Truncating mutations of MAGEL2 cause Prader-Willi phenotypes and autism

Schaaf, Christian P.; Gonzalez-Garay, Manuel L.; Xia, Fan; Potocki, Lorraine; Gripp, Karen W.; Zhang, Baili; Peters, Brock A.; McElwain, Mark A.; Drmanac, Radoje; Beaudet, Arthur L.; Caskey, C. Thomas; Yang, Yaping

doi:10.1038/ng.2776

Cited by 272 publications

(276 citation statements)

References 27 publications

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“…Recently, truncating mutations of MAGEL2 were also associated with PWS. 20 The discussion regarding expression of SNORD115 by non-neuronal cells can be applied to MAGEL2. Therefore, like for SNORD115, MAGEL2 expression could not be tested here.…”

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2014

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“…In each case, the volunteer was counseled for the family risk and encouraged to contact at risk family members who may benefit from focused genetic studies. Three of the families have reported that they have had their familial genetic diagnosis resolved at this time [paraganglioma (49), Prader-Willi syndrome (50,51), and ankylosing spondylitis (AS) (52)]. One additional family is under study [Tourette syndrome (53)].…”

Section: Incorporation Of Three-generation Pedigrees Into the Geneticmentioning

confidence: 99%

Personalized genomic disease risk of volunteers

Gonzalez-Garay

McGuire

Pereira

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Significance Replacing traditional methods for genetic testing of inheritable disorders with next-generation sequencing (NGS) will reduce the cost of genetic testing and increase the information available for the patients. NGS will become an invaluable resource for the patient and physicians, especially if the sequencing information is stored properly and reanalyzed as bioinformatics tools and annotations improve. NGS is still at the early stages of development, and it is full of false-positive and -negative results and requires infrastructure and specialized personnel to properly analyze the results. This paper will explain our experience with an adult population, our bioinformatics analysis, and our clinical decisions to assure that our genetic diagnostics were accurate to detect carrier status and serious medical conditions in our volunteers.

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“…5 The Magel2 KO mouse is now considered a mouse model for PWS and autism spectrum disorder (ASD) because truncated mutations in the Magel2 gene have been reported in some patients with ASD. 6 Restricted production of mature OXT despite normal prohormone production was detected specifically in the hypothalamus of the Magel2 KO pups. Altogether, these data suggest that OXT is involved in the pathophysiology of PWS and ASD.…”

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confidence: 99%