The transcriptional regulator ADNP links the BAF (SWI/SNF) complexes with autism

Abstract

Mutations in ADNP were recently identified as a frequent cause of syndromic autism, characterized by deficits in social communication and interaction and restricted, repetitive behavioral patterns. Based on its functional domains, ADNP is a presumed transcription factor. The gene interacts closely with the SWI/SNF complex by direct and experimentally verified binding of its C-terminus to three of its core components. A detailed and systematic clinical assessment of the symptoms observed in our patients allows a detailed comparison with the symptoms observed in other SWI/SNF disorders. While the mutational mechanism of the first 10 patients identified suggested a gain of function mechanism, an 11th patient reported here is predicted haploinsufficient. The latter observation may raise hope for therapy, as addition of NAP, a neuroprotective octapeptide named after the first three amino acids of the sequence NAPVSPIQ, has been reported by others to ameliorate some of the cognitive abnormalities observed in a knockout mouse model. It is concluded that detailed clinical and molecular studies on larger cohorts of patients are necessary to establish a better insight in the genotype phenotype correlation and in the mutational mechanism.

The Compassionate Side of Neuroscience: Tony Sermone’s Undiagnosed Genetic Journey—ADNP Mutation

“…Remarkably, ADNP is one of a relatively small group of genes that appear to lead to autism in a substantial proportion of cases. Immediately following our initial report, two additional patients were identified that share many of the reported characteristics (Pescosolido et al 2014;Vandeweyer et al 2014). On top of that, Coe et al (2014) reported five patients with a truncating ADNP mutation in a screening of 4716 patients with autism/ID.…”

The Promise of Multi-Omics and Clinical Data Integration to Identify and Target Personalized Healthcare Approaches in Autism Spectrum Disorders

“…Once recurrent genetic loci have been identified through genetic testing, individuals with ASD and an identified genetic event should be evaluated clinically in order to determine whether phenotypic characteristics suggest a unique ASD subtype (e.g., CHD8) . Previous associations have been found between genes associated with ASD and intellectual disability (Kaufman et al, 2010), and already specific gene disrupting mutations identified through molecular subtyping show co-morbidity with significant cognitive deficits (e.g., ADNP, PTEN) (Frazier et al, 2014;Helsmoortel et al, 2014;Vandeweyer et al, 2014).…”

“…Even in its early stages, molecular subtyping with multiple integrated data methods has been shown to be successful in ASD research Frazier et al, 2014;Vandeweyer et al, 2014). Using exome and targeted sequencing technology, recurrent de novo disruptive mutations, such as CHD8, ADNP, DYRK1A, and PTEN have been found in individuals with ASD (Iossifov et al, 2014;O'Roak et al, 2012aO'Roak et al, , 2012b.…”

“…Comprehensive phenotyping of a growing number of individuals with these disruptive mutations indicates a high likelihood of autism and unique medical, psychiatric, and morphological characteristics that suggest specific genetic subtypes for ASD Frazier et al, 2014;van Bon et al, 2015). Autism, intellectual disability, and dysmorphic features have been found in individuals with a disruptive mutation to ADNP, along with multiple reports of visual and cardiac defects (Vandeweyer et al, 2014;Helsmoortel et al, 2014).…”

“…This is exemplified in ASD research: following the identification of recurrent gene disruptions associated with ASD, neurological and behavioral mapping is taking place through imaging and psychometric testing, identifying distinct phenotypic features that accompany a targeted genotype Frazier et al, 2014;Vandeweyer et al, 2014;van Bon et al, 2015).…”