFSs are functional units and that loss of the encoded genes confers selective pressure, leading to cancer development. The latter view is supported by emerging evidence showing that expression of a given CFS is associated with genome integrity and that inactivation of CFS-resident tumor suppressor genes leads to dysregulation of the DNA damage response (DDR) and increased genomic instability. These two viewpoints of CFS function are not mutually exclusive but rather coexist; when breaks at CFSs are not repaired accurately, this can lead to deletions by which cells acquire growth advantage because of loss of tumor suppressor activities. Here, we review recent advances linking some CFS gene products with the DDR, genomic instability, and carcinogenesis and discuss how their inactivation might represent a selective advantage for cancer cells.

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“…76,77 Finally, patients with SLC1A2 mutations, affecting the glutamate transporter EAAT2, manifest DEE occasionally in tandem with movement disorders such as upper limb dyskinesia. 86,87 Additionally, patients with mutations in WWOX, a gene with a role in apoptosis and tumour suppression, 88 present with treatment-resistant DEE. Patients also often have pronounced dystonia and athetosis.…”

Section: Sodium Channel Genesmentioning

confidence: 99%

The expanding spectrum of movement disorders in genetic epilepsies

Papandreou

Danti

Spaull

et al. 2019

Develop Med Child Neuro

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An ever‐increasing number of neurogenetic conditions presenting with both epilepsy and atypical movements are now recognized. These disorders within the ‘genetic epilepsy‐dyskinesia’ spectrum are clinically and genetically heterogeneous. Increased clinical awareness is therefore necessary for a rational diagnostic approach. Furthermore, careful interpretation of genetic results is key to establishing the correct diagnosis and initiating disease‐specific management strategies in a timely fashion. In this review we describe the spectrum of movement disorders associated with genetically determined epilepsies. We also propose diagnostic strategies and putative pathogenic mechanisms causing these complex syndromes associated with both seizures and atypical motor control. What this paper adds Implicated genes encode proteins with very diverse functions. Pathophysiological mechanisms by which epilepsy and movement disorder phenotypes manifest are often not clear. Early diagnosis of treatable disorders is essential and next generation sequencing may be required.

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WWOX-related encephalopathies: delineation of the phenotypical spectrum and emerging genotype-phenotype correlation

Cited by 69 publications

References 32 publications

Novel mutations in WWOX, RARS2, and C10orf2 genes in consanguineous Arab families with intellectual disability

Novel mutations in WWOX, RARS2, and C10orf2 genes in consanguineous Arab families with intellectual disability

Tumor Suppressor Genes within Common Fragile Sites Are Active Players in the DNA Damage Response

The expanding spectrum of movement disorders in genetic epilepsies

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