Evidence of Autism Spectrum Disorder Caused By A Mutation In ATRX Gene

Abstract Background: ATRX gene mutations are commonly associated with alpha-thalassaemia mental retardation syndrome (ATRX syndrome). This X-linked disorder is characterized by intellectual disability to a higher or lesser degree, in which alpha-thalassaemia feature is not always present. Here, we report the first case of a Spanish child with a missense ATRX mutation (Thr1621Met) and an Autism Spectrum Disorder (ASD) diagnosis. Except for intellectual disability, no typical signs of ATRX syndrome were found in the patient. Methods: A 23-month-old male patient was clinically evaluated at the Department of Paediatrics of the “Complejo Hospitalario Universitario de Albacete”, Spain. The baby was diagnosed with ASD according to the established criteria by the American Psychiatric Association (DMS-5). To determine the genetic cause of the pathology, an exome sequencing of a targeted gene panel of 215 genes associated to autism, intellectual disability, and/or seizure was carried out on an Ion Proton (Life Technologies) platform. The mutation was confirmed in the baby and analysed in the rest of the members of the family by PCR-terminator cycle sequencing. Results: Thr1621Met ATRX hemizygous mutation was identified in the ASD patient. Proband´s mother was identified as an asymptomatic heterozygous carrier and the mutation was not found in the father neither the sister. Thr1621Met change is predicted to have a pathogenic effect and it has been previously associated with ATRX syndrome in only one German family with phenotypic variability. Limitations: Given the limited number of families with ATRX mutations and, concretely, with Thr1621Met, it is very difficult to establish a genotype-phenotype relationship. Also, we cannot rule out the existence of other genetic, epigenetic and/or environmental factors that may modulate the phenotype of the patient. Furthermore, a functional analysis of Thr1621Met would be necessary to clarify the molecular mechanism by which this mutation causes ASD. Conclusions: Results suggest one common altered molecular pathway in both, ATRX syndrome and ASD pathologies that opens new research lines in ASD aetiology. Furthermore, the results confirm the extent phenotypic variability associated with ATRX mutations and focus the attention on an exhaustive clinical examination to achieve the most accurate diagnosis.