Genetic diagnosis of autism spectrum disorders (ASD) can be established in only a minority of patients. Known genetic causes include copy number variants and monogenic defects, such as Rett and fragile-X syndromes. The genetic heterogeneity within ASD is striking, with even the most frequent causes responsible for only 1% of cases at the most. The large majority of cases remains with no molecular diagnosis even after next-generation sequencing. Helsmoortel et al. reports ten patients with ASD and other shared clinical features, including intellectual disability and facial dysmorphisms caused by a mutation in ADNP, a transcription factor involved in the SWI/SNF remodeling complex. ADNP+/- mice were previously shown to have tauopathy, neuronal cell death and abnormalities in social behavior and cognitive functioning. The C-terminal portion of ADNP directly interacts with ARID1A, SMARCA4 and SMARCC2, three essential components of the BAF complexes, the functional eukaryotic equivalent of the SWI/SNF complex in yeast that regulates gene expression. This complex is essential for dendritic outgrowth and axonal development. Mutations in other components of these complexes (SMARCB1, SMARCA4, SMARCA2, SMARCE1, ARID1A and ARID1B) have been reported in patients with nonsyndromic intellectual disability with hypotonia and speech delay and recognizable syndromes such as Coffin-Siris and Nicolaides-Baraitser syndromes. Collectively, these disorders are sometimes referred to as ‘SWI/SNF-related intellectual disability syndromes’.
Finally, the authors estimated ADNP to be mutated in at least 0.17% of ASD cases, making it one of the most frequent ASD-associated genes known to date.
Posted by Nicola Brunetti-Pierri, MD, FACMG