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.
Highlights
Since its discovery in 2002, Aristaless-related homeobox gene (ARX; MIM# 300382; GenBank: NM_139058.2) has been implicated in X-linked intellectual disability (XLID) (Bienvenu et al 2002; Shoubridge et al 2010)
Patients may present with intellectual disability (ID) without additional clinical features, the concomitant observation of neurological deficits, with or without brain and/or genital anomalies suggests a number of recognizable syndromes
Of the 8 variants identified, 5 ARX variants were detected using multiplex screening that enables the simultaneous investigation of FMR1, AFF2, and ARX genes (Jorge et al 2013) and three ARX variants were detected by direct sequencing of the gene
Summary
Since its discovery in 2002, Aristaless-related homeobox gene (ARX; MIM# 300382; GenBank: NM_139058.2) has been implicated in X-linked intellectual disability (XLID) (Bienvenu et al 2002; Shoubridge et al 2010). The ARX gene, cytogenetically located on Xp21.3, encompasses 12.5 kb of genomic DNA and includes five coding exons encoding a 562 amino acid protein. This gene is a pairedtype homeodomain transcription factor expressed predominately in the fetal and adult brain, testis, skeletal muscle, and pancreas. The ARX-associated spectrum of disorders includes Partington syndrome (OMIM 309510) (Partington et al 2004), Early Infantile Epileptic Encephalopathy (OMIM 308350) (Kato et al 2007), Agenesis of Corpus Callosum with Abnormal Genitalia (OMIM 300004) (Proud et al 1992), and X-Linked Lissencephaly with Ambiguous Genitalia (OMIM 300215) (Kitamura et al 2002). Despite a broad range of phenotypes associated with mutations in ARX, ID is a consistent clinical feature
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