Abstract
Angelman syndrome (AS) is a neurodevelopmental disorder characterized by mental retardation, absent speech, ataxia, and a happy disposition. Deletions of the 15q11q13 region are found in approximately 70% of AS patients. The deletions are sub-classified into class I and class II based on their sizes of approximately 6.8 and approximately 6.0, respectively, with two different proximal breakpoints and a common distal breakpoint. Utilizing a chromosome 15-specific comparative genomic hybridization genomic microarray (array-CGH), we have identified, determined the deletion sizes, and mapped the breakpoints in a cohort of 44 cases, to relate those breakpoints to the genomic architecture and derive more precise genotype-phenotype correlations. Interestingly four patients of the 44 studied (9.1%) had novel and unusually large deletions, and are reported here. This is the first report of very large deletions of 15q11q13 resulting in AS; the largest deletion being >10.6 Mb. These novel deletions involve three different distal breakpoints, two of which have been earlier shown to be involved in the generation of isodicentric 15q chromosomes (idic15). Additionally, precise determination of the deletion breakpoints reveals the presence of directly oriented low-copy repeats (LCRs) flanking the recurrent and novel breakpoints. The LCRs are adequate in size, orientation, and homology to enable abnormal recombination events leading to deletions and duplications. This genomic organization provides evidence for a common mechanism for the generation of both common and rare deletion types. Larger deletions result in a loss of several genes outside the common Angelman syndrome-Prader-Willi syndrome (AS-PWS) critical interval, and a more severe phenotype.
Highlights
Genomic rearrangements affecting the proximal segment of human chromosome 15 result in a number of welldefined clinical phenotypes.[1,2] This region of chromosome 15 (15q11q13) is extremely complex in its organization and susceptibility to rearrangements
Newer genomic array-based technologies have helped to define the nature of the common deletions of 15q11q13 resulting in Angelman syndrome (AS) and to identify novel deletion rearrangements of proximal 15q resulting in AS
There is a trend for class I individuals to have lower expressive and total language abilities and an increased likelihood of meeting criteria for a comorbid diagnosis of autism
Summary
Genomic rearrangements affecting the proximal segment of human chromosome 15 result in a number of welldefined clinical phenotypes.[1,2] This region of chromosome 15 (15q11q13) is extremely complex in its organization and susceptibility to rearrangements. Genotype – phenotype correlations in novel 15q11q13 deletions T Sahoo et al mapping to 15q11q13, a region that includes a 44 Mb domain subject to genomic imprinting.[3,4,5] Several different chromosomal abnormalities involving 15q11q13 have been identified in cases of autism often with a dependence on parent of origin.[6,7,8] AS (MIM 105830) is a neurodevelopmental disorder characterized by mental retardation, absent speech, dysmorphic features, ataxia, seizures, and typical behavioral abnormalities, including a happy sociable disposition.[9] AS is caused by deficiency of maternally inherited UBE3A (E6-associated protein ubiquitin-protein ligase gene), located within the imprinted region on chromosome 15q11q13.10 Deletions of the 15q11q13 region account for approximately 70% of the AS patients. Children with class I deletions required more medications to control their seizures in comparison with the class II group.[14]
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