Unraveling the pathogenesis of ARX polyalanine tract variants using a clinical and molecular interfacing approach
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, usi...
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| Published in: | Molecular genetics & genomic medicine Vol. 3; no. 3; pp. 203 - 214 |
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
United States
John Wiley & Sons, Inc
01-05-2015
BlackWell Publishing Ltd |
| Subjects: | |
| Online Access: | Get full text |
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| Summary: | 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.
Molecular screening of ARX gene is frequent in patients with intellectual disability (ID) presenting with infantile epilepsy or movement disorder or brain and genital malformations. Targeted ARX mutation screening (exon 2), followed by sequencing of all coding regions, enabled the diagnosis of ARX‐related disorders in eight patients from six families, presenting with different clinical phenotypes. Data from our study and others lead us to recommend that this targeted screening be done in all patients referred for fragile‐X testing, particularly those with apparent nonsyndromic ID of unknown cause, or in which the “Partington” hand dystonia is recognized. |
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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Funding Information Unit for Multidisciplinary Research in Biomedicine, UMIB, ICBAS-UP, Porto, Portugal was funded by FEDER funds of the Operational Program for Competitiveness Factors – COMPETE through FCT – Foundation for Science and Technology under the project: Fcomp-01-0124-FEDER-015896. The Neurogenetics research program in the Department of Paediatrics, University of Adelaide, Australia was funded by the Australian National Health and Medical Research Council (Grant No. 1063025). C. S. is supported by the Australian Research Council (Future Fellowship FT120100086). These authors contributed equally to this work. |
| ISSN: | 2324-9269 2324-9269 |
| DOI: | 10.1002/mgg3.133 |