A Novel Hemizygous ARX Variant in an Infant with Global Developmental Delay

Abstract

An ARX variant is a genetic change in the ARX (aristaless related homeobox) gene located on the X chromosome (Xp21.3). ARX encodes a transcription factor involved in early brain development, and pathogenic variants are associated with a broad spectrum of X-linked neurodevelopmental disorders. Interpreting a rare ARX variant can be challenging when acquired perinatal injury may also contribute to the phenotype. We describe a 12-month-old boy with profound global developmental delay, spastic quadriplegia, laryngomalacia, and neonatal seizures that were resolved during the neonatal period. His history suggested perinatal asphyxia, while routine brain magnetic resonance imaging (MRI) revealed no major structural abnormalities. Initial metabolic investigations, including a positive urinary glycosaminoglycan spot test, did not establish a metabolic diagnosis; mucopolysaccharidosis was excluded by lysosomal enzyme assays. Clinical exome sequencing identified a hemizygous ARX missense variant, NM_139058.3:c.634G>A (p.Gly212Ser), which was absent from the population databases. Conflicting computational predictions and the available ACMG/AMP evidence supported classification as a variant of uncertain significance (VUS), rather than a definitive molecular diagnosis. Independent review also identified an erroneous automated domain annotation. Parental segregation testing and Sanger confirmation remain pending. This case illustrates the importance of integrating phenotype, variant - level evidence, and careful annotation review while avoiding premature attribution of causality.