Review
Genome-wide expression studies in Autism spectrum disorder, Rett syndrome, and Down syndrome

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Abstract

Though different in their aetiology, autism spectrum disorder (ASD), Rett syndrome (RTT) and Down syndrome (DS) are three neurodevelopmental disorders sharing significant clinical and neuropathological overlaps. Genome-wide expression studies are reviewed and available datasets from post-mortem brains reanalyzed to identify genes and gene pathways dysregulated in all three disorders. Our results surprisingly converge upon immune, and not neurodevelopmental genes, as the most consistently shared abnormality in genome-wide expression patterns. A dysregulated immune response, accompanied by enhanced oxidative stress and abnormal mitochondrial metabolism seemingly represents the common molecular underpinning of these neurodevelopmental disorders. This conclusion may be important for the definition of pharmacological therapies able to ameliorate clinical symptoms across these disorders.

Introduction

Autism Spectrum Disorder (ASD), Rett Syndrome (RTT) and Down Syndrome (DS) are three developmental disorders affecting mainly, though by no means exclusively, the central nervous system (CNS). The incidence of ASD and DS is as high as 60–70/10,000 (Fombonne, 2009, Rutter, 2005), and 14–25/10,000 (Antonarakis et al., 2004), respectively. RTT is a relatively rare disease, affecting approximately 1/10,000–15,000 females (Leonard et al., 1997). The male:female gender ratio is 4:1 for ASD, whereas DS shows only a slight male excess (Kovaleva, 2002), and RTT, being an X-linked dominant disorder, affects only females (Weaving et al., 2005).

The causes of DS and RTT are genomic/genetic in nature, and have been elucidated for the vast majority of cases: DS is caused by a complete, or occasionally partial, triplication of chr. 21 (Lejeune et al., 1959), whereas approximately 80% of RTT patients carry de novo mutations inactivating the X-linked gene MECP2, which encodes the methyl-CpG binding transcriptional repressor MeCP2 (Amir et al., 1999, Chahrour and Zoghbi, 2007, Colvin et al., 2004). Unlike these two diseases, only approximately 10% of ASD cases have been associated with a known genetic or cytogenetic cause, though heritability estimates are the highest among psychiatric disorders (i.e., > 90%, as estimated by twin studies) (Persico and Bourgeron, 2006). Syndromic forms of ASD have been associated with (a) de novo chromosomal rearrangements (duplications of maternal 15q11–13; deletions of chr. 2q37, 7q31, 22q11; microdeletions of chr. 22q11.2 and 16p11.2); (b) other well-known genetic or genomic disorders, including neurofibromatosis, tuberous sclerosis, Angelman syndrome, Cornelia de Lange syndrome, and DS; (c) mitochondrial disorders; (d) copy number variants (CNVs) and/or mutations affecting neuroligins (NLGN3 and NLGN4), the SH3 and multiple ankyrin repeat domains gene (SHANK3), neurexin 1 (NRXN1), methyl-CpG-binding protein 2 (MECP2), homeobox A1 (HOXA1), and the phosphatase and tensin homologue gene (PTEN), among others (for review see Cohen et al., 2005, Lintas and Persico, 2009, Palmieri and Persico, 2010, Weiss, 2009, Zafeiriou et al., 2007). Hence, the cause of ASD is known only in a small minority of cases, although increasing attention is being placed on rare genetic variants and CNVs affecting “synaptic” and neurodevelopmental genes (Betancur et al., 2009, Buxbaum, 2009), as well as on immune abnormalities (see below).

Section snippets

Clinical and neuropathological overlap between autism spectrum disorder, Rett Syndrome and Down syndrome

Although different in origin, these three developmental disorders show significant clinical and neuropathological overlaps. Autistic traits are always present in RTT females and approximately 8% of DS patients are autistic (Cohen et al., 2005, Zafeiriou et al., 2007). Mild to severe mental retardation (MR) is present in approximately 70% of ASD cases (Fombonne, 2005), and in virtually all cases of RTT and DS. Seizures, a hallmark of RTT, also occur in approximately 30% and 37% of ASD and DS

Genome-wide expression studies

The advent of microarray technologies allows the design and implementation of genome-wide expression profiling, which is helping to unravel the molecular basis of phenotypic variation in many disease states. The partial, yet significant overlap between ASD, RTT and DS briefly discussed above, points toward the possible existence of shared molecular underpinnings. High-throughput screening of genome-wide expression profiles can be a powerful tool in investigating this hypothesis. Our review will

Convergence upon dysregulated immune gene expression in RTT, ASD, and DS post-mortem brains

To directly evaluate the degree of overlap between gene expression patterns in RTT, ASD, and DS, we downloaded all available GEO datasets (http://www.ncbi.nlm.nih.gov/gds) and analyzed data belonging to 3 RTT (superior frontal gyrus from Deng et al., 2007; GEO dataset record n. GSE6955); 6 ASD (superior temporal gyrus from Garbett et al., 2008), and 7 DS patients (dorsolateral prefrontal cortex from Lockstone et al., 2007; GEO dataset record n. GSE5390). Analyses were restricted to post-mortem

Conclusions

The studies briefly summarized here and the outcome of our analyses collectively suggest that dysreactive immune processes coupled with decreased ATP production and/or increased oxidative stress may play a significant role in these three disorders (Fig. 2), potentially contributing to determine the onset, severity, and spectrum of clinical symptoms, especially in reference to regression, stereotypies and mental retardation. For example, several children carrying pathogenic mutations in

Acknowledgments

This work is supported by the Italian Ministry for University, Scientific Research and Technology (Programmi di Ricerca di Interesse Nazionale, prot. n. 2006058195), the Italian Ministry of Health (RFPS-2007-5-640174), the Autism Speaks Foundation (Princeton, NJ), the Autism Research Institute (San Diego, CA), the Fondazione Gaetano e Mafalda Luce (Milan, Italy), and Autism Aids Onlus (Naples, Italy).

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