Objectives: In order to identify the genetic causes leading to the disorder and provide an appropriate recurrence risk to the families we evaluated in genetic counseling a group of patients with a diagnosis of ASD, namely Autistic Disorder or Pervasive Developmental Disorder-Not Otherwise Specified(PPD-NOS) according to DSM-IV classification. We have attempted the characterization in term of frequency, size, and nature of CNVs in our population of patients with ASD. We have searched for new CNVs that could be implicated as genetic causes or modifier factors in the patient’s phenotype and looked for new genes that could correlate with the disease.
Methods: By the use of oligonucleotide array with 44.000 probes and an average resolution of about 100-130 kb (44K, Agilent) we have analyzed 50 unrelated subjects with ASD. Inheritance has been determined using the same technique.
Results: We have identified private rearrangements in 4 out of 50 patients analyzed. In one patient, a 16p13.11 duplication was identified, already reported to be associated with Autistic Disorder (AD). In another patient with AD, a 17q12 duplication was identified, inherited by an apparently normal father and a possible positional effect in a nearby gene was hypothesized (Mencarelli MA et al; 2008 and Katzaki E et al; 2009). Two patients with AD presented two inherited rearrangements each, in one, a deletion in 1p22.1 inherited by the mother and a deletion in 4q35.2 inherited by the father were detected. In the other with AD, a deletion in 9p21.3 inherited by the mother and a duplication in 11q23.1 inherited by the father were identified. A possible mechanism by which a double structural variation can impact the patients phenotypes, apart gene dosage and disruption (currently implicated by CNVs), is that of genes included in two different regions having a possible interaction in a common molecular pathway
Conclusions:
Array CGH analysis has been revealed a useful tool not only for the identification of the genetic cause in patients with MCA/MR but also in providing evidence of the pathogenetic role of CNVs in patients with ASD. Our results confirm that rearrangements involving the 16p13 region are recurrent (2%) in ASD. As well we have identified in the 4% of patients double rearrangements that can lead to hypothesize the possibility of digenic inheritance. Future studies on ASD will require the collection of a larger number of patients and the attempt to identify new disease genes should take into account the possible interaction between genes located in different chromosomal regions.