Autism spectrum disorder is a complex, heterogeneous, behaviorally-defined disorder with a 4:1 male:female gender distortion . Although environmental elements, such as peri- and post-natal stress, have been reported to contribute to the development of autism, monozygotic twin studies along with evidence of chromosomal abnormalities, mutations in single genes, and multiple gene polymorphisms in autistic individuals, clearly show that autism is a largely genetic disorder [2–5].
Single mutations in neuroligin 3 and 4, cell adhesion molecules present at the post-synaptic side of the synapse, and in SHANK3, a scaffolding protein found in excitatory synapses, have been described in autistic individuals [6, 7]. In the majority of cases, however, an overall lack of Mendelian inheritance suggests the involvement of multiple genes [5, 8]. Indeed, genome-wide screens and candidate gene approaches have identified a number of chromosomal regions and genes linked with autism [9–19]. For example, a strong association between autism and SLC25A12, a gene encoding the mitochondrial aspartate/glutamate carrier AGC1 expressed in neurons and in neural stem cells, has been reported in 2 separate studies [17, 19]. Similarly, an analysis of chromosome 16p revealed an association between autism and the protein kinase c-beta gene (PRKCB1), which is expressed in granule cells of the brain and B lymphocytes .
Although most of the genetic analyses, to date, have focused on genes expressed in the brain, the pathophysiology of autism suggests that other systems such as the immune system and the pituitary-hypothalamic axis may be involved [21, 22]. In some autistic individuals, for example, abnormal secretion of pro-opio-melanocortin (POMC), adrenocorticotropin (ACTH), cortisol, and beta-endorphin has been noted [22–25].
We recently performed a genome-wide linkage scan in a group of families with autism and phrase speech delay identified in the Autism Genetic Resource Exchange (AGRE) DNA repository . Among the 7 genomic regions that showed a significant increase in identity-by-descent sharing in sibling pairs with autism, 4 corresponded to regions that have previously been linked to autism (chromosome 5, 13, 16, and 17) . Based on these results, in the current study, we focused on chromosome 5q31 and identified 3 genes that we hypothesized could be involved in the development of autism: 1) paired-like homeodomain transcription factor 1 (PITX1), which is a key regulator of hormones within the pituitary-hypothalamic axis such as ACTH, cortisol, and beta-endorphin [22, 26, 27]; 2) histone family member H2AFY, which is involved in X-inactivation in females and therefore could be a positional candidate that could explain the 4:1 male:female gender distortion present in autism [1, 28]; and 3) Neurogenin 1 (NEUROG1), which is a transcription factor involved in neurogenesis . Using single point association analyses and haplotype analyses, we found significant evidence for an association of autism with PITX1 but not with H2AFY or NEUROG1.