 |
|
|
|
Merlin G. Butler, Nataliya Kibiryeva, William Fischer, Douglas C. Bittel Children’s Mercy Hospital and Clinics and University of Missouri-Kansas City School of Medicine, Kansas City, MO Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by infantile hypotonia, feeding difficulties, hypogonadism, mental deficiency, hyperphagia leading to obesity in early childhood, learning problems and behavioral difficulties. A paternal 15q11-q13 deletion is found in about 70% of PWS subjects and the remaining cases have uniparental maternal disomy 15, imprinting defects or translocations. The proximal deletion breakpoint in the 15q11-q13 region occurs at one of two sites located within either of two large duplicons allowing for identification of two typical deletion subgroups. The larger type I (TI) deletion involving breakpoint 1 (BP1) is nearer to the centromere and located proximal to the microsatellite marker D15S1035 (nucleotide number 20,459,962), while the smaller type II (TII) deletion involves breakpoint 2 (BP2) which is distal to D15S1035. Breakpoint 3 (BP3) is located at the distal end of the 15q11-q13 region and common to both typical deletion subgroups. Using newer technology with high resolution oligonucleotide aCGH analysis (244K DNA microarray slides, Agilent Technologies, Santa Clara, CA), we examined the position of the chromosome 15 breakpoints in 12 individuals with type I deletions (7 females, 5 males; mean age +/- s.d., 24.7 +/- 9.5 y) and 13 individuals with type II deletions (9 females, 4 males; mean age +/- s.d., 18.6 +/- 6.1 y). BP1 spanned a region from 18.68 to 20.20 Mb (mean +/- s.d., 19.89 +/- 0.57) measured from the p terminus while BP2 spanned from 20.81 to 21.36 Mb (mean +/- s.d., 21.19 +/- 0.17). BP3 spanned the region from 25.94 to 27.04 Mb (mean +/- s.d., 26.47 +/- 0.41) in individuals with a type I deletion while BP3 spanned the region from 26.12 to 27.29 (mean +/- s.d., 26.52 +/- 0.44) in those with a type II deletion. The size of the TI deletion ranged from 5.72 Mb to 8.15 Mb (mean +/- s.d., 6.58 +/- 0.73) and the TII deletion ranged from 4.77 Mb to 6.40 Mb (mean +/- s.d., 5.31 +/- 0.53). Hence, the size of the region where BP1 occurred was 1.52 Mb while the size of the region for BP2 was smaller (0.55 Mb). The size of the BP3 region was 1.35 Mb for the combined TI and TII subgroups. With this technology the size of either deletion type appeared larger than previously thought and a subset of subjects with TI deletions (e.g., breakpoint at 18.68 Mb) would include in addition to the four genes previously recognized between BP1 and BP2 (i.e., GCP5, CYFIP1, NIPA, NIPA2) at least three other genes/transcripts (i.e., LOC283755, POTE5, OR4N4). As anticipated, several other regions with copy number variation were detected involving other chromosomes. Additional studies are required to further characterize these regions of copy number variation among PWS and control subjects. Thus, the use of high resolution oligonucleotide microarrays will allow for more detailed genomic data and for more precise location and assignment of breakpoints (therefore potential gene involvement) as well as more detailed genotype – phenotype correlations. edited: 02/09/2012 |