Microduplication 22q11.2 – Overview
and Review of the Literature
Microduplication 22q11.2 is a relatively newly recognized
syndrome. While its counterpart, the 22q11.2 microdeletion syndrome,
is relatively common (estimated in 1 in 4000 births) (Shaffer
and Lupski, 2000), the 22q11.2 microduplication was
first reported in 1999 (Edelmann, 1999). Since then, fewer than
100 individuals with this genetic finding have been reported in
the medical literature. However, it is probably not as rare as
it would seem, because the technology sensitive enough to detect
it has only become widely available in the last few years.
Some
individuals with this microduplication are “normal”- that is,
they have average intelligence, no major birth defects, and no
major medical illnesses. We also know that individuals with the samemicroduplication
can have significant problems with learning, behaviour, growth,
muscle tone, and a variety of minor birth defects have been
reported as well. Individuals with the same duplication but very
different problems can be found in the same family (eg.,
parent-child, siblings). In fact, the findings are so variable
that it is almost impossible to determine whether the presence
of a microduplication at 22q11.2 is the cause of
these problems, or simply one of many genetic and environmental risk
factors that work
together to contribute to a given individual’s phenotype. An
article by Courtens, Schramme and Laridon (2008) actually
suggested that the 22q11.2 microduplication could be a benign
polymorphism (a
variation in the chromosome which has no adverse effects on the
individual). However, large numbers of normal individuals have
now been screened for microduplications such as this, and it is not a
common finding.
There is good reason to suspect that the 22q11.2
microduplication has at least some effect on phenotype, although
it may be quite mild. Most of the reported individuals have a
rather large region of the chromosome duplicated – about 3 Mb.
This region contains about 40 genes that we already know are
important for normal development. Others have an even larger
region (from 4 to 6 Mb) duplicated, which still others have a
smaller duplication (about 1.5 Mb). Thus far, there does not
seem to be a direct correlation between the size of the
duplication and the severity of the symptoms, suggesting that
the rest of the individual’s genetic make-up is more important
than the size of the duplicated region itself.
Clinical Characteristics
The
clinical characteristics of individuals reported thus far with
the 22q11.2 microduplication are extremely variable. The
original reports were of individuals who had been investigated
for the 22q11.2 deletion syndrome (also known as
Velocardiofacial syndrome or VCFS), and instead of finding the
expected deletion, they found a duplication of the same region.
Because of the way the duplication was discovered, the reports
are biased towards
those who have features in common with VCFS, such as cleft
palate, velopharyngeal insufficiency, heart defects, absent
thymus, learning disabilities, and certain dysmorphic facial
features. Later reports are less biased, because they were
discovered using a newer, different technology called microarray
analysis. This test scans the entire genome (ie, all the
chromosomes) for deletions and duplications. The indications for
doing this test range from birth defects (single or multiple),
learning difficulties (mild to severe), dysmorphic features,
unusual health conditions, or any combination of these. Because
this testing is rarely done in healthy, non-dysmorphic people of
average intelligence, so we do not know the frequency of this
duplication in an unbiased population.
Keeping the above in mind, some of the reported features in
individuals with the duplication are:
Risk of Inheritance: Like
any deletion or duplication present on one of the non-sex
chromosomes, if a parent carries it, each child will have a 50%
chance of inheriting it. However, it is impossible to predict
the phenotype that the child will have based on this finding.
Unlike the 22q11.2 deletion, which is only rarely (about 7% of
the time) inherited from a parent, the 22q11.2 duplication seems
to be more frequently inherited. This may be because the
phenotype is generally milder (and therefore individuals who
carry it are more likely to reproduce), but further studies are
needed to confirm this.
Prevalence: Although
the exact prevalence of the 22q11.2 microduplication is unknown,
the most unbiased study to date (Ou, 2008) looked at 7000
samples from individuals with any degree of intellectual
disability and/or congenital anomalies, and found 10 cases of
the microduplication, for an approximately prevalence of 1/700.
Incidentally, they found more than three times as many (33)
cases of the 22q11.2 microdeletion. They also found a further 9
cases with “atypical” duplications in and around the 22q11.2
region. These atypical duplications overlapped somewhat with the
commonly duplicated region.
As
mentioned above, the prevalence in the general population is not
known, but the full duplication appears to be rare.
© 2010, Dr. Melissa Carter, medical advisor to C22C
LINKS:
Many supports for the 22q11.2 deletion are now including support for people with the duplication. Please see support links at our page for 22q11.2 deletion syndrome
Affiliate member, Canadian Organization for Rare Disorders