Array comparative genomic hybridization (aCGH) analysis in Prader–Willi syndrome

Butler, Merlin G.; Fischer, William; Kibiryeva, Nataliya; Bittel, Douglas C.

doi:10.1002/ajmg.a.32249

Cited by 79 publications

(84 citation statements)

References 29 publications

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“…The breakpoints which bookend the 22q11.2 deletion leading to the 22q11.2 deletion syndrome (DiGeorge, Velocardiofacial or Shprintzen syndromes) approximate the LCRs more closely than the breakpoints of the 15q11-q13 deletion that results in Prader-Willi syndrome (PWS) or Angelman syndrome (Butler et al, 2008). The proximal deletion breakpoints in chromosome 15 in PWS spanned 1.5 Mb (for typical Type I deletion) to 0.5 Mb (for typical Type II deletion) (Butler et al, 2008) while in our subjects the proximal and distal breakpoints on 22q11 spanned approximately 350 kb each.…”

Section: Discussionmentioning

confidence: 99%

“…Copy number variants were identified with CGH Analytics software using the Aberration Detection Method 2 (ADM-2) analysis algorithm (Agilent Technologies, Santa Clara, CA) as previously described (Butler et al, 2008). The ADM-2 qualityweighted interval score algorithm identifies aberrant intervals (e.g., CNVs) in a sample that has consistently high or low log ratios based on their statistical score.…”

Section: Subjectsmentioning

confidence: 99%

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Refining the 22q11.2 deletion breakpoints in DiGeorge syndrome by aCGH

Bittel

Yu²,

Newkirk³

et al. 2009

Cytogenet Genome Res

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Hemizygous deletions of the chromosome 22q11.2 region result in the 22q11.2 deletion syndrome also referred to as DiGeorge, Velocardiofacial or Shprintzen syndromes. The phenotype is variable but commonly includes conotruncal cardiac defects, palatal abnormalities, learning and behavioral problems, immune deficiency, and facial anomalies. Four distinct highly homologous blocks of low copy number repeat sequences (LCRs) flank the deletion region. Mispairing of LCRs during meiosis with unequal meiotic exchange is assumed to cause the recurrent and consistent deletions. The proximal LCR is reportedly located at 22q11.2 from 17.037 to 17.083 Mb while the distal LCR is located from 19.835 to 19.880 Mb. Although the chromosome breakpoints are thought to localize to the LCRs, the positions of the breakpoints have been investigated in only a few individuals. Therefore, we used high resolution oligonucleotide-based 244K microarray comparative genomic hybridization (aCGH) to resolve the breakpoints in a cohort of 20 subjects with known 22q11.2 deletions. We also investigated copy number variation (CNV) in the rest of the genome. The 22q11.2 breaks occurred on either side of the LCR in our subjects, although more commonly on the distal side of the reported proximal LCR. The proximal breakpoints in our subjects spanned the region from 17.036 to 17.398 Mb. This region includes the genes DGCR6 (DiGeorge syndrome critical region protein 6) and PRODH (proline dehydrogenase 1), along with three open reading frames that may encode proteins of unknown function. The distal breakpoints spanned the region from 19.788 to 20.122 Mb. This region includes the genes GGT2 (gamma-glutamyltransferase-like protein 2), HIC2 (hypermethylated in cancer 2), and multiple transcripts of unknown function. The genes in these two breakpoint regions are variably hemizygous depending on the location of the breakpoints. Our 20 subjects had 254 CNVs throughout the genome, 94 duplications and 160 deletions, ranging in size from 1 kb to 2.4 Mb. The presence or absence of genes at the breakpoints depending on the size of the deletion plus variation in the rest of the genome due to CNVs likely contribute to the variable phenotype associated with the 22q11.2 deletion or DiGeorge syndrome.

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Section: Discussionmentioning

confidence: 99%

Section: Subjectsmentioning

confidence: 99%

Refining the 22q11.2 deletion breakpoints in DiGeorge syndrome by aCGH

Bittel

Yu²,

Newkirk³

et al. 2009

Cytogenet Genome Res

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“…73 Finally, several recent studies have detected novel submicroscopic 8p abnormalities using a new generation of microarray analysis. For example, Butler et al 74 using an array comparative genomic hybridization analysis in Prader-Willi syndrome, detected that most Prader-Willi syndrome subjects had CNVs on 8p and 3q. The autistic-like symptomatology in Prader-Willi syndrome 75 and the association with schizophrenia and affective psychosis 76 are also well known.…”

Section: Chromosome 8p Neuropsychiatric Disorders and Cancermentioning

confidence: 99%

Chromosome 8p as a potential hub for developmental neuropsychiatric disorders: implications for schizophrenia, autism and cancer

Tabarés‐Seisdedos

Rubenstein²

2009

Mol Psychiatry

217

157

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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Prader-Willi syndrome (PWS) is a multisystem, contiguous gene disorder caused by an absence of paternally expressed genes within the 15q11.2-q13 region via one of the three main genetic mechanisms: deletion of the paternally inherited 15q11.2-q13 region, maternal uniparental disomy and imprinting defect. The deletion class is typically subdivided into Type 1 and Type 2 based on their proximal breakpoints (BP1-BP3 and BP2-BP3, respectively). Despite PWS being a well-characterized genetic disorder the role of the specific genes contributing to various aspects of the phenotype are not well understood. Methylationspecific multiplex ligation-dependent probe amplification (MS-MLPA) is a recently developed technique that detects copy number changes and aberrant DNA methylation. In this study, we initially applied MS-MLPA to elucidate the deletion subtypes of 88 subjects. In our cohort, 32 had a Type 1 and 49 had a Type 2 deletion. The remaining seven subjects had unique or atypical deletions that were either smaller (n¼5) or larger (n¼2) than typically described and were further characterized by array-based comparative genome hybridization. In two subjects both the PWS region (15q11.2) and the newly described 15q13.3 microdeletion syndrome region were deleted. The subjects with a unique or an atypical deletion revealed distinct phenotypic features. In conclusion, unique or atypical deletions were found in B8% of the deletion subjects with PWS in our cohort. These novel deletions provide further insight into the potential role of several of the genes within the 15q11.2 and the 15q13.3 regions.

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Array comparative genomic hybridization (aCGH) analysis in Prader–Willi syndrome

Cited by 79 publications

References 29 publications

Refining the 22q11.2 deletion breakpoints in DiGeorge syndrome by aCGH

Refining the 22q11.2 deletion breakpoints in DiGeorge syndrome by aCGH

Chromosome 8p as a potential hub for developmental neuropsychiatric disorders: implications for schizophrenia, autism and cancer

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

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