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

Abstract

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. Methylation-specific 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 (n=5) or larger (n=2) 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 ∼8% 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.

Figure 1

Seven unique or atypical PWS deletions. The position of genes and genetic markers (circles) in the chromosomal 15q11.2-q14 region are shown. In the PWS region (shown in blue), there are six paternal-only expressed unique copy genes (MKRN3, MAGEL2, NECDIN, C15orf2 and SNURF-SNRPN and a family of six snoRNA gene clusters). Only UBE3A and ATP10A (shown in red), related to AS, have maternal-only expression in mouse and humans, and this imprinted expression is limited to certain tissue-specific regions (ie, mostly regions in the brain). The bipartite imprinting center (IC) lies proximal to SNURF-SNRPN and within the 3 Mb PWS/AS imprinted region. The cluster of GABA receptor genes (GABRB3, GABRA5 and GABRG3), OCA2 (Type 2 albinism) and HERC2 are not imprinted and have biparental expression (shown in open black circle). The jagged vertical lines denote the common PWS deletion BPs, which lie within the segmental duplications associated with BP1–BP5. Type 1 deletions extend from BP1 to BP3 and Type 2 deletions extend from BP2 to BP3. The seven unique or atypical deletions (ie, neither Type 1 or 2) identified from this study are shown in solid lines with base pair positions of BPs confirmed by aCGH. These base pair positions are derived from the UCSC genome browser March 2006 (hg18) freeze (http://www.genome.ucsc.edu/). There is a lack of agreement in the literature regarding the order of the genes between BP1 and BP2. Note that there are more copies of the SNORD116 and SNORD115 snoRNA genes than are shown, and map distances are not drawn exactly to scale.

Figure 2

The two PWS subjects with large atypical deletions and lacking the typical PWS facial gestalt. Case 6 at 9 months (a), years (b) and 7 years (c, d). At 9 months (a) she appears well nourished with a weight for length at the 75th percentile. Features include a depressed and wide nasal bridge, blunted columella, round face and long, smooth philtrum. Case 7 at 13 months (e, f), 24 months (g) and 4 years (h). Note the thin, frail appearance with G-tube in place as an infant with a weight for length at <3rd percentile (e, f). Weight began to increase at 24 months. Facial features include a prominent metopic suture, round face, depressed and wide nasal bridge, blunted columella, and short and smooth philtrum.