Identification of novel deletions of 15q11q13 in Angelman syndrome by array-CGH: molecular characterization and genotype–phenotype correlations

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 B6.8 and B6.0, 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 410.6 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.

Clinical and genetic aspects of Angelman syndrome

“…Those with the large deletion are more likely to exhibit clinical hypopigmentation (discussed above). There is some suggestion that individuals with larger deletions (e.g., BP1-BP3 [class I] break points) may have more language impairment or autistic traits 47 than those with BP2-BP3 (class II) break points (Fig. 2).…”

“…2). 47 The BP1, BP2, and BP3 regions are characterized by low-copy repeat regions that contain repeats mainly derived from the ancestral HECT domain and RCc1 domain protein 2 genes (HERC2). 100 The BP sites distal to BP3 contain other low-copy repeat regions (e.g., without HERC2 duplications) that share chromosome 15-derived repeated DNA elements.…”

Unique and atypical deletions in Prader–Willi syndrome reveal distinct phenotypes

“…The array-based comparative genome hybridization (aCGH) included a total of over 38 000 oligos across 15q, with a higher density of oligos spanning B10 Mb of the 15q11.2-q14 interval at the Baylor College of Medicine (Agilent Technologies Inc., Santa Clara, CA, USA). 7 …”

“…For the purpose of this study, we used the designation of Type 1 deletion to encompass the region between BP1 and BP3 (B6 Mb in size), and Type 2 deletion to encompass the region from BP2 to BP3 (B5.3 Mb in size). [5][6][7] However, there are rare PWS and AS patients with an atypical distal BP at BP4 or BP5. 8,9 Additionally, in a few patients, the 15q11.2-q13 region may be deleted as a result of an unbalanced translocation, which will yield unique BPs within proximal 15q.…”

Nichtinvasive pränatale Tests in der Zukunft

“…Es ist auch bereits gelungen, das gesamte fetale Genom mittels cfDNA-Analyse aus dem mütterlichen Blut zu sequenzieren [3,4] [23,24] 70 [23,24] Cri-du-Chat-Syndrom 5p15 1:50.000 [25] 10-30 Mb [26,27] 99 [26,27] sche Indikationen bzw. …”