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 mothers 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
"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.
[Editors 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
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 fathers germline." He stresses that
mutations are "no ones fault"; their cause is unknown.