Ohtahara syndrome in a family with an ARX protein truncation mutation (c.81C&gt;G/p.Y27X)

Fullston, Tod; Brueton, Louise; Willis, Tracey; Philip, Sunny; MacPherson, Lesley; Finnis, Merran; Gécz, Jozef; Morton, Jenny

doi:10.1038/ejhg.2009.139

Cited by 30 publications

(32 citation statements)

References 20 publications

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“…Generally, patients with PT variants leading to total loss-of-function (LOF) have more severe XLAG, whereas patients with polyalanine expansions generally have ISSX or a form of intellectual disability [Kato et al, 2004]. Recently, cousins with c.81C>G (p.Tyr27*) and two brothers with c.34G>T (p.Glu12*) in ARX were reported with ISSX [Fullston et al, 2010; Moey et al, 2016]; none had the clinical features of XLAG as would be expected from a total loss of functional protein. Both, the p.Tyr27* and the p.Glu12* pathogenic variants, reinitiated translation at p.M41 suggesting that an N-terminally truncated ARX partially rescued the more severe brain malformation phenotype.…”

Section: Discussionmentioning

confidence: 99%

Nonsense pathogenic variants in exon 1 of PHOX2B lead to translational reinitiation in congenital central hypoventilation syndrome

Cain

Kim

Quast

et al. 2017

American J of Med Genetics Pt A

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Pathogenic variants in PHOX2B lead to congenital central hypoventilation syndrome (CCHS), a rare disorder of the nervous system characterized by autonomic dysregulation and hypoventilation typically presenting in the neonatal period, although a milder late-onset (LO) presentation has been reported. More than 90% of cases are caused by polyalanine repeat mutations (PARMs) in the C-terminus of the protein; however non-polyalanine repeat mutations (NPARMs) have been reported. Most NPARMs are located in exon 3 of PHOX2B and result in a more severe clinical presentation including Hirschsprung disease (HSCR) and/or peripheral neuroblastic tumors (PNTs). A previously reported nonsense pathogenic variant in exon 1 of a patient with LO-CCHS and no HSCR or PNTs leads to translational reinitiation at a downstream AUG codon producing an N-terminally truncated protein. Here we report additional individuals with nonsense pathogenic variants in exon 1 of PHOX2B. In vitro analyses were used to determine if these and other reported nonsense variants in PHOX2B exon 1 produced N-terminally truncated proteins. We found that all tested nonsense variants in PHOX2B exon 1 produced a truncated protein of the same size. This truncated protein localized to the nucleus and transactivated a target promoter. These data suggest that nonsense pathogenic variants in the first exon of PHOX2B likely escape nonsense mediated decay (NMD) and produce N-terminally truncated proteins functionally distinct from those produced by the more common PARMs.

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Section: Discussionmentioning

confidence: 99%

Nonsense pathogenic variants in exon 1 of PHOX2B lead to translational reinitiation in congenital central hypoventilation syndrome

Cain

Kim

Quast

et al. 2017

American J of Med Genetics Pt A

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“…These mutations include early truncating mutations (suggested to re‐initiate translation at a subsequent methionine) (Fullston et al. ) and missense and nonsense mutations in the Aristaless domain (Giordano et al. ; Kato et al.…”

Section: Discussionmentioning

confidence: 99%

Unraveling the pathogenesis of ARX polyalanine tract variants using a clinical and molecular interfacing approach

Marques

Sá

Soares

et al. 2015

Molec Gen & Gen Med

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The Aristaless-related homeobox (ARX) gene is implicated in intellectual disability with the most frequent pathogenic mutations leading to expansions of the first two polyalanine tracts. Here, we describe analysis of the ARX gene outlining the approaches in the Australian and Portuguese setting, using an integrated clinical and molecular strategy. We report variants in the ARX gene detected in 19 patients belonging to 17 families. Seven pathogenic variants, being expansion mutations in both polyalanine tract 1 and tract 2, were identifyed, including a novel mutation in polyalanine tract 1 that expands the first tract to 20 alanines. This precise number of alanines is sufficient to cause pathogenicity when expanded in polyalanine tract 2. Five cases presented a probably non-pathogenic variant, including the novel HGVS: c.441_455del, classified as unlikely disease causing, consistent with reports that suggest that in frame deletions in polyalanine stretches of ARX rarely cause intellectual disability. In addition, we identified five cases with a variant of unclear pathogenic significance. Owing to the inconsistent ARX variants description, publications were reviewed and ARX variant classifications were standardized and detailed unambiguously according to recommendations of the Human Genome Variation Society. In the absence of a pathognomonic clinical feature, we propose that molecular analysis of the ARX gene should be included in routine diagnostic practice in individuals with either nonsyndromic or syndromic intellectual disability. A definitive diagnosis of ARX-related disorders is crucial for an adequate clinical follow-up and accurate genetic counseling of at-risk family members.

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“…These are the newly described genes in which mutations, intragenic expansions, deletions and/or duplications frequently are associated with spasms. Some children with ARX and STXBP1 mutations initially presented with early infantile epileptic encephalopathy (EIEE, Ohtahara syndrome) [17, 50–52] and illustrate a spectrum of infancy-onset epileptic encephalopathies. EIEE, early myoclonic encephalopathy (EME), and ISS remain enigmatic in their relationship to one another, and patient series of these infantile epilepsies overlap in genotype [49, 53–55], suggesting factors of incomplete penetrance and variable expressivity.…”

Section: Iss With Predisposing Genotype Knownmentioning

confidence: 99%

Genetic and Biologic Classification of Infantile Spasms

Paciorkowski

Thio

Dobyns

2011

Pediatric Neurology

146

125

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Infantile spasms are an age-dependent epilepsy that are highly associated with cognitive impairment, autism, and movement disorders. Previous classification systems have focused on a distinction between symptomatic and cryptogenic etiologies, and have not kept pace with the recent discoveries of mutations in genes in key pathways of central nervous system development in patients with infantile spasms. Children with certain genetic syndromes are much more likely to have infantile spasms, and we review the literature to propose a genetic classification of these disorders. Children with these genetic associations with infantile spasms also have phenotypes beyond epilepsy that may be explained by recent advances in the understanding of underlying biological mechanisms. We therefore also propose a biologic classification of the genes highly associated with infantile spasms, and articulate models for infantile spasms pathogenesis based on that data. The two best described pathways of pathogenesis are abnormalities in the gene regulatory network of GABAergic forebrain development, and abnormalities in molecules expressed at the synapse. We intend for these genetic and biologic classifications to be flexible, and hope that they will encourage much needed progress in syndrome recognition, clinical genetic testing, and ultimately the development of new therapies that target specific pathways of pathogenesis.

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Ohtahara syndrome in a family with an ARX protein truncation mutation (c.81C>G/p.Y27X)

Cited by 30 publications

References 20 publications

Nonsense pathogenic variants in exon 1 of PHOX2B lead to translational reinitiation in congenital central hypoventilation syndrome

Nonsense pathogenic variants in exon 1 of PHOX2B lead to translational reinitiation in congenital central hypoventilation syndrome

Unraveling the pathogenesis of ARX polyalanine tract variants using a clinical and molecular interfacing approach

Genetic and Biologic Classification of Infantile Spasms

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