Paternally inherited microdeletion at 15q11.2 confirms a significant role for the SNORD116 C/D box snoRNA cluster in Prader–Willi syndrome

Abstract

Prader-Willi syndrome (PWS) is a neurobehavioral disorder manifested by infantile hypotonia and feeding difficulties in infancy, followed by morbid obesity secondary to hyperphagia. It is caused by deficiency of paternally expressed transcript(s) within the human chromosome region 15q11.2. PWS patients harboring balanced chromosomal translocations with breakpoints within small nuclear ribonucleoprotein polypeptide N (SNRPN) have provided indirect evidence for a role for the imprinted C/D box containing small nucleolar RNA (snoRNA) genes encoded downstream of SNRPN. In addition, recently published data provide strong evidence in support of a role for the snoRNA SNORD116 cluster (HBII-85) in PWS etiology. In this study, we performed detailed phenotypic, cytogenetic, and molecular analyses including chromosome analysis, array comparative genomic hybridization (array CGH), expression studies, and single-nucleotide polymorphism (SNP) genotyping for parent-of-origin determination of the 15q11.2 microdeletion on an 11-year-old child expressing the major components of the PWS phenotype. This child had an B236.29 kb microdeletion at 15q11.2 within the larger Prader-Willi/Angelman syndrome critical region that included the SNORD116 cluster of snoRNAs. Analysis of SNP genotypes in proband and mother provided evidence in support of the deletion being on the paternal chromosome 15. This child also met most of the major PWS diagnostic criteria including infantile hypotonia, early-onset morbid obesity, and hypogonadism. Identification and characterization of this case provide unequivocal evidence for a critical role for the SNORD116 snoRNA molecules in PWS pathogenesis. Array CGH testing for genomic copy-number changes in cases with complex phenotypes is proving to be invaluable in detecting novel alterations and enabling better genotype-phenotype correlations. European Journal of Human Genetics (2010Genetics ( ) 18, 1196Genetics ( -1201 doi:10.1038/ejhg.2010; published online 30 June 2010Keywords: Prader-Willi syndrome; snoRNA; microdeletion; array CGH INTRODUCTION Prader-Willi syndrome (PWS; MIM 176270) is a neurobehavioral disorder caused by the lack of paternal expression of imprinted genes in the human chromosome region 15q11.2q13. PWS manifests as infantile hypotonia, genital hypoplasia, and neonatal feeding difficulties, followed by hyperphagia leading to profound obesity in early childhood and into adulthood. 1,2 Large interstitial deletions of B6-6.8 Mb at 15q11.2q13 of paternal origin are the cause in over 70% of cases. The majority of the remaining cases have maternal uniparental disomy (UPD) 15, and a small percentage have imprinting defects. Deletions at 15q11.2q13 of maternal origin result in Angelman syndrome (MIM 105830). Identification and characterization of the recurrent deletion breakpoints have revealed low-copy repeat-mediated nonallelic homologous recombination as the unifying mechanism for the common deletions and duplications across this interval. 3,4 A number of paternally expressed genes mapping with...

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

“…5 This finding is also in accordance with the recent data demonstrating the regulatory role of GC skew repeat elements or long non-coding RNA (116HG) derived from the SNORD116 region. 14,16 This case therefore strengthens an evidence for the role of the SNORD116 region that has recently been highlighted in the molecular pathophysiology of PWS, [6][7][8] either as fully processed box C/D snoRNA species or as long non-coding host transcripts (116HG). [16][17][18][19] Next step will be to investigate the functions of these RNAs and their role in the pathogenesis of PWS.…”

“…Unfortunately, both the parents of the father were deceased and no material was available to test this hypothesis (Supplementary Figure 3S). Comparison of demonstrative cases of PWS-like cases with short deletions of the minimal functional PWS gene locus including the SNORD116 region [6][7][8] shows that the phenotypes are very similar (Supplementary Table 1S SNORD116 deletion in Prader-Willi Syndrome E Bieth et al in the proband, SNORD107, SNORD64, SNORD108, SNORD109B and, more importantly, SNURF-SNRPN and the SNORD115 cluster were not deleted (Figure 2a). In all previously described cases, at least one of these genes was preserved.…”

“…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. …”

Prader-Willi syndrome

“…[104][105][106] All three have multiple clinical features typical of PWS including neonatal hypotonia, infantile feeding problems, rapid weight gain by 2 years of age, hyperphagia, hypogonadism, developmental delay/intellectual disability, and speech and behavioral problems. However, these three individuals also have features not typical of classical PWS, including tall stature as a child, large head circumference, lack of a "PWS facial gestalt, " and hand features not typical of PWS.…”

NF1 microduplications: identification of seven nonrelated individuals provides further characterization of the phenotype

“…17 Oligonucleotide-based microarray analysis was originally performed on DNA from subjects 5, 6, and 7 using a custom 12-plex 135K-feature whole-genome oligonucleotide microarray (SignatureChip Oligo Solution v2.0, custom-designed by Signature Genomic Laboratories, Spokane, WA, and manufactured by Roche NimbleGen, Madison, WI) using previously described methods. 25 DNA from subjects 1, 2, and 4 were rerun on the SignatureChip Oligo Solution v2.0 12-plex to refine the size of the duplication. Results were visualized using custom microarray analysis software (Genoglyphix, Signature Genomic Laboratories).…”