Angelman Today November / December edition 2013 | Page 6

By Dr. Charles A. Williams
In the last edition, I reviewed
the four genetic mechanisms
that can disrupt the Angelman
syndrome (AS) gene:
chromosome deletion,
imprinting defect, mutation in
UBE3A and paternal
uniparental disomy. When an
individual with AS has one of
these defects, it is typically
present in every cell of the
body, since the defect existed at
the time of conception when the
sperm and egg fused to form
the first cell of the embryo. All
of the subsequent cells are thus
derived from this original cell.
It is possible in rare situations
however for the AS defect to
occur after the first cell
divisions of the embryo such
that there is a normal and an
abnormal cell line; the general
term for this phenomenon is
cell mosaicism.
Mosaicism in an individual
with AS means that a few cells
in their body (and also in their
brain) are normal. These
normal cells coexist with all of
the other cells that have the AS
defect. Mosaicism in AS most
often occurs in imprinting
defects that do not involve
deletions of the imprinting
center (the great majority of
those with imprinting defects
are of this non-deletion type).
About 10 to 30% of individuals
with the non-deletion type may
have a small percent of their
cells that are normal.

We detect evidence of this by the
DNA methylation test that is
performed on blood. When the test
suggests mosaicism, we presume
(but do not really know) that cells
in the brain also have a similar
percentage of normal cells. In
instances of imprinting mosaicism,
the percent of normal cells is

usually less than 20%. Individuals
with AS who are imprinting-type
mosaics can have relatively higher
developmental ability. Some have
been noted to speak words and
even to put words together, more
than is seen in the typical child
with AS who is non-mosaic. They
may also have better motor ability
(e.g., almost normal walking) and
relatively higher cognitive skills
The three other mechanisms that
cause AS are much less likely to
have mosaicism but a few rare
instances have been reported.
Chromosome studies (either
molecular or FISH-type) may
identify a small percent of cells

without the typical 15q11.2-q13
deletion. For example, 80% of the
cells in the blood may have the
typical AS deletion while 20% of
the cells are normal. The same can
theoretically occur for those with
AS due to uniparental disomy. To
my knowledge, mosaicism for
UBE3A mutation, identified by
blood study in an individual with
AS, has not been reported but that
is also theoretically possible.
In a mother who has an AS child
with a UBE3A mutation,
mosaicism involving UBE3A has
been detected in her in what is
termed "germline" mosaicism.
Here, the mother's blood cells are
normal but apparently in her
ovaries there are egg (e.g., germ)
cells that have the UBE3A
mutation. This situation is
presumed to be present, for
example, when the mother gives
birth to two subsequent children
with AS, each having the same
UBE3A mutation, but studies of
the mother's blood are completely
normal. The diagram illustrates
this type of germline mosaicism
(blue cells are the normal cells) and
contrasts it to the other type of
mosaicism that is discussed above,
termed “constit utional” meaning
that cells throughout the body are
involved.
Understanding mosaicism in AS
can be complicated especially
when considering the possibility of
germline mosaicism in mothers,
since this rare condition can lead to
recurrence of AS among siblings.