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Prader-Willi Syndrome Genetics

PWS is a complex genetic syndrome resulting from the absence of expression of genes found in the region of the paternally inherited 15q11-q13 chromosome; most commonly due to a paternal 15q11-q13 deletion. There are three recognized genetic subtypes:
  • a paternal de novo deletion of 15q11-q13 (70% of cases);
  • maternal disomy 15, where both chromosomes 15 come from the mother (25-29% of cases); and,
  • an imprinting defect (in the remaining) with a microdeletion of the imprinting center or an epimutation controlling the expression of imprinted genes in the region. See Imprinting (GeneTests).
There are nearly a dozen genes or transcripts mapped to the 15q11-q13 region that are known to be imprinted; most are paternally expressed (active) or maternally silent. Several of these genes are candidates for causing features seen in PWS including SNURF/SNRPN, NDN, snoRNAs, MKRN3, and MAGEL2. Many of the paternally expressed genes in the region play a role in brain development and function, key for producing the clinical phenotype seen in PWS.
Most cases of PWS are sporadic; however, at least 20 families have been reported with more than one affected member, including reports in twins. The chance for familial recurrence is estimated to be less than 1%. However, this risk may be as high as 50% in some families where an imprinting defect causes defective control of differentially expressed genes in both the PWS child and the unaffected father. See Prader-Willi Syndrome Review (GeneReviews) and Chromosome 15 in PWS (PWSA USA) for more information.
To confirm clinical findings of PWS, genetic testing is recommended. Genetic testing is complex and recommended approaches to genetic testing for children suspected of having PWS vary among specialists - consulting pediatric genetics in your area is advised. If the diagnosis is confirmed, identification of the genetic subtype is important to guide clinical management and to advise regarding recurrence risks.
Advances in genetic technology allow for more accurate and early identification of PWS and genetic subtypes. This includes the larger typical type I deletion involving the proximal 15q11-q13 breakpoint BP1 and the distal breakpoint BP3, while the smaller typical type II deletion involves the proximal breakpoint BP2 and the distal breakpoint BP3. Primarily, those with the larger type I deletion have more behavioral problems; similarly, more clinical variation is seen in those with maternal disomy 15 (complete heterodisomy, segmental isodisomy, or complete isodisomy of chromosome 15) or in those rare PWS individuals with imprinting defects (microdeletions or epimutations). High recurrence risks (50%) are seen in fathers carrying microdeletions of the imprinting center.
To confirm clinical findings of PWS, some clinicians begin with methylation analysis of the PWS critical region on CH 15q11 (99% sensitive).
  • If this test is positive, cytogenetic analysis with FISH (fluorescent in situ hybridization using the SNRPN probes will identify the 15q11-q13 deletion seen in the majority of subjects (70-75%). Explanation of FISH (genome.gov)
  • If the methylation test is negative, PWS is unlikely to be the diagnosis and other diagnoses should be considered. If PWS is still strongly suspected, targeted sequence analysis may be available at a small number of reference labs. PWS Genetic Testing (GeneTests)
DNA methylation is 99% sensitive but does not differentiate among the potential causes, including small deletions, maternal disomy 15, or an imprinting defect.
MS-MLPA kit for DNA analysis of PWS is helpful and undertaken in both clinically approved research-based laboratories. Not only will this DNA kit determine the DNA methylation pattern consistent with PWS but will identify the copy number (deletion) for the 15q11-q13 region. It will, however, not identify maternal disomy 15 or necessarily an imprinting defect. Additional PWS genetic subtypes (maternal disomy 15 and/or imprinting defects) will require CNV/SNP DNA microarray analysis or in a small subset of PWS cases, parental DNA may be required to genotype DNA markers for determining maternal disomy 15 and/or an imprinting defect.
Some clinicians prefer to start with a cytogenetic analysis with FISH using the SNRPN probes to identify the typical 15q11-q13 deletion. If neither a deletion of chromosome 15 or any other cytogenetic abnormality is identified, DNA methylation testing is then performed. If the methylation study is positive for PWS, then testing for other subtypes (maternal disomy or imprinting defect) should be pursued.
CNV/SNP microarray analyses: Recent report of GHR gene polymorphism may impact growth rate acceleration. Testing for this polymorphism, which is seen in about 50% of Caucasian individuals with PWS and may contribute to the rate of scoliosis, should be considered in the treatment and care of PWS infants, children, and adolescents while undertaking GH treatment. [Butler: 2013]

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Information & Support

For Professionals

Genetics in Primary Care Institute (AAP)
The goal of this site is to increase collaboration in the care of children with known or suspected genetic disorders. Includes health supervision guidelines and other useful resources; a collaboration among the Health Resources & Services Administration, the Maternal and Child Health Bureau, and the American Academy of Pediatrics.

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Pediatric Genetics

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Prader-Willi Clinics

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Helpful Articles

Burnside RD, Pasion R, Mikhail FM, Carroll AJ, Robin NH, Youngs EL, Gadi IK, Keitges E, Jaswaney VL, Papenhausen PR, Potluri VR, Risheg H, Rush B, Smith JL, Schwartz S, Tepperberg JH, Butler MG.
Microdeletion/microduplication of proximal 15q11.2 between BP1 and BP2: a susceptibility region for neurological dysfunction including developmental and language delay.
Hum Genet. 2011;130(4):517-28. PubMed abstract / Full Text

Authors

Reviewing Authors: Merlin G. Butler, MD, PhD - 11/2014
Alan F. Rope, MD - 11/2008
Content Last Updated: 2/2015

Funding/Support

This page was developed in partnership with the Heartland Genetic Services Collaborative and was funded in part by a Health Resources Services Administration (HRSA) cooperative agreement (U22MC03962). We appreciate the Prader-Willi Syndrome Association (USA) for their outstanding support of individuals with PWS and their families and for the information they provide on their website – www.pwsausa.org – to which we have provided several links within the Diagnosis Module.

Page Bibliography

Butler MG, Roberts J, Hayes J, Tan X, Manzardo AM.
Growth hormone receptor (GHR) gene polymorphism and Prader-Willi syndrome.
Am J Med Genet A. 2013;161A(7):1647-53. PubMed abstract / Full Text