Small mosaic deletion encompassing the snoRNAs and SNURF‐SNRPN results in an atypical Prader–Willi syndrome phenotype

Anderlid, Britt‐Marie; Lundin, Johanna; Malmgren, Helena; Lehtihet, Mikael

doi:10.1002/ajmg.a.36307

Cited by 28 publications

(31 citation statements)

References 30 publications

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“…The prevalence of this class of mutations is presumably underestimated because it cannot be detected by the classical DNA methylation analysis. The patients described until now have a quite typical PWS phenotype, even if normal stature and normal intellectual development have been reported . This case shows some of the major criteria of the syndrome, such as neonatal hypotonia, hypogonadism, hyperphagia, obesity, distinctive facial features.…”

Section: Discussionmentioning

confidence: 65%

“…Symptoms directly related to a hypothalamic dysfunction, such as hypogonadism, hyperphagia, obesity, hypothyroidism, seem to have a higher prevalence, consistently with the strong expression of the SNORD116 snoRNAs in the hypothalamus. Short stature is present in only 3 of the reported cases: it could be interesting to measure the GH and IGF‐1 levels in patients with the small SNORD116 deletions, in order to determine if they are higher than in the patients with the classic deletion.…”

Section: Discussionmentioning

confidence: 99%

“…Four of them present at least 6 of the 7 major diagnostic criteria of PWS, while 1 of them presents 5 major criteria (stature is normal and hypogonadism is absent) . Another 1, who carries a mosaic deletion, shows an atypical phenotype, characterized by hypogonadism, hyperphagia, obesity, but without neonatal hypotonia, nor intellectual disability . The reported deletions range from 118 to 800 kb.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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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.

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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“…Of note, deletions encompassing SNURF-SNRPN may result in atypical PWS phenotype. 13 While the SNORD115 region is genetically intact, its expression could be affected by the absence of the SNORD116 gene cluster or hypothetical regulatory elements in the surrounding region. SNORD115 expression in normal subjects has been shown to be present in neuronal cells and absent in peripheral tissues.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2014

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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.

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“…87 Detection of smaller or single-gene deletions has even provided insight into the etiology of well-established syndromes, like Prader-Willi syndrome. [88][89][90][91] In other microdeletion syndromes, the critical gene is identified when pathogenic point mutations are found in the gene, for example, KANSL1 in 17q21.31 microdeletions 92,93 and SETD5 in 3p25.3 microdeletions. 94 As newer genome-wide technologies such as exome and genome sequencing begin to gain broader clinical use, integration of data from CNV and sequencing studies are becoming another powerful tool to find novel human disease genes.…”

Section: Genotype-phenotype Correlationsmentioning

confidence: 99%

Chromosomal Microarrays: Understanding Genetics of Neurodevelopmental Disorders and Congenital Anomalies

Patel

Rosenfeld

2016

J Pediatr Genet

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Small mosaic deletion encompassing the snoRNAs and SNURF‐SNRPN results in an atypical Prader–Willi syndrome phenotype

Cited by 28 publications

References 30 publications

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

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

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

Chromosomal Microarrays: Understanding Genetics of Neurodevelopmental Disorders and Congenital Anomalies

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