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Title: Splice variant in ARX leading to loss of C-terminal region in a boy with intellectual disability and infantile onset developmental and epileptic encephalopathy.
Austin Authors: Shoubridge, Cheryl;Jackson, Matilda;Grinton, Bronwyn;Berkovic, Samuel F ;Scheffer, Ingrid E ;Huskins, Shannon;Thomas, Alison;Ware, Tyson
Affiliation: Department of Paediatrics, Royal Hobart Hospital, Hobart, Tasmania, Australia
Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia
Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Florey and Murdoch Children's Research Institutes, Melbourne, Victoria, Australia
Department of Medical Imaging, Royal Hobart Hospital, Hobart, Tasmania, Australia
Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Department of Medicine, University of Tasmania, Hobart, Tasmania, Australia
Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
Issue Date: 2019 2019-05-30
Publication information: American journal of medical genetics. Part A 2019; 179(8): 1483-1490
Abstract: Pathogenic variants in the X-chromosome Aristaless-related homeobox (ARX) gene contribute to intellectual disability, epilepsy, and associated comorbidities in affected males. Here, we report a novel splice variant in ARX in a family with three affected individuals. The proband had early onset developmental and epileptic encephalopathy, his brother and mother had severe and mild intellectual disability, respectively. Massively parallel sequencing identified a novel c.1449-1G>C in intron 4 of the ARX gene, predicted to abolish the splice acceptor site, retaining intron 4 and leading to a premature termination codon immediately after exon 4. As exon 5 is the last exon of the ARX gene, the premature termination codon at position p.L484* would be predicted to escape nonsense-mediated mRNA decay, potentially producing at least some C-terminally truncated protein. Analysis of cDNA from patient lymphoblastoid cells confirmed retention of intron 4 and loss of detectable expression of ARX mRNA across exon 4 to exon 5. We review published cases of variants that lead to altered or early termination of the ARX protein, but not complete loss of function, and are associated with phenotypes of intellectual disability and infantile onset developmental and epileptic encephalopathies, including Ohtahara and West syndromes. Taken together, this novel splice variant retaining intron 4 is likely to be the cause of the early onset developmental and epileptic encephalopathy in the proband.
DOI: 10.1002/ajmg.a.61216
ORCID: 0000-0002-0157-3084
PubMed URL: 31145546
Type: Journal Article
Subjects: ARX
Ohtahara syndrome
intellectual disability
Appears in Collections:Journal articles

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