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. 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.

Adult-onset deletion of the Prader-Willi syndrome susceptibility gene Snord116 in mice results in reduced feeding and increased fat mass

“…Of these, the smallest deletions that give rise to classical PWS phenotypic features are in a region that encompasses the small nucleolar RNA (snoRNA) SNORD116 (6)(7)(8)(9)(10). The analogue of this gene in mice, Snord116, is present in the corresponding murine PWS critical region, conserved on chromosome 7 (11,12).…”

Highly restricted deletion of the SNORD116 region is implicated in Prader–Willi Syndrome

“…4,5 However, so far, all reported clinical cases of limited deletion of the SNORD116 cluster associated with PWS have also involved adjacent genes: SNURF-SNRPN or SNORD115. [6][7][8][9] We report the first case of a patient with the highly typical features of PWS who presented a restricted deletion of the SNORD116 region which did not affect the expression of SNURF-SNRPN and did not delete any portion of the SNORD115 locus. …”

Methylation profile of SNRPN gene and its correlation with weight and chronological age

“…Based on these results, no significance differences were observed between the obese and nonobese groups. Kim et al (2012) used a different approach to measure the SNRPN methylation in a group of 80 subjects with early-onset morbid obesity; although the results of their study showed no statistically significant differences, the mean methylation in exon 1 of SNPRN (0.54 ± 00.6) did not differ from the mean methylation level seen in the control group of four subjects (0.55 ± 00.7). These results also suggest that the DNA methylation profile of SNRPN (in blood) does not correlate to the BMI (Kim et al, 2012).…”