Evaluation of the chromosome 2q37.3 gene CENTG2 as an autism susceptibility gene.
Autism is a highly heritable neurodevelopmental syndrome with a complex genetic etiology for which no disease genes have yet been definitively identified. We ascertained three subjects with autism spectrum disorders and chromosome 2q37.3 terminal deletions, and refined the deletion breakpoint regions using polymorphism mapping and fluorescence in situ hybridization (FISH) probes. We then genotyped polymorphic markers downstream from the breakpoint region in a sample of autism affected sibling pair families. Both the chromosomal breakpoints and linkage analyses focused our attention on the gene centaurin gamma-2 (CENTG2), an attractive candidate gene based also on its function and pattern of expression. We therefore assessed CENTG2 for its involvement in autism by (1) screening its exons for variants in 199 autistic and 160 non-autistic individuals, and (2) genotyping and assessing intra-genic polymorphisms for linkage and linkage disequilibrium (LD). The exon screen revealed a Ser --> Gly substitution in one proband, an Arg --> Gly substitution in another, and a number of additional variants unique to the autism families. No unique variants were found in the control subjects. The genotyping produced strong evidence for linkage from two intronic polymorphisms, with a maximum two-point HLOD value of 3.96 and a posterior probability of linkage (PPL) of 51%. These results were contradicted, however, by substantially weaker evidence for linkage from multi-point analyses and by no evidence of LD. We conclude, therefore, that 2q37.3 continues to be a region of interest for autism susceptibility, and that CENTG2 is an intriguing candidate gene that merits further scrutiny for its role in autism.
Wassink
Thomas H
TH
Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, 52242, USA. thomas-wassink@uiowa.edu
Piven
Joseph
J
Vieland
Veronica J
VJ
Jenkins
Laura
L
Frantz
Rebecca
R
Bartlett
Christopher W
CW
Goedken
Rhinda
R
Childress
Deb
D
Spence
M Anne
MA
Smith
Moyra
M
Sheffield
Val C
VC
D020727:ADP-Ribosylation Factors / Q000235:genetics*; D000595:Amino Acid Sequence; D001321:Autistic Disorder / Q000235:genetics*; D002872:Chromosome Deletion; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics*; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats; D009154:Mutation; D011110:Polymorphism, Genetic; D017386:Sequence Homology, Amino Acid; D016615:Telomere / Q000235:genetics
C470574:AGAP1 protein, human; D020690:GTPase-Activating Proteins; D020727:ADP-Ribosylation Factors