89e6cf82-e158-45db-b937-96dc3c9968a5
title
Association of the homeobox transcription factor,  ENGRAILED 2 , 3, with autism spectrum disorder.
a1195aab-d093-426c-997a-f1cdbcebe38d
abstract
Mouse mutants of the homeobox transcription factor Engrailed2 (En2) and autistic individuals display similar cerebellar morphological abnormalities, which include hypoplasia and a decrease in the number of Purkinje cells. Human  EN2  maps to 7q36, a chromosomal region that has demonstrated suggestive linkage to autism spectrum disorder (ASD). To investigate  EN2  for evidence of association with ASD, four single-nucleotide polymorphisms (SNPs) ( rs3735653 ,  rs1861972 ,  rs1861973 ,  rs2361689 ) that span the majority of the 8.0 kb gene were assessed by the transmission/disequilibrium test. Initially, 138 triads of autistic individuals and their parents were tested. Two intronic SNPs ( rs1861972  and  rs1861973 ) demonstrated significant association with autism ( rs1861972 , P=0.0018;  rs1861973 , P=0.0003; haplotype, P=0.000005). Flanking exonic SNPs ( rs3735653  and  rs2361689 ) did not display association. This analysis was then extended to include 167 small nuclear ASD pedigrees and significant association was again only observed for  rs1861972  and  rs1861973  under both the narrow and broad diagnostic criteria (narrow:  rs1861972  P=0.0290,  rs1861973  P=0.0073, haplotype P=0.0009; broad:  rs1861972  P=0.0175,  rs1861973  P=0.0107, haplotype P=0.0024). These data demonstrate association between a cerebellar patterning gene and ASD, suggesting a role for  EN2  as a susceptibility locus and supporting a neurodevelopmental defect hypothesis in the etiology of autism.