title: 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.
authors.affiliation: Unidade de Genética Molecular, Centro de Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar do Porto, EPE Porto, Portugal ; Unit for Multidisciplinary Research in Biomedicine, UMIB, ICBAS-UP Porto, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Marques
authors.affiliation: Unidade de Genética Médica, Centro de Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar do Porto, EPE Porto, Portugal ; Unit for Multidisciplinary Research in Biomedicine, UMIB, ICBAS-UP Porto, Portugal.
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Sá
authors.affiliation: Unidade de Genética Médica, Centro de Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar do Porto, EPE Porto, Portugal.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Soares
authors.affiliation: Department of Pediatrics, Centro Hospitalar do Porto, EPE Porto, Portugal.
authors.forename: Maria do Céu
authors.initials: Mdo C
authors.lastname: Mota
authors.affiliation: Department of Pediatrics, Hospital Santa Maria Maior, EPE Barcelos, Portugal.
authors.forename: Carla
authors.initials: C
authors.lastname: Pinheiro
authors.affiliation: Department of Pediatrics, Hospital Distrital de Santarém, EPE Santarém, Portugal.
authors.forename: Lisa
authors.initials: L
authors.lastname: Aguiar
authors.affiliation: Department of Pediatrics, Unidade Hospitalar de Portimão, Centro Hospitalar do Algarve Portimão, Portugal.
authors.forename: Marta
authors.initials: M
authors.lastname: Amado
authors.affiliation: Department of Pediatrics, Unidade Hospitalar de Portimão, Centro Hospitalar do Algarve Portimão, Portugal.
authors.forename: Christina
authors.initials: C
authors.lastname: Soares
authors.affiliation: Department of Pediatrics, Unidade Hospitalar de Portimão, Centro Hospitalar do Algarve Portimão, Portugal.
authors.forename: Angelina
authors.initials: A
authors.lastname: Calado
authors.affiliation: Department of Genetics, Hospital de Santa Maria Lisboa, Portugal.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Dias
authors.affiliation: Department of Genetics, Hospital de Santa Maria Lisboa, Portugal.
authors.forename: Ana Berta
authors.initials: AB
authors.lastname: Sousa
authors.affiliation: Unidade de Genética Médica, Centro de Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar do Porto, EPE Porto, Portugal ; Unit for Multidisciplinary Research in Biomedicine, UMIB, ICBAS-UP Porto, Portugal.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Fortuna
authors.affiliation: Unidade de Genética Molecular, Centro de Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar do Porto, EPE Porto, Portugal ; Unit for Multidisciplinary Research in Biomedicine, UMIB, ICBAS-UP Porto, Portugal.
authors.forename: Rosário
authors.initials: R
authors.lastname: Santos
authors.affiliation: Department of Neurology, Royal Children's Hospital Melbourne, Victoria, Australia ; Murdoch Childrens Research Institute Melbourne, Victoria, Australia, 3052 ; University of Melbourne Department of Paediatrics Melbourne, Victoria, Australia, 3052.
authors.forename: Katherine B
authors.initials: KB
authors.lastname: Howell
authors.affiliation: Department of Neurology, Royal Children's Hospital Melbourne, Victoria, Australia ; Murdoch Childrens Research Institute Melbourne, Victoria, Australia, 3052 ; University of Melbourne Department of Paediatrics Melbourne, Victoria, Australia, 3052.
authors.forename: Monique M
authors.initials: MM
authors.lastname: Ryan
authors.affiliation: Department of Neurology, Royal Children's Hospital Melbourne, Victoria, Australia ; Murdoch Childrens Research Institute Melbourne, Victoria, Australia, 3052 ; University of Melbourne Department of Paediatrics Melbourne, Victoria, Australia, 3052.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Leventer
authors.affiliation: Department of Medical Genetics, Sydney Children's Hospital High St., Randwick, New South Wales, 2031, Australia.
authors.forename: Rani
authors.initials: R
authors.lastname: Sachdev
authors.affiliation: SA Pathology at the Women's and Children's Hospital North Adelaide, South Australia, Australia.
authors.forename: Rachael
authors.initials: R
authors.lastname: Catford
authors.affiliation: SA Pathology at the Women's and Children's Hospital North Adelaide, South Australia, Australia.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Friend
authors.affiliation: Department of Paediatrics, University of Adelaide Adelaide, South Australia, 5006, Australia ; Robinson Research Institute, University of Adelaide Adelaide, South Australia, 5006, Australia.
authors.forename: Tessa R
authors.initials: TR
authors.lastname: Mattiske
authors.affiliation: Department of Paediatrics, University of Adelaide Adelaide, South Australia, 5006, Australia ; Robinson Research Institute, University of Adelaide Adelaide, South Australia, 5006, Australia.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Shoubridge
authors.affiliation: Unidade de Genética Molecular, Centro de Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar do Porto, EPE Porto, Portugal ; Unit for Multidisciplinary Research in Biomedicine, UMIB, ICBAS-UP Porto, Portugal.
authors.forename: Paula
authors.initials: P
authors.lastname: Jorge
keywords: ARX; Aristaless-related homeobox gene; expanded polyalanine tract; intellectual disability; pathogenic variant