Editing Prader–Willi syndrome (section)

== Genetics ==
[[File:Angelman.PNG|right]]
PWS is related to an epigenetic phenomenon known as [[Genomic imprinting|imprinting]]. Normally, a fetus inherits an imprinted maternal copy of PW genes and a functional paternal copy of PW genes. Due to imprinting, the maternally inherited copies of these genes are virtually silent, and the fetus therefore relies on the expression of the paternal copies of the genes.<ref name="pmid7795645">{{cite journal|last1=Buiting|first1=K|last2=Saitoh|first2=S|last3=Gross|first3=S|last4=Dittrich|first4=B|last5=Schwartz|first5=S|last6=Nicholls|first6=RD|last7=Horsthemke|first7=B|s2cid=7184110|title=Inherited microdeletions in the Angelman and Prader-Willi syndromes define an imprinting centre on human chromosome 15.|journal=Nature Genetics|date=April 1995|volume=9|issue=4|pages=395–400|pmid=7795645|doi=10.1038/ng0495-395}}</ref><ref>{{cite web |url=http://medicalxpress.com/news/2014-05-major-breakthrough-prader-willi-syndrome-parental.html |title=Major breakthrough in understanding Prader-Willi syndrome, a parental imprinting disorder |publisher=Medicalxpress.com |access-date=June 18, 2015 |url-status=live |archive-url=https://web.archive.org/web/20150428215805/http://medicalxpress.com/news/2014-05-major-breakthrough-prader-willi-syndrome-parental.html |archive-date=April 28, 2015  }}</ref> In PWS, however, there is mutation/deletion of the paternal copies of PW genes, leaving the fetus with no functioning PW genes. The PW genes are the [[Small nuclear ribonucleoprotein polypeptide N|''SNRPN'']] and [[NDN (gene)|''NDN'']] genes, along with clusters of [[snoRNA]]s: [[Small nucleolar RNA SNORD64|SNORD64]], SNORD107, SNORD108 and two copies of SNORD109, 29 copies of [[small nucleolar RNA SNORD116|SNORD116]] (HBII-85) and 48 copies of [[small nucleolar RNA SNORD115|SNORD115]] (HBII-52). These genes are located on [[chromosome 15 (human)|chromosome 15]], located in the region 15q11-13.<ref>{{OMIM|17627|Prader-Willi Syndrome; PWS}}</ref><ref>{{cite journal |vauthors=de los Santos T, Schweizer J, Rees CA, Francke U | title = Small evolutionarily conserved RNA, resembling C/D box small nucleolar RNA, is transcribed from PWCR1, a novel imprinted gene in the Prader-Willi deletion region, which is highly expressed in brain | journal = American Journal of Human Genetics | volume = 67 | issue = 5 | pages = 1067–82 | date = November 2000 | pmid = 11007541 | pmc = 1288549 | doi = 10.1086/303106 }}</ref><ref>{{cite journal |vauthors=Cavaillé J, Buiting K, Kiefmann M, Lalande M, Brannan CI, Horsthemke B, Bachellerie JP, Brosius J, Hüttenhofer A | title = Identification of brain-specific and imprinted small nucleolar RNA genes exhibiting an unusual genomic organization | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 97 | issue = 26 | pages = 14311–6 | date = December 2000 | pmid = 11106375 | pmc = 18915 | doi = 10.1073/pnas.250426397 | bibcode = 2000PNAS...9714311C | doi-access = free }}</ref><ref>"Prader-Willi Syndrome - MeSH - NCBI." National Center for Biotechnology Information. U.S. National Library of Medicine, n.d. Web. November 1, 2016. <{{cite web |url=https://www.ncbi.nlm.nih.gov/mesh/68011218 |title=Prader-Willi Syndrome - MeSH - NCBI |access-date=November 1, 2016 |url-status=live |archive-url=https://web.archive.org/web/20161103233837/https://www.ncbi.nlm.nih.gov/mesh/68011218 |archive-date=November 3, 2016  }}>.</ref> This so-called PWS/AS region in the paternal chromosome 15 may be lost by one of several genetic mechanisms, which in the majority of instances occurs through chance mutation. Other, less common mechanisms include [[uniparental disomy]], sporadic [[mutations]], chromosome [[translocations]], and gene deletions.{{citation needed|date=May 2022}}

