Genetic Testing for Prader-Willi Syndrome

From the calls we get in our national and chapter offices, and the information we read in other publications, it’s clear there is still a great lack of understanding about testing for Prader-Willi syndrome. In all fairness, it’s an extremely complicated issue and an area of new developments. To update our members, we share here some recent communications from our scientific advisors.

Dr. Suzanne Cassidy, our Scientific Advisory Board chair, reports:

"The cause of Prader-Willi syndrome is now known to be the absence of normally active genetic material on the long arm of chromosome 15. It is always lack of the active DNA that should have been contributed by the father (the mother’s copy of this genetic information is normally inactive) that causes Prader-Willi syndrome, and this absence may occur in three different ways. [The three ways are: a deletion on the paternal chromosome 15, a mutation on the paternal chromosome 15, and maternal uniparental disomy--i.e., both chromosome 15s from the mother and none from the father.] Also, accurate diagnostic testing for all affected individuals with Prader-Willi syndrome is now available. The methodology is somewhat unique and does not usually involve chromosome analysis anymore.

"While chromosome analysis will only detect a proportion of patients with Prader-Willi syndrome, the newer molecular tests to identify the presence of a deletion (fluorescence in situ hybridization, or FISH) or uniparental disomy 15 (polymerase chain reaction, or PCR) will together identify about 99 percent of cases.

[Editor’s note: Uniparental disomy 15 is the cause of PWS in about 30 percent of the cases. When the PCR test is used to detect maternal disomy, blood samples from the affected person and both parents are usually required for the highest degree of accuracy.]

"Methylation analysis, which determines the parent of origin of chromosome 15q (which is always maternal in Prader-Willi syndrome) will detect virtually all cases of the disorder and costs about half that of a chromosome analysis. However, it is not available everywhere."

Dr. Cassidy recommends that "those who had chromosome analysis in the past [regardless of the results] should have the newer, more accurate testing done, both for management and for family planning purposes, since some causes can recur in a family, and prenatal diagnosis is available."

The bottom line: It is both possible and important to confirm the diagnosis of PWS through genetic testing and to find out whether your family carries an increased risk of recurrence.

 More on the Inherited Form of PWS

In the August 1996 issue of The Gathered View, we reported the findings of Dr. Robert Nicholls (a member of PWSA's Scientific Advisory Board) and colleagues concerning rare cases of PWS (about 2 percent or less of all cases) caused by an imprinting mutation on an apparently intact paternal chromosome 15, rather than a deletion or uniparental disomy.

A PWSA member wrote to us expressing concern about this transmittable form of PWS and asked whether siblings of a child with PWS should be tested to find out if they are carriers of such a mutation. Dr. Nicholls responds:

"Any family who has their child diagnosed with an imprinting mutation should seek professional advice from their genetic counselor and pediatrician, and if these are unfamiliar with the latest research, they should be referred to a center such as ours [at Case Western Reserve University] that works with imprinting mutations and the latest research.

"With imprinting mutations, about half the patients (families) have a very small deletion in the region we refer to as the imprinting center (IC). The other half of the patients have no deletion, although this has just been referred to in passing in the literature. The imprinting center regulates the setting of imprints in the male and female germline, and it controls this for all imprinted genes in chromosome 15q11-q13. Thus PWS imprinting mutation patients, with either the tiny deletion or no deletion, have inactive paternally inherited imprinted genes. The half of these patients with a tiny deletion (referred to as a microdeletion in our published papers) [differ from] the typical deletion group, because the latter patients have a very large deletion that includes not only imprinted genes, but the Angelman syndrome gene and nonimprinted genes. For those families with an imprinting mutation which has a tiny deletion, we can offer ‘at risk’ testing and when necessary, prenatal testing."

Dr. Nicholls also notes that some of these mutations are not inherited but "arise as new mutations in the father’s germline." He stresses that mutations are "no one’s fault"; their cause is unknown.