Angelman syndrome (AS) was initially described in 1965 by the paediatrician Harry Angelman in three unrelated children presenting with severe motor and cognitive delays, microcephaly, absent speech, ataxic gait, and seizures, in association with distinctive facial features that include a large open mouth, widely spaced teeth, midface retrusion, and prognathism.1
Subsequent clinical reports described typical behaviour in individuals with AS, including a happy sociable disposition, inappropriate laughter, and flapping of the arms.2,3
The 15q11‐q13 region was implicated in the pathogenesis of AS, when some individuals were found to have deletions or rearrangements in the proximal long arm of chromosome 15.4,5,6
The same genomic segment on proximal 15q had previously been implicated in Prader‐Willi syndrome (PWS);7
subsequently it was shown that deletions of the maternal chromosome produce AS and deletions of the paternal chromosome produce PWS.8,9
AS may ensue from four different molecular mechanisms, all of which result in deficiency of the maternally inherited E6 associated protein ubiquitin protein ligase 3A gene (UBE3A
). These include deletion of the maternal chromosome 15q11‐q13 region (70%), paternal uniparental disomy for chromosome 15 (2%),10,11
mutations of the UBE3A
and mutations or deletions of the imprinting centre (5%).14,15
The genomic organisation of the 15q11‐q13 region is complex and is perhaps one of the most variable regions of the human genome.16,17
This region is known to harbour multiple low copy repeats that probably mediate these deletions, duplications, and inversions.17,18,19
There are two types of deletions seen in AS, encompassing a region of over 6 Mb20
(Sahoo et al
, 2005; personal communication). A common distal breakpoint (BP3) and two proximal breakpoints (BP1 and BP2) define the frequently occurring types of deletions.16,18,21,22,23
The deletions that extend from BP1 to BP3 are designated class I deletions, and those extending from BP2 to BP3 are designated class II deletions (fig 1A, B). The majority of deletions in AS and PWS are class II.22
Some well known genes, many of them imprinted, are located in the interval between BP2 and BP3, including the gene encoding small nuclear ribonucleoprotein polypeptide‐N (SNRPN
, and the imprinting centre.
Figure 1Plot of the hybridisation results for representative case with class I deletion. (A) Raw, normalised (Norm) and combined (Comb) log2 ratio plots of array hybridisation are shown. The combined ratio plot provides a final estimate of gain, (more ...)
Some recent studies aimed at identifying phenotypic differences in PWS and AS patients with different deletion sizes have revealed interesting genotype‐phenotype relationships. Adults with PWS harbouring class I deletions had a greater incidence of obsessive‐compulsive behaviour, and more deficits in adaptive skills as compared with individuals with smaller class II deletions.24
Similar studies in AS demonstrated that all individuals with class I deletions showed a complete lack of vocalisation, while those with class II deletions were able to produce at least some syllabic sounds.25
Neither of these studies examined symptoms of autism. Because (a
) previous studies demonstrate significant overlap between AS and autism,26,27,28
and symptoms of autism persist over time in AS; (b
) the obsessive‐compulsive behaviours, deficits in adaptive behaviour, and deficits in language skills found in previous studies comparing deletion types in AS and PWS are part of the broad autism phenotype, and (c
) the AS/PWS critical region has been implicated in autism,29,30,31,32,33,34
we thought it important to examine the relationship between autism and deletion class in AS. As seizures occur in nearly 80% of children with AS,35
we also examined the relationship between the degree of seizure severity, EEG findings, and the number of medications required to achieve good seizure control across deletion classes.
Currently, the characterisation of deletion classes in the 15q11‐q13 region is performed by fluorescence in situ hybridisation studies (FISH) or microsatellite marker analysis. The advent of molecular tools such as array comparative genomic hybridisation (array CGH) allows us to define these rearrangements in a more detailed and comprehensive manner. A recent report has highlighted the usefulness of CGH arrays to characterise the AS/PWS region.16
For the current study, we analysed a group of 22 deletion bearing AS patients using a chromosome 15 specific array CGH to further characterise their deletion, and to examine genotype‐phenotype correlations.
The objectives of this study were threefold: (a) to characterise by array CGH a cohort of AS patients with deletions, (b) to examine the expression of autism spectrum disorder in this cohort, and (c) to analyse genotype‐phenotype differences between participants. It was hypothesised that accurate characterisation of the underlying molecular defect could help predict clinical outcomes, and therefore aid with early, appropriate interventions.