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

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.

An Emerging Female Phenotype with Loss‐of‐Function Mutations in the Aristaless‐ Related Homeodomain Transcription Factor ARX

“…Our report underscores that a carrier female phenotype is likely to be under ascertained for ARX. This is supported by a recent examination of heterozygous females from families identified with ARX mutations [Marsh, et al, 2009] and examples of gender bias (92% male:8% female) in a recent cohort of patients referred for molecular analysis of ARX [Marques, et al, 2015]. Under ascertainment may be occurring due to several contributing factors.…”

Genetics and mechanisms leading to human cortical malformations

“…Of note, heterozygous female carriers can show a variety of psychiatric conditions such as anxiety, depression and schizophrenia jointly with learning disability [130]. Genomic variations in ARX have also been reported in some unaffected individuals [131]. Nevertheless, in general, different types of ARX mutations lead to severe phenotypes.…”

Genetics and genotype–phenotype correlations in early onset epileptic encephalopathy with burst suppression

“…[1][2][3][4] Known genetic causes of EOEE-BS include brain malformations (eg, polymicrogyria and lissencephaly), inborn errors of metabolism (eg, pyridoxine-and other vitamin-dependent epilepsies, mitochondrial disorders, and amino acidopathies), and other genetic etiologies (eg, pathogenic variants in ARX, KCNQ2, SCN2A, SIK1, SLC25A22, STXBP1). 2,[5][6][7][8][9][10][11][12][13] Based on current literature, single gene variants explain at least 20 to 30% of epileptic encephalopathies. [14][15][16] We sought to determine the contribution of genetic etiologies to EOEE-BS and to delineate genotype-phenotype correlations in a cohort of patients with EOEE-BS without malformations of cortical development.…”