Prader–Willi-Like Phenotype Caused by an Atypical 15q11.2 Microdeletion

Abstract

We report a 17-year-old boy who met most of the major Prader–Willi syndrome (PWS) diagnostic criteria, including infantile hypotonia and poor feeding followed by hyperphagia, early-onset morbid obesity, delayed development, and characteristic facial features. However, unlike many children with PWS, he had spontaneous onset of puberty and reached a tall adult stature without growth hormone replacement therapy. A phenotype-driven genetic analysis using exome sequencing identified a heterozygous microdeletion of 71 kb in size at chr15:25,296,613-25,367,633, genome build hg 19. This deletion does not affect the SNURF-SNRPN locus, but results in the loss of several of the PWS-associated non-coding RNA species, including the SNORD116 cluster. We compared with six previous reports of patients with PWS who carried small atypical deletions encompassing the snoRNA SNORD116 cluster. These patients share similar core symptoms of PWS while displaying some atypical features, suggesting that other genes in the region may make lesser phenotypic contributions. Altogether, these rare cases provide convincing evidence that loss of the paternal copy of the SNORD116 snoRNA is sufficient to cause most of the major clinical features of PWS.

A Comprehensive Review of Genetically Engineered Mouse Models for Prader-Willi Syndrome Research

“…Results obtained from the Snord116 KO models are in accordance with the current leading hypothesis that the absence of SNORD116 gene clusters indeed plays a causative role in the early onset of PWS pathogenesis. SNORD116 genomic regions became a prime focus following the discovery of PWS patients harboring a rare minimal deletion of the SNORD116 gene cluster ( Figure 1 A) [ 34 , 35 , 36 , 37 , 38 , 39 ].…”

CRISPR/Cas9 Epigenome Editing Potential for Rare Imprinting Diseases: A Review

“…In contrast to AS where one main disease-causing gene has been confirmed, there are 15 genes in the PWS critical region [111,124]. However, evidence from collective efforts in deciphering the molecular genetics of PWS is suggesting that the C/D box snoRNA cluster SNORD116, expressed from its host transcript 116 HG, might be the key player in PWS [125]. C/D box snoRNAs are small nuclear RNAs that methylates ribosomal RNAs.…”

Prader-Willi syndrome: reflections on seminal studies and future therapies

“…PWS patients with SD in the proximal SNHG14 transcript encompassing the SNORD116 cluster are reported to demonstrate milder phenotype and absence of some clinical traits associated with PWS [17][18][19][20][21][22]. These patients still possess the hallmark traits of hypotonia, hypogonadism and hyperphagia/obesity albeit in milder forms.…”

“…These patients still possess the hallmark traits of hypotonia, hypogonadism and hyperphagia/obesity albeit in milder forms. Some patients had normal to tall stature and absence of PWS facial features [ 19 – 22 ]. These findings might indicate that the absence of SNORD116 plays a crucial role in the development of PWS phenotype.…”

“…The importance of this cluster to PWS pathology is very high, because all reported deletions and mutations associated with PWS lead to loss of expression from this region. A number of atypical PWS deletions have narrowed the putative PWS critical region to approximately 80 kB primarily spanning the SNORD116 cluster ( figure 4 ) [ 17 – 22 ]. While most known snoRNAs have been shown to target the modification of rRNA, the SNORD116 snoRNAs are classified as ‘orphans' because no known targets have been identified and their sequences show no significant complementarity to rRNAs.…”