An Emerging Female Phenotype with Loss‐of‐Function Mutations in the Aristaless‐Related Homeodomain Transcription Factor ARX. Issue 5 (15th February 2017)

• Record Type: Journal Article
• Authors: Mattiske, Tessa; Moey, Ching; Vissers, Lisenka E.; Thorne, Natalie; Georgeson, Peter; Bakshi, Madhura; Shoubridge, Cheryl
• Is Part Of: Human mutation. Volume 38:Issue 5(2017)
• Page Start: 548
• Page End: 555
• Publication Date: 2017-02-15
• Subjects: X‐linked lissencephaly‐2 -- X‐linked lissencephaly -- ARX -- Aristaless‐related homeobox -- intellectual disability -- seizure -- LISX2 -- XLAG; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.23190
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract : We identified a novel ARX truncating mutation (c.982delCinsTTT∕p.(Q328Ffs*32))in a family ascertained by a female proband displaying a phenotype of mild learning disabilities, seizure disorder and agenesis of the corpus callosum, in conjunction with a phenotype of XLAG in deceased male siblings. Review of the phenotypes of affected females with published ARX mutations indicates screening of the ARX gene in female patients with intellectual disability, seizure phenotypes and corpus callosum agenesis, particularly if there is evidence of X‐linkage and no surviving males is warranted. ABSTRACT: The devastating clinical presentation of X‐linked lissencephaly with abnormal genitalia (XLAG) is invariably caused by loss‐of‐function mutations in the Aristaless ‐related homeobox ( ARX ) gene. Mutations in this X‐chromosome gene contribute to intellectual disability (ID) with co‐morbidities including seizures and movement disorders such as dystonia in affected males. The detection of affected females with mutations in ARX is increasing. We present a family with multiple affected individuals, including two females. Two male siblings presenting with XLAG were deceased prior to full‐term gestation or within the first few weeks of life. Of the two female siblings, one presented with behavioral disturbances, mild ID, a seizure disorder, and complete agenesis of the corpus callosum (ACC), similar to the mother's phenotype. A novel insertion mutation in Exon 2 of ARX was identified, c.982delCinsTTT predicted to cause a frameshift at p.(Q328Ffs * 37). Our finding is consistent with loss‐of‐function mutations in ARX causing XLAG in hemizygous males and extends the findings of ID and seizures in heterozygous females. We review the reported phenotypes of females with mutations in ARX and highlight the importance of screening ARX in male and female patients with ID, seizures, and in particular with complete ACC.