Phelan-McDermid syndrome and the Greenwood Genetic Center: a story three decades (and counting) in the making.

03.13.17

When you think about genetic research, the first things that probably pop into your mind are lab benches, white coats, sterile environments, and rigid
protocols: a very cold and aseptic atmosphere. Well, you won’t find any of this in the story you are about to read. This, instead, is a story about
bringing the genetics outside the lab and connecting with the people who need it more than anyone else: patients and their parents.

Families and children with PMS at the First Support Group meeting in Greenville, SC, 1998. Thanks for the picture to Dawn Seiler, proud mother of Nick,
and Nick Assendelft, proud father of Jacob and Vice President of the Phelan-McDermid Syndrome Foundation.

It all began almost 30 years ago when Drs. Katy Phelan, Curtis Rogers, and Robert Saul from the Greenwood Genetic Center (GGC) described a patient with
a loss of genetic material on the long portion of chromosome 22, first as a poster presentation the American Society of Human Genetics meeting in 1988,
then in a paper published in the American Journal of Medical Genetics in 1992. In simple words, they reported a new genetic condition, caused by the
loss of several neighbor genes, and characterized by delay in reaching the developmental milestones and other feature that we will explore later. At
that time, the technology was more rudimentary than today, therefore the possibility of detecting losses of genetic material was limited to relatively
large deletions, spanning for several millions of nucleotides (the building units of our DNA). However, once the new condition was first described,
new reports followed with similar cases, including one from Dr. Heather McDermid and her collaborators from the University of Alberta, so the name
Phelan-McDermid syndrome (PMS) was eventually designated by parents of those diagnosed with PMS to indicate this novel entity.

So far the story is not much different from any other discovery in the genetic field, but here is where the unique part begins. The possibility to look
for the abnormality on chromosome 22 brought a molecular answer to several families that had received different clinical diagnoses, from cerebral palsy
to intellectual disability with multiple congenital anomalies. Now, they had to face this new syndrome, so they turned to the people that first described
the syndrome, Katy Phelan and Curtis Rogers. And the two doctors answered the call. Actually, multiple calls, so frequent that Dr. Phelan started to
call “telephone buddies” the members of the first 15 families that got in contact with her. That was the beginning of an extraordinary collaboration
between GGC and the families of the patients with PMS, a collaboration later cemented by the presence of Drs. Phelan and Rogers in the Board of Directors
of the Phelan-McDermid Syndrome Foundation (PMSF), as Founder and Chairman Emeritus, respectively.

Several years after the original paper, the phone calls led to the First Support Group meeting in Greenville, SC (see photo), realized with the help of
GGC and the Mikel Foundation, then the first informational website on PMS was launched (2001), and the Foundation was established (2002). The detailed
history can be found on the PMSF website (http://22q13.org/j15/), along with lists of events and ways to support the Foundation, and the link to the
Phelan-McDermid Syndrome International Registry, an exceptional tool for physicians and researchers involved in PMS.

The collaboration between GGC and the families with PMS was not just limited to the pure diagnosis: during the biennial meetings the team from GGC collected
blood samples and clinical information, the parents were able to meet the people working on the syndrome, ask their questions and share their concerns.
Physicians and researchers provided their knowledge and expertise and received in return an incredible amount of positive energy and motivation. The
families, caught in the daily struggle with the genetic disorder, were able to -share their experiences with other families and with the medical experts.
It is somehow reassuring, if your child has just received a diagnosis of a rare genetic syndrome, to be able to talk with another parent who is facing
the same challenges and, at the same time, to be pointed towards a doctor who regularly sees dozens of similar cases.

But, what are those challenges? Why is it so important to keep such a strong channel of communication between families and physicians? PMS is not exactly
a typical genetic syndrome: first of all, the patients may present with a wide array of symptoms. The most common features reported in PMS cases include
intellectual disability of several degrees, impaired speech that can range from no words to few sentences or even normal language skills, and low muscle
tone, especially at birth. Other common traits include behavioral issues, from simple irritability to autism, seizures, reported in 1 out of 3-4 patients,
and other neurological symptoms, such as abnormal reflexes or impaired regulation of the body temperature.

Considering such high variability, it is not surprising that collecting detailed clinical information and being able to keep a schedule of regular follow
up evaluations is critical for the physicians to manage the symptoms and provide the best information possible to the families.

If things were not complicated enough, the clinical variability is matched by an equally high genetic variability. Unlike the vast majority of conditions
caused by genetic deletions, PMS does not have recurrent breakpoints, therefore the amount of lost genetic material is different in each individuals
and can range from about 100,000 to over 9 million nucleotides. To use a simple analogy, typical deletion syndromes occur due to misalignment of certain
DNA sequences (named copy number variants, or CNVs) that are present in high numbers in our genome, are highly replicated and interspersed randomly
through the chromosomes. Imagine that the two chromosomes in a pair are getting together just as you wear a buttoned-down shirt: the buttons get in
the holes just like the CNVs pair with their counterparts on the twin chromosome. Now picture yourself on a busy morning: you are trying to button
up your shirt in a hurry and you skip a button, you put it in the wrong hole and you create a loop, which starts with the last button correctly aligned
and ends with the next one that gets in the hole. With chromosomes, when a button (CNV) “skips” an alignment, the resulting loop gets cut off and the
genetic material in that portion of chromosome is lost. This is what happens in typical deletion syndromes. But PMS, remember, is not quite typical
and instead of buttons uses a zipper. When you have a misalignment with a zipper, you have no clue of how many teeth you might have skipped, and you
don’t know where the resulting loop begins and where it ends. Similarly, in patients with PMS, the deletions on chromosome 22 do not seem to have a
designated start or breakpoint (indicating the point where the chromosome “breaks”), although almost all cases involve the end of the long arm portion
of the chromosome, hence the adjective “terminal”.

And finally, to make things even more confusing, there are cases of PMS in which chromosome 22 is intact, but there is a change in the sequence of one
of the genes usually involved in the deletions, named SHANK3.

It is easy to understand how, even after 25 years from its first report, PMS still poses numerous challenges, both in the clinical and molecular fields.
In order to answer these challenges, GGC has contributed a significant effort through the years and is still proud to work side by side with the PMSF,
presenting the results of such efforts to their meetings (see photos), continuing to provide clinical and counseling services, and proposing new research
projects focused on better understanding the mechanisms underlying PMS and giving to the families new insights and eventually the possibility of treatment.
The story is still going, and it is up to physicians and parents to write the next chapters, together like it has been in the last three decades.

Drs. Luigi Boccuto, Katy Phelan, and Curtis Rogers (from left to right) were some of the authors of the best poster at the recent 10th biennial International Conference and McPosium sponsored by the Phelan-McDermid Syndrome Foundation in Orlando, FL, July 20-23, 2016.

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