A de novo 1p34.2 microdeletion identifies the synaptic vesicle gene RIMS3 as a novel candidate for autism.
BACKGROUND
A child with autism and mild microcephaly was found to have a de novo 3.3 Mb microdeletion on chromosome 1p34.2p34.3. The hypothesis is tested 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, array comparative genomic hybridisation (aCGH) was performed using a 19 K whole genome human bacterial artificial chromosome (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, mutation screening was performed using polymerase chain reaction (PCR) based Sanger sequencing in 512 unrelated autism patients and 462 control subjects.


RESULTS
A de novo 3.3 Mb deletion containing approximately 43 genes in chromosome 1p34.2p34.3 was identified and subsequently confirmed using fluorescence in situ hybridization (FISH). Literature review and bioinformatics analyses identified Regulating Synaptic Membrane Exocytosis 3 (RIMS3) 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 1161 controls.


CONCLUSIONS
This 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.
Kumar
Ravinesh A
RA
Department of Human Genetics, University of Chicago,Chicago, Illinois 60637, USA.
Sudi
Jyotsna
J
Babatz
Timothy D
TD
Brune
Camille W
CW
Oswald
Donald
D
Yen
Mayon
M
Nowak
Norma J
NJ
Cook
Edwin H
EH
Christian
Susan L
SL
Dobyns
William B
WB
D019943:Amino Acid Substitution; D001321:Autistic Disorder / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D055028:Comparative Genomic Hybridization; D004252:DNA Mutational Analysis; D030541:Databases, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics*; D017384:Sequence Deletion
D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C485850:RIMS3 protein, human