Towards Identification of Individual Etiologies by Resolving Genomic and Biological Conundrums in Patients with Autism Spectrum Disorders

Abstract

Recent genomic research into autism spectrum disorders (ASD) has revealed a remarkably complex genetic architecture. Large numbers of common variants, copy number variations and single nucleotide variants have been identified, yet each of them individually afforded only a small phenotypic impact. A polygenic model in which multiple genes interact either in an additive or a synergistic way appears the most plausible for the majority of ASD patients. Based on recently identified ASD candidate genes, transgenic mouse models for neuroligins/neurorexins and genes such as Cntnap2,Cntn5, Tsc1, Tsc2, Akt3, Cyfip1, Scn1a, En2, Slc6a4, and Bckdk have been generated and studied with respect to behavioral and neuroanatomical phenotypes and sensitivity to drug treatments. From these models, a few clues for potential pharmacologic intervention emerged. The Fmr1,Shank2 and Cntn5 knockout mice exhibited alterations of glutamate receptors, which may become a target for pharmacologic modulation. Some of the phenotypes of Mecp2 knockout mice can be ameliorated by administering IGF1. In the near future, comprehensive genotyping of individual patients and siblings combined with the novel insights generated from the transgenic animal studies may provide us with personalized treatment options. Eventually, autism may indeed turn out to be a phenotypically heterogeneous group of disorders (‘autisms') caused by combinations of changes in multiple possible candidate genes, being different in each patient and requiring for each combination of mutations a distinct, individually tailored treatment.

A Candidate Gene Association Study Further Corroborates Involvement of Contactin Genes in Autism

“…These negative findings may be due to the limited size of the patient cohort in the present study. A previous CNV study showed a cosegregating loss of part of CNTN5 in a single family, which, because of its segregation pattern within this family, is likely to be pathogenic by causing haploinsufficiency for this gene [van Daalen et al, 2011, Poot, 2013. In the present candidate gene association study of the same patient cohort, from which this particular patient was removed, the SNP with the strongest signal was located in CNTN5 .…”

“…The contactin-5 protein also binds to the amyloid precursor-like protein 1 (APLP1), thus, possibly forming a network by physical interactions of encoded proteins [Shimoda et al, 2012]. Since involvement of CNTN5 in ASD has been supported by both the CNV and the present candidate gene association study, further neurobiological and, in particular, neurobehavioral studies of this gene appear warranted [Poot, 2013].…”

“…Plausible molecular hypotheses for such a model may include either physical interaction of encoded proteins or regulatory networks of transcription factors [Poot et al, 2010b[Poot et al, , 2011Leblond et al, 2012;Huguet et al, 2013], which all merit further study. If specific polygenic constellations would be uncovered in individual patients, this may pave the way to distinguishing molecular subtypes of ASD, which eventually may become targets for individualized treatment approaches [Poot, 2013].…”

“…Due to the relatively small patient cohort, of these studies, the overrepresentation of these contactin genes was not statistically significant [van Daalen et al, 2011;Nava et al, 2013]. Another limitation of these studies was their focus on CNVs, such that other mutagenic mechanisms independent of gene dosage will be neglected [Poot et al, 2011;Poot, 2013]. The hypothesis that contactin genes may be involved in ASD by non-CNV-dependent mechanisms can be tested by performing an association study of all contactin and contactinassociated genes in the same patient cohort.…”

Late Breaking Chromosomes

“…A third mechanism may be perturbation of networks of epistatic interaction between genes by pairs of CNVs [Leblond et al, 2012;Poot, 2013]. A fourth, related mechanism may be the loss of binding sites for transcription factors, such as FOXP2 due to a deletion covering intron 1 of CNTNAP2 , as has been reported in a single patient with delayed development of speech and autism [Poot et al, 2010b].…”