SNORD116 deletions cause Prader‐Willi syndrome with a mild phenotype and macrocephaly

Abstract

Prader-Willi syndrome is a complex condition caused by lack of expression of imprinted genes in the paternally derived region of chromosome 15 (15q11q13). A small number of patients with Prader-Willi phenotype have been discovered to have narrow deletions, not encompassing the whole critical region, but only the SNORD116 cluster, which includes genes codifying for small nucleolar RNAs. This kind of deletion usually is not detected by the classic DNA methylation analysis test. We present the case of a male patient with a mild Prader-Willi phenotype and a small deletion including SNORD116, diagnosed by methylation-sensitive multiplex ligation-dependent probe amplification (MLPA. The patient showed neonatal hypotonia, hyperphagia, obesity, central hypogonadism, hypothyroidism, strabismus. Stature and intellectual development are within the normal range. The presence of macrocephaly, observed in other cases of SNORD116 deletions as well, is uncommon for the classic phenotype of the syndrome.

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

“…Additionally, in four of the seven subjects, at least one of the adjacent genes, including the SNURF-SNRPN locus, SNORD107, SNORD64, SNORD108, and SNORD115 cluster, was also deleted [5][6][7]9]. The microdeletion in our patient is very similar to the cases reported by Bieth et al [8] and Fontana et al [10]. The deletion in Bieth's subject was 118 kb in size, encompassing the SNORD109A gene, the whole SNORD116 cluster, and the non-coding exons of the IPW transcript.…”

“…He had no sleep disturbances, skin picking or other behavioral problems. Of note, in our patient and the ones reported by Bieth et al [8] and Fontana et al [10], food-related behavioral problems (e.g., foraging and sneaking) were milder than typically seen in individuals with PWS. They had the lowest BMIs at 31, 28.45, and 25.1, respectively (through dietary restriction), with a range of 39-50 for the other subjects.…”

“…Interestingly, our patient had spontaneous puberty and reached an adult height above the 95th percentile. The subject with PWS reported by Fontana et al [10] had delayed puberty but his adult stature was within the normal range (174 cm; between the 25th and 50th percentile). He also had normal sized hands and feet and intellectual development (intelligence quotient (IQ) of 80) with mild learning disability, which is very similar to our patient.…”

“…This deletion results in the loss of several of the PWS-associated non-coding RNA species, including the SNORD116 cluster. In the literature, only six PWS cases that were caused by small atypical deletions spanning snoRNAs at 15q11.2 have been reported before, with deletion sizes ranging from 80 to 236 kb (see Table 1), all of which overlap the SNORD116 region [5][6][7][8][9][10]. Altogether, these rare cases provide further insights into genotype-phenotype correlations.…”

C/D‐box snoRNAs form methylating and non‐methylating ribonucleoprotein complexes: Old dogs show new tricks

“…Comparing all microdeletions identifies a region containing SNORD116 and SNORD 109, suggesting that the loss of these SNORDs plays a central role in PWS disease etiology [34–38] (Figure 2A). …”