Background: We report a child with autism and mild microcephaly who was found to have a de novo 3.3 Mb microdeletion on chromosome 1p34.2p34.3. Here, we test the hypothesis that this microdeletion contains one or more genes that underlie the autism phenotype in this child and in other children with autism spectrum disorders.
Methods: To search for submicroscopic chromosomal rearrangements in the child, we performed array comparative genomic hybridization (aCGH) using a 19K whole-genome human BAC array and the Illumina 610-Quad BeadChip microarray. Ingenuity Pathway Analysis (IPA) was used to construct functional biological networks to identify candidate autism genes. To identify putative functional variants in candidate genes, we performed mutation screening using PCR-based Sanger sequencing in 512 unrelated autism patients and 462 control subjects.
Results: We identified a de novo 3.3 Mb deletion containing ~43 genes in chromosome 1p34.2p34.3 that we confirmed using fluorescence in situ hybridization (FISH). Literature review and bioinformatics analyses identified RIMS3 (Regulating Synaptic Membrane Exocytosis 3) as the most promising autism candidate gene. Mutation screening of this gene in autism patients identified five inherited coding variants, including one (p.E177A) that segregated with the autism phenotype in a sibship, was predicted to be deleterious, and was absent in 1,161 controls.
Conclusions: Our case report and mutation screening data suggest that RIMS3 is an autism causative or contributory gene. Functional studies of RIMS3 variants such as p.E177A should provide additional insight into the role of synaptic proteins in the pathophysiology of autism.