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

Abstract

The SNORD116 locus lies in the 15q11-13 region of paternally expressed genes implicated in Prader-Willi Syndrome (PWS), a complex disease accompanied by obesity and severe neurobehavioural disturbances. Cases of PWS patients with a deletion encompassing the SNORD116 gene cluster, but preserving the expression of flanking genes, have been described. We report a 23-year-old woman who presented clinical criteria of PWS, including the behavioural and nutritional features, obesity, developmental delay and endocrine dysfunctions with hyperghrelinemia. We found a paternally transmitted highly restricted deletion of the SNORD116 gene cluster, the shortest described to date (118 kb). This deletion was also present in the father. This finding in a human case strongly supports the current hypothesis that lack of the paternal SNORD116 gene cluster has a determinant role in the pathogenesis of PWS. Moreover, targeted analysis of the SNORD116 gene cluster, complementary to SNRPN methylation analysis, should be carried out in subjects with a phenotype suggestive of PWS. European Journal of Human Genetics (2015) 23, 252-255; doi:10.1038/ejhg.2014.103; published online 11 June 2014 INTRODUCTION Prader-Willi Syndrome (PWS) is a neurodevelopmental disorder caused by the lack of expression of paternal alleles in 15q11-13. 1,2 The PWS phenotype includes neonatal hypotonia, early hyperphagia, morbid obesity, short stature, hypogonadism, cognitive impairment, and behavioural and psychiatric problems. Molecular mechanisms including large deletions, maternal uniparental disomy or imprinting defects explain 98% of cases which are easily diagnosed with a SNRPN methylation analysis. The study of rare cases resulting from reciprocal translocations and atypical 15q11q12 microdeletions without methylation abnormalities has defined a critical region containing the functional PWS gene locus. 3 This minimal region contains several snoRNAs gene clusters including SNORD116 and SNORD115. Mice lacking the SNORD116 orthologue display a partial PWS phenotype. 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.

A Comprehensive NGS Data Analysis of Differentially Regulated miRNAs, piRNAs, lncRNAs and sn/snoRNAs in Triple Negative Breast Cancer

“…While it was downregulated in our TNBC samples, snoRD114 was previously reported to be overexpressed in acute promyelocytic leukemia (APL) 77, suggesting, tissue specific action of this cluster of snoRNAs. The role of the snoRD113, snoRD114 and snoRD116 cluster region is becoming an important molecular target 78. For example, genetic mapping of snoRD116 has been recently reported to be absent or change its expression and affect other snoRNAs in Prader-Willi syndrome (PWS), a complex rare genetic condition caused by a loss of normally expressed genes on chromosome 15 from the paternal parent 79, 80.…”

SNORD116 and SNORD115 change expression of multiple genes and modify each other's activity

“…All microdeletions encompass the SNORD116 cluster, suggesting a central role of these SNORDs. Although these patients share nutritional features, hypogonadism, behavioral problems and intellectual disability with PWS patients, the patients with microdeletions have a tall stature as children, a large head circumference and hand features atypical for PWS, suggesting that genes other than SNORD116 contribute to PWS (Sahoo et al, 2008; de Smith et al, 2009; Duker et al, 2010; Bieth et al, 2015). …”

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).…”