**1. Introduction**

Autism is a behaviourally defined developmental disorder characterised by impairments in social communication, restricted interests and repetitive behaviours [1]. Abnormalities in these three developmental areas tend to cluster together in affected individuals. In DSM-IV, Autism is part of a larger continuum of disorders collectively called Pervasive Developmental Disor‐ ders. Autism spectrum disorders (ASD) refer to Autism, Pervasive developmental disorder, not otherwise specified, and Asperger syndrome. All individuals with ASDs have qualitative abnormalities of social development in combination with disorders of communication and/or stereotyped repetitive interests and behaviors. The social skills that develop naturally in typ‐ ically-developing children do not do so in children with ASD. In addition, there are several behaviors and co-morbid symptoms that relate to each of the three classical impairments. Re‐ cent studies have reported rates of co-occurring intellectual disability in the range of 25-50%. Neither developmental delay nor cognitive impairment are required for an ASD diagnosis.

Fombonne and colleagues recently estimated the prevalence of strictly–defined autism at ap‐ proximately 15-20 per 10,000 people [2]. When the definition of autism is relaxed to include Autism Spectrum Disorders, the prevalence estimated expands to approximately 60 in in 10,000 children [2, 3].

Little is known of the biological basis of ASD and the future development of rational knowl‐ edge based treatments will depend on a comprehensive understanding of innate biological predisposition and its interaction with environmental factors. The identification and charac‐ terisation of the genetic variation and genes involved in ASD is a route towards this goal. This chapter outlines the various approaches that have been applied to this task, in the context of rapidly evolving technology and human genome resources, and summarises the state of

© 2013 Gill et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

knowledge at this time, anticipating future developments, and outlining the implications for clinical management.

apart. Linkage studies take advantage of this non-random assortment of genetic variation. A linkage study calculates whether a known genetic variant and a disease mutation (represented by the disease trait) are linked and if so, roughly localises the causative mutation. Following the successes of using these approaches in the discovery of multiple loci implicate in Mendelian disorders, researchers were encouraged to apply linkage methodology to more complex traits, such as ASD where Mendelian principles may apply, at least in a proportion of families. How‐ ever, in ASD, only a few scans have highlighted loci with *significant* linkage, highlighting loci

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In 1998, the International Molecular Genetic Study of Autism Consortium (IMGSAC) [10] re‐ ported modest evidence for linkage. This included *significant* linkage arising on chromosome 7q32-q34. Supplemented analyses of IMGSAC families provided additional support for link‐ age at 7q22, 16p13, and 2q31 [11, 12]. The long arm of chromosome 7 has received particular attention with additional support reported for 7q21 [13], 7q22 [14], 7q31 [15, 16], 7q32 [17] and

Few individual families exist where ASD segregates in an obvious Mendelian fashion that is large enough to provide significant evidence for linkage by themselves. Most linkage studies required the assumption that a significant proportion of the families in the sample might be linked to a given locus and few were sufficiently large to accommodate even modest locus heterogeneity. Under a 'common disorder - common variant' model, multiply affected families will occur but linkage methods would be considerably underpowered. The effects of DNA variation with low penetrance are more easily identified using a genetic association study

Fine-mapping and candidate gene association studies at implicated regions on 7q have impli‐ cated a number of potential susceptibility genes including *RELN*, *MET*, *CNTNAP2* and *EN2*. Persico and colleagues [18] studied five DNA variants or polymorphisms across the *RELN* gene locus, including a GGC repeat variant located close to the *RELN* gene translation initiator codon. Located at 7q22, *RELN* encodes an extracellular matrix protein Reelin, which plays a pivotal role in the development of laminar structures including cerebral cortex, cerebellum and hippocampus. Using a genetic association approach, Persico and colleagues identified a nominally significant association with this 5'-UTR GCC-triplet-repeat polymorphism [18]. This finding was further supported by some studies [19-25] but not others [26-31]. *MET*, located at 7q31 received considerable attention following a high-profile association reported by Camp‐ bell and colleagues. The *MET* gene encodes a protein involved in MET (Mesenchymal epithelial transition factor) receptor tyrosine kinase signalling which has been implicated in brain growth and maturation – offering biological plausibility to its candidature. As with other candidate genes in ASD, the original findings have been supported in some [32], but not other studies [33] [34]. A similar scenario played out for the *EN2* homeobox gene located at 7q36 [35, 36]. Arking and colleagues [37] observed an association at *CNTNAP2* in the NIHM/AGRE collec‐ tion. The main association observed was for rs7794745 located in intron 2 of the gene (*Discovery P* = 0.00002, *Validation P* = 0.005). The *CNTNAP2* (7q35) gene encodes the contactin-associated protein-like 2 protein, which is a member of the neurexin family and thought to play a role in axonal differentiation and guidance. Li and colleagues also found mild support for *CNTNAP2*

including chromosome 7q, 2q and 3q.

design in a sample of cases drawn from a population.

7q36 [16].
