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22q11.2 Deletion Syndrome: Tracking a Rare Genetic Disease in the Bronx

Einstein researchers Bernice E. Morrow, Ph.D. and Robert Marion, M.D. having a conversation

Researchers Bernice E. Morrow, Ph.D. and Robert Marion, M.D.

Those of us who work on rare diseases at Einstein and Montefiore Medical Center form a kind of family.  Our goal is to make a difference in the lives of patients who are affected by the conditions we study. At the heart of our work is a patient, someone who has touched us and made us want to help them.

This is definitely the case with 22q11.2 Deletion Syndrome (22q11DS). We were drawn to this chromosomal disorder through experiences we had during our training. Those experiences have stayed with us through long academic careers, they’ve bound us together as a team, and they’re still motivating us.

As two geneticists with a desire to help patients–many of them children–we’d like to share some our experiences and explain how they’ve affected our work and our lives.

BOB: The 22q11DS is definitely a Bronx syndrome; it was originally described here at Montefiore Medical Center. I first learned about it in 1980. I was a pediatric resident at Jacobi Medical Center doing an elective at Montefiore’s Center for Craniofacial Disorders with Dr. Robert Shprintzen, the center’s director, who was a Professor in Einstein’s Department of Plastic Surgery.

On the first day of the elective, Bob invited me to join him in evaluating Ryan, a six-month-old referred for evaluation. Ryan had been born with multiple anomalies: in addition to a cleft palate, he’d had congenital heart disease (tetralogy of Fallot) and an unusual facial appearance.  When he saw Ryan, Bob showed great interest; he believed the baby had a “new” disorder that he had recently described, a condition that in addition to clefting also caused congenital heart disease (conotruncal defects) and a characteristic facial appearance (prominent, “bulbous” nose, small jaw and minor ear anomalies). In his initial publication, on the basis of these three cardinal features, Bob had named this condition “Velo-Cardio-Facial Syndrome.” For short, it came to be known as “VCFS.”

The story of Ryan (who clearly was affected with VCFS) and his family stayed with me during the months and years after I saw him. Wanting to find ways to help him and others like him, I spent a lot of time during my training hanging out with Bob at the center, working on helping to characterize the disorder. In addition to the cardinal features originally elucidated by Bob and his colleagues, we added dozens of additional clinical features.

The presence of intermittent low levels of calcium in the blood (which had hypoparathyroidism as its basis) and recurrent upper and lower respiratory tract infections that suggested a T-cell deficiency led us to consider the overlap between VCFS and the previously-described DiGeorge syndrome. Because the latter had recently been found to be associated with a microdeletion in chromosome 22q11.2, we began to study our patients for this deletion. Using appropriate testing, Ryan and virtually every other patient who had been identified by Bob was found to have a 22q11.2 deletion.

In the years after his initial description, Bob amassed a database containing hundreds of patients. Although he had the ability to identify the clinical features, he needed help in figuring out what was happening at the molecular level. In the early 1990’s, Bob turned to Dr. Raju Kucherlapati, then Chair of Einstein’s Department of Genetics, for help. Through Raju, Bob met a young instructor named Bernice Morrow. Bernice was working in Raju’s lab.

BERNICE:  I entered Raju’s lab after completing a postdoctoral position with the purpose of working on a chromosome 12 genome project (yes, chromosome 12, not chromosome 22), but was a bit disappointed doing pure genomics work.  One day, Bob Shprintzen and Rosalie Goldberg, a genetic counselor, came to talk to Raju about a “new” syndrome they had identified with 22q11.2 deletions. A week later, we went to Montefiore and saw a little girl with VCFS.

I felt an immediate connection to her. At that moment, I knew I wanted to dedicate my career to finding genes for the disorder. Since there was no genomic map of the interval, we started with our strengths to make a genetic map of the 22q11.2 region.  With the generosity of Raju and the two Bobs at Montefiore, I suddenly had over 100 DNA samples from patients and their parents.

A very strange thing happened when we tested families for the size and position of the 22q11.2 deletion: over 90 percent had the same sized deletion. Since almost all the deletions occurred as a de novo event (neither parent transmitted the deletion, it occurred spontaneously on its own), the fact that all had the exact same size deletion was surprising. The answer to this puzzle came later, when we found by chance, that a large block of identical sequences flanked the deletion. It turns out that all humans have low copy repeated sequences in some regions of the genome; occasionally, errors in meiosis (a type of cell division) can lead to having a deletion or even a duplication in those locations, including 22q11.2.

The good news was that we could figure out the molecular mechanism responsible; the bad news was that it would not be possible to determine which genes were important for the syndrome because the deleted regions contained 3 million base pairs!  This prompted a collaboration among several Einstein labs including those headed by Raju, cell biology chair Art Skoultchi and me that generated mouse deletion mutants. That ultimately led to the discovery of TBX1, a gene that encodes a transcriptional regulatory factor. TBX1 turned out to be largely responsible for the main physical problems seen in these patients.

Though the size of the deletion is nearly always the same, the phenotypic expression of 22q11DS is extremely variable from patient to patient. While some have mild medical symptoms, others are very sick. Similarly, one affected individual can have a heart defect and few behavioral problems, while another can have a normal heart with schizophrenia. One of the main problems faced by families is trying to predict exactly how severe their child’s particular phenotype is going to be.

With the advent of affordable, high throughput genome-wide molecular assays, our lab and our colleagues at the Children’s Hospital of Philadelphia formed an International 22q11.2 Consortium that enabled us to obtain over 1,500 DNA samples from 22q11DS patients throughout America (North and South) and Europe. Supplementary funding for some of this work came from the Einstein-Montefiore CTSA grant. We are in the process of performing genome-wide association analyses. Most recently, a new Brain and Behavior Consortium for 22q11DS was formed to identify genes for schizophrenia. These projects, funded by the NIH are of interest because they serve as models to understand the molecular basis of human disease.

BOB: Another problem faced by families is to try to find excellent medical care for their children. As Bernice has mentioned, this is a complicated condition, with many organ systems involved. A child with 22q11DS may have a cleft palate, speech and language issues, congenital heart disease, an immunologic deficiency, endocrinologic and developmental and psychiatric disorders. It’s easy to see how parents with a child with this condition could spend virtually all of their time going from doctor to doctor looking for the necessary help.

In 2013, Bernice and I began to talk about this problem. We agreed that, as a way to help these families, we would begin a multidisciplinary clinic at Einstein and Montefiore, a center that would bring together in one place all of the specialists needed to care for children and adults with 22q11DS.  And so, in the next few months, the Montefiore/Einstein Center for 22q11.2 will open at the Hutch Metro Center. The center, which will have clinical, research and training components, will be a place where translational medicine is practiced.

BERNICE: The new center, which is a collaboration between our research community and our clinicians, will be a model that can be copied by other groups who work with rare diseases. It will also be an excellent forum for teaching both Ph.D. and M.D. students, so that the next generation is aware of such rare disorders and can use their talents to better understand, treat and hopefully, prevent them.

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