Alpha-thalassemia X-linked intellectual disability syndrome identified by whole exome sequencing in two boys with white matter changes and developmental retardation

• We report two cases of atypical ATRX syndrome.
• Our cases presented with white matter changes and mental retardation.
• Whole-exome sequencing identified two missense mutations in the ATRX gene.
• Our cases expanded the genetic and clinical spectrum of ATRX syndrome.

Alpha-thalassemia X-linked intellectual disability (ATRX) syndrome is a genetic syndrome caused by mutation of the ATRX gene associated with chromatin remodeling. Recently, a wide spectrum of brain MRI abnormalities and clinical manifestations has been recognized. We describe two male patients with genetically confirmed ATRX syndrome, both presented with developmental delay and white matter changes without typical clinical characteristics of ATRX. Whole-exome sequencing revealed the presence of ATRX mutations: a novel c.6472A > G mutation in Case 1 and a previously reported c.6532C > T mutation in Case 2. These two cases expanded the genetic and clinical spectrum of ATRX syndrome, including brain MRI abnormalities. Our results suggest that male patients with developmental delay and widespread white matter changes, even without distinctive facial dysmorphism and hematologic abnormalities, should be suspected as ATRX syndrome. We support the clinical utility of whole-exome sequencing, particularly in ultra-rare neurological diseases with nonspecific developmental disabilities and atypical presentation.