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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.
To confirm clinical findings of PWS, some clinicians begin with methylation analysis of the PWS critical region on CH 15q11.
To confirm clinical findings of PWS, some clinicians begin with methylation analysis of the PWS critical region on CH 15q11.
- If this test is positive, cytogenetic analysis with FISH (fluorescent in situ hybridization, see Explanation of FISH (genome.gov)) using the SNRPN probes will identify the 15q11-q13 deletion seen in the majority of subjects (70-75%);
- 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 (see PWS genetic testing (GeneTests)).
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.
See PWS genetic testing (GeneTests) for laboratories that offer testing for PWS, and Resources>Services below for consultation resources.
Resources
Services
Pediatric Medical Genetics
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Authors
| Authors: | Merlin G. Butler MD, PHD, 9/2008 Judy L. Welch RN, BSN, 9/2008 |
| Reviewing Authors: | Alan Rope MD, 11/2008 Merlin G. Butler MD, PHD, 8/2008 |
| Content Last Updated: | 10/2008 |