Review
The comorbidity of autism with the genomic disorders of chromosome 15q11.2-q13

https://doi.org/10.1016/j.nbd.2008.08.011Get rights and content

Abstract

A cluster of low copy repeats on the proximal long arm of chromosome 15 mediates various forms of stereotyped deletions and duplication events that cause a group of neurodevelopmental disorders that are associated with autism or autism spectrum disorders (ASD). The region is subject to genomic imprinting and the behavioral phenotypes associated with the chromosome 15q11.2-q13 disorders show a parent-of-origin specific effect that suggests that an increased copy number of maternally derived alleles contributes to autism susceptibility. Notably, nonimprinted, biallelically expressed genes within the interval also have been shown to be misexpressed in brains of patients with chromosome 15q11.2-q13 genomic disorders, indicating that they also likely play a role in the phenotypic outcome. This review provides an overview of the phenotypes of these disorders and their relationships with ASD and outlines the regional genes that may contribute to the autism susceptibility imparted by copy number variation of the region.

Section snippets

The complexities of the genomic landscape of chromosome 15q11.2-q13

Chromosome 15 has been identified as one of seven chromosomes enriched in segmental low copy repeats (LCRs) or duplicons (Bailey et al., 2002). These duplicons provide a mechanism in which LCR-mediated misalignment during meiosis I leads to unequal nonallelic homologous recombination generating a series of common breakpoints (BPs) along the 15q11.2-q13 (Christian et al., 1999, Robinson et al., 1993a, Robinson et al., 1993c, Robinson et al., 1998b).

The proximal three BP correspond to complex

Prader–Willi syndrome

PWS is classically characterized by hypotonia and failure to thrive in infancy, which evolves into a complex neurobehavioral phenotype accompanied by cognitive impairment, hyperphagia leading to obesity, obsessive compulsive behaviors that include hoarding and skin picking, with an increased risk of autism spectrum disorders (ASD). In addition, patients with PWS typically have hypogonadism, dysmorphic facial features, small hands and feet and may be hypopigmented (reviewed in Cassidy et al.,

The duplication syndromes

Interstitial duplications of proximal 15q11.2-13 often appear to be the reciprocal events of the PWS/AS deletions with LCR-mediated recombinations occurring through BP1–3 or BP2–3 (Repetto et al., 1998). However, more distal LCR also contribute with some duplication chromosomes and interstitial duplications and triplications extending to BP4 and BP5 (Wandstrat et al., 1998). In addition, duplications of this region can occur via U-type crossover events in meiosis (Robinson et al., 1998a),

Neurologically relevant 15q11.2-13 genes with altered expression in 15q11.2-q13 deletions and duplications

While the 13 MB region encompassed by the scope of 15q11.2-q13 deletion and duplication syndromes contains at least 30 characterized genes, the overwhelming focus of gene expression studies has been on the genes showing imprinted expression, as these are presumably the most likely to show parent-of-origin specific gene expression differences. The smallest of the regional duplications detected by CNV analysis includes only the ATP10A and GABRB3 genes, implicating them as critical genes for the

Epigenetic factors regulating 15q11.2-q13

Chromosome 15q11.2-q13 parental imprinting patterns and long-range gene expression effects are mediated by a bi-partite imprinting control region (ICR) upstream of the large paternal transcription unit from SNRPN through UBE3A. The PWS-ICR is hypermethylated on the silent maternal allele and deletion of this region on the paternal chromosome is sufficient to cause PWS (Sutcliffe et al., 1994). An AS-ICR located 35 kb upstream of the PWS-ICR is required for establishing the maternal methylation

Nuclear organization and homologous pairing of 15q11.2-q13 alleles in human neurons

Chromosome dosage changes to 15q11.2-q13 may also impact the normal balance of homologous chromosome 15 interactions previously observed in both lymphocytes and neurons (LaSalle and Lalande, 1996, Thatcher et al., 2005). Similar to X chromosome counting mechanisms that require transient homologous X chromosome pairing during development for proper X chromosome inactivation in females (Xu et al., 2006), some gene expression patterns within 15q11.2-q13 appear to require interactions between both

Future directions

Although maternal duplications of 15q11.2-q13 are the most common cytogenetic cause of autism, not all individuals with duplications have classic autism, so understanding the mole-cular basis of the clinical heterogeneity is imperative. The clinical heterogeneity among individuals with similar duplications suggests that genetic or epigenetic modifiers influence gene expression of 15q11.2-q13 genes or the downstream targets of these genes. Generation of a mouse model with excess maternal dosage

Acknowledgments

The authors are supported by grants from the National Institutes of Health [NIH F31 MH078377 (AH), NIH R01 HD48799 (JML), NIH P3P01 HD35470 (NCS), NIH R01 HD37874 (NCS), P20-RR020173 (NCS)], and Nemours (NCS and DW). We are indebted to the Isodicentric Exchange, Advocacy and Support Group and families with idic(15) for their participation in the ongoing research into the investigation of the phenotype of patients with idic(15) and interstitial duplication 15 chromosomes. The authors also thank

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