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Association of INPP1, PIK3CG, and TSC2 gene variants with autistic disorder: implications for phosphatidylinositol signalling in autism
  1. F J Serajee1,
  2. R Nabi1,
  3. H Zhong1,
  4. A H M Mahbubul Huq1,2
  1. 1Department of Pediatrics
  2. 2Department of Neurology, Wayne State University, Detroit, USA
  1. Correspondence to:
 Dr A H M Mahbubul Huq
 Division of Neurology, Children’s Hospital of Michigan, 3901 Beaubien Blvd, Detroit, MI 48201, USA;

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Epidemiological studies have shown that about 43–86% of individuals with tuberous sclerosis complex have a pervasive developmental disorder similar to autism.1 Mutations in tuberous sclerosis genes TSC1 and TSC2 disrupt the phosphatidylinositol signalling pathway downstream of the insulin / insulin-like growth factor receptor in the control of cell growth.2–5 We investigated single nucleotide polymorphisms in three phosphatidylinositol signalling genes that map to consensus areas of linkage to autism, using 196 trios from the Autism Genetics Resource Exchange. Polymorphisms in inositol polyphosphate-1-phosphatase (INPP1) at the 2q32, γ catalytic subunit of phosphatidyl 3-OH-kinase gene (PIK3CG) at 7q22, and TSC2 gene at 16p13.3, were investigated for association with autistic disorder. Transmission disequilibrium tests and haplotype analyses demonstrated a nominally positive association of polymorphisms in INPP1, PIK3CG, and TSC2 genes with autism, suggesting that phosphatidylinositol signalling may have a role in susceptibility to autism.

Autism spectrum disorders [MIM 209850], which include autism, Asperger’s syndrome, and pervasive developmental disorder not otherwise specified, are characterised by impairments in communications and social interactions and the presence of stereotyped behaviours. Family, twin, and linkage data suggest that inheritance of autism is complex.6–8 Latent class analysis of twin and family data suggests that between two to 10 loci may act epistatically,6 although more than 15 loci have been suggested.9 Recent genome screening studies found that many regions distributed over many chromosomes had a multipoint maximum lod score greater than one.9–14 Several studies found evidence of linkage in overlapping regions, which are likely to represent true linkage findings. The most consistent results are for regions on chromosome 7q, 2q and 16p13.3.11,15–17 The 16p13.3 region harbours the locus for TSC2 gene.18

Autism occurs in a number of genetic conditions, such as fragile X,19,20 phenylketonuria,21 tuberous …

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  • The study described here was supported in part by a grant from the Children’s Research Center of Michigan.