Region 15q11-13 is implicated in both PWS and [[Angelman syndrome]] (AS). While PWS results from the loss of PW genes within this region on the paternal chromosome, loss of a different gene (''[[UBE3A]]'') within the same region on the maternal chromosome causes AS.<ref>{{cite journal |last1=Cassidy |first1=SB |last2=Dykens |first2=E |title=Prader-Willi and Angelman syndromes: sister imprinted disorders. |journal=Am J Med Genet |date=2000 |volume=97 |issue=2 |pages=136–146 |doi=10.1002/1096-8628(200022)97:2<136::aid-ajmg5>3.0.co;2-v |pmid=11180221|s2cid=20832857 }}</ref> PWS and AS represent the first reported instances of disorders related to imprinting in humans.{{citation needed|date=May 2022}}

The risk to the sibling of an affected child of having PWS depends on the genetic mechanism that caused the disorder. The risk to siblings is <1% if the affected child has a gene deletion or uniparental disomy, up to 50% if the affected child has a mutation of the imprinting control region, and up to 25% if a parental chromosomal translocation is present. [[Prenatal testing]] is possible for any of the known genetic mechanisms.{{citation needed|date=May 2022}}

A [[microdeletion]] in one family of the snoRNA HBII-52 has excluded it from playing a major role in the disease.<ref>{{cite journal |vauthors=Runte M, Varon R, Horn D, Horsthemke B, Buiting K | s2cid = 23190709 | title = Exclusion of the C/D box snoRNA gene cluster HBII-52 from a major role in Prader-Willi syndrome. | journal = Hum Genet | volume = 116 | issue = 3 | pages = 228–30 | year = 2005 | pmid = 15565282 | doi = 10.1007/s00439-004-1219-2 }}</ref>

Studies of human and mouse model systems have shown deletion of the 29 copies of the [[C/D box]] snoRNA [[Small nucleolar RNA SNORD116|SNORD116]] (HBII-85) to be the primary cause of PWS.<ref>{{cite journal | vauthors = Skryabin BV, Gubar LV, Seeger B, Pfeiffer J, Handel S, Robeck T, Karpova E, Rozhdestvensky TS, Brosius J | title = Deletion of the MBII-85 snoRNA gene cluster in mice results in postnatal growth retardation | journal = PLOS Genet. | volume = 3 | issue = 12 | pages = e235 | year = 2007 | pmid = 18166085 | pmc = 2323313 | doi = 10.1371/journal.pgen.0030235 | df = mdy-all | doi-access = free }}</ref><ref>{{cite journal |vauthors=Sahoo T, del Gaudio D, German JR, Shinawi M, Peters SU, Person RE, Garnica A, Cheung SW, Beaudet AL | title = Prader-Willi phenotype caused by paternal deficiency for the HBII-85 C/D box small nucleolar RNA cluster. | journal = Nat Genet | volume = 40 | issue = 6 | pages = 719–21 | year = 2008 | pmid = 18500341 | pmc = 2705197 | doi = 10.1038/ng.158 }}</ref><ref name="pmid18320030">{{cite journal | vauthors = Ding F, Li HH, Zhang S, Solomon NM, Camper SA, Cohen P, Francke U | title = SnoRNA Snord116 (Pwcr1/MBII-85) deletion causes growth deficiency and hyperphagia in mice | journal = PLOS ONE | volume = 3 | issue = 3 | pages = e1709 | date = March 2008 | pmid = 18320030 | pmc = 2248623 | doi = 10.1371/journal.pone.0001709  | bibcode = 2008PLoSO...3.1709D | doi-access = free }}</ref><ref>{{cite journal |vauthors=Ding F, Prints Y, Dhar MS, Johnson DK, Garnacho-Montero C, Nicholls RD, Francke U | s2cid = 12256515 | title = Lack of Pwcr1/MBII-85 snoRNA is critical for neonatal lethality in Prader-Willi syndrome mouse models | journal = Mamm Genome | volume = 16 | issue = 6 | pages = 424–31 | year = 2005 | pmid = 16075369 | doi = 10.1007/s00335-005-2460-2 }}</ref><ref>{{cite journal |vauthors=de Smith AJ, Purmann C, Walters RG, Ellis RJ, Holder SE, Van Haelst MM, Brady AF, Fairbrother UL, Dattani M, Keogh JM, Henning E, Yeo GS, O'Rahilly S, Froguel P, Farooqi IS, Blakemore AI | title = A Deletion of the HBII-85 Class of Small Nucleolar RNAs (snoRNAs) is Associated with Hyperphagia, Obesity and Hypogonadism | journal = Hum. Mol. Genet. | volume = 18 | issue = 17 | pages = 3257–65 | date = June 2009 | pmid = 19498035 | pmc = 2722987 | doi = 10.1093/hmg/ddp263 }}</ref>