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Type: Journal article
Title: Unraveling the pathogenesis of ARX polyalanine tract variants using a clinical and molecular interfacing approach
Author: Marques, I.
Sá, M.
Soares, G.
Mota, M.
Pinheiro, C.
Aguiar, L.
Amado, M.
Soares, C.
Calado, A.
Dias, P.
Sousa, A.
Fortuna, A.
Santos, R.
Howell, K.
Ryan, M.
Leventer, R.
Sachdev, R.
Catford, R.
Friend, K.
Mattiske, T.
et al.
Citation: Molecular genetics & genomic medicine, 2015; 3(3):203-214
Publisher: Wiley
Issue Date: 2015
ISSN: 2324-9269
Statement of
Isabel Marques, Maria João Sá, Gabriela Soares, Maria do Céu Mota, Carla Pinheiro, Lisa Aguiar, Marta Amado, Christina Soares, Angelina Calado, Patrícia Dias, Ana Berta Sousa, Ana Maria Fortuna, Rosário Santos, Katherine B. Howell, Monique M. Ryan, Richard J Leventer, Rani Sachdev, Rachael Catford, Kathryn Friend, Tessa R. Mattiske, Cheryl Shoubridge, Paula Jorge
Abstract: 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.
Keywords: ARX; Aristaless-related homeobox gene; expanded polyalanine tract; intellectual disability; pathogenic variant
Rights: © 2015 The Authors. This is an open access article under the terms of the Creative Commons Attribution License [], which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
RMID: 0030032190
DOI: 10.1002/mgg3.133
Grant ID:
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