P3C242: Rare Genetic Cause of Autism Spectrum Disorder Detected by Whole Exome Sequencing

Introduction: Autism spectrum disorder (ASD) is a heterogenous group of neurodevelopmental disorders characterized by impaired social and communication skills and stereotypical behavior. Prevalence of ASD is growing and is estimated at 1 in 36 children. ASD is highly heritable, and studies suggest genetic factors play a significant role. Many genetic causes of autism are now well known. Meanwhile, candidate genes involved in the development of autism are frequently reported in the literature. Here, we present a case of ASD caused by a rare genetic mutation of the BRD4 gene detected on whole exome sequencing (WES).

Case Description: This patient was a 5-year-old female who presented with developmental delay, poor social interactions, repetitive self-directed behaviors, sensory issues and a history of toe walking. Birth history and family history were unremarkable. Developmental history was significant for speech delays and social deficits noted after the first year of life. Physical exam was notable for non-dysmorphic facial features and poor eye contact. Brain MRI and routine EEG results were unremarkable. Mitochondrial studies were normal. WES revealed a de novo heterozygous BRD4 gene variant (c. 1009 G>A, p. D337N) classified as a variant of uncertain significance.

Discussion: The BRD4 gene encodes a protein involved in binding acetylated histones with a suggested key role in neuronal function and transcription regulation underlying learning and memory. BRD4 gene variants have been previously described in association with autosomal dominant Cornelia de Lange and Cornelia de Lange type syndrome, as well as the following phenotypes: microcephaly, global developmental delay, intellectual/learning disability, psychiatric disorders, dysmorphic features. To our knowledge, only four cases of BRD4 gene defects that might be associated with autism have previously been reported by the Simons Foundation. This is the first full report in the literature associating BRD4 gene defect with autism spectrum disorder.

Conclusion: This report of a rare genetic cause of autism spectrum disorder diagnosed using WES highlights the importance of genetic evaluation in the workup of ASD and suggests a candidate gene, BRD4. Further studies are needed to fully understand the role of the BRD4 gene in the development of ASD.