Editors' ChoiceAutism Spectrum Disorder

SNFing for Clues to the Genetics of Autism

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Science Translational Medicine  23 Apr 2014:
Vol. 6, Issue 233, pp. 233ec72
DOI: 10.1126/scitranslmed.3009253

Unlike Gertrude Stein’s rose, autism is not autism is not autism—it is actually a spectrum of disorders characterized by varying degrees of language, social, and behavioral deficits. The Center for Disease Control and Prevention estimates the prevalence for autism spectrum disorder (ASD) as 1 in 68 children, and efforts to identify related genetic aberrations confirm that ASD can be caused by mutations in many different genes, with the most common causes explaining only ~1% of cases. Recently, Helsmoortel and colleagues identified mutations in a gene that explains another 0.1 to 0.2% of cases. Their study shows the power of combining patient cohorts for gene discovery in a complex disorder and highlights the importance of chromatin remodeling in normal brain development.

Using whole-exome sequencing in 10 patient-parent trios, the authors identified a single patient with a de novo mutation in the ADNP gene, which encodes a chromatin-remodeling protein. Although there were two patients (of 2932 screened) in the literature with mutations in the same gene, the finding was not statistically significant. However, additional screening led to the identification of seven more patients with mutations in ADNP, for a total of 10 out of 5776 affected individuals from eight different cohorts. In nine of nine cases tested, the mutation was de novo rather than inherited, and all of the mutations clustered within a 1.5-kb region near the end of the last exon of ADNP.

ADNP encodes a protein subunit of the BAF complex—a human equivalent of the yeast SWI/SNF complex—which is important for chromatin remodeling and the regulation of gene expression during neuronal development. Mutations in genes encoding six other subunits of the same complex cause intellectual disability syndromes, highlighting the importance of this complex for normal brain development. Notably, rare mutations in other chromatin remodeling genes have also been identified in ASD and related disorders. The next step will be to SNifF out the downstream effects caused by dysregulation of the BAF complex and identify potential targets for therapeutic intervention. Although mutations in each SWI/SNF subunit are rare, perhaps a common molecular target holds promise for the treatment of a broader set of patients with disorders related to chromatin regulation.

C. Helsmoortel et al., A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP. Nat. Genet. 46, 380–384 (2014). [PubMed]

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