CHOP Genetic Counselor Builds Connections with 22q11.2 Deletion Syndrome Families

The 22q Foundation Australia and New Zealand presented McDonald-McGinn with the Tony Lipson Dedication to Service Award in September 2024.

For almost every health issue associated with 22q11.2 deletion syndrome (22q11.2DS), Children's Hospital of Philadelphia's Donna McDonald-McGinn, MS, CGC, Chief of the Section of Genetic Counseling at CHOP, has a touching story to tell – whether it's a family who founded a national charity in memory of their child, a new patient who is missing a kidney, or international collaborators who became close friends.

Meeting patients and spreading awareness around the world, McDonald-McGinn and her colleagues at CHOP's renowned 22q and You Center have made an international disease community feel small and a confusing condition feel manageable.

A missing piece of DNA on chromosome 22 – the second smallest chromosome in the human body – can disrupt multiple areas in a child's development. For some, this common chromosomal difference manifests as differences in learning style. For others, it's a heart defect. For most, it's a variable combination of medical problems, cognitive deficits, and behavioral challenges.

In September, the 22q Foundation Australia and New Zealand presented McDonald-McGinn with the Tony Lipson Dedication to Service Award, an honor that recognizes exceptional professionals advancing research and improving lives affected by 22q11.2DS. The accolade reflects her long-standing career piecing together the genetic condition's mysteries, patient by patient, study by study, over three decades.

"I was completely surprised," McDonald-McGinn said of the award, which she accepted at the foundation's 30th Anniversary Gala Dinner in Sydney. "I shared with the audience that it is really an honor and absolute pleasure to work with families affected by chromosome 22q differences and that this award is a celebration with them because all the advances we have made as a scientific community are based on what the patients and families have taught us and continue to teach us."

One of the primary goals of the 22q and You Center is to consider what researchers have learned about patients and families affected by chromosome 22q11.2 differences, and then apply that knowledge to the same types of problems in the general population, such as better ascertainment and improved therapeutics for anxiety, attention-deficit hyperactivity disorder, autism, and schizophrenia.

Early Days of 22q at CHOP

McDonald-McGinn began her work on chromosome 22q11.2DS in the early 1990s, following the discovery by CHOP's Elaine Zackai, MD, Director of Clinical Genetics, and Beverly Emanuel, PhD, Scientific Director of the 22q and You Center, that children with symptoms of DiGeorge Syndrome (DGS), which involves a triad of immune problems, low calcium, and congenital heart disease, often had a chromosome 22q11.2 deletion.

Their discovery resulted in a seminal Journal of Pediatrics paper in 1982. Once Dr. Emanuel developed a laboratory test called fluorescence in situ hybridization (FISH) specific to the 22q11.2 region, it became abundantly clear that the chromosome 22q11.2 microdeletion was also the cause of multiple other clinical diagnoses, including velocardiofacial syndrome and conotruncal anomaly face syndrome, originally thought to be separate conditions.

Moreover, the deletion of the 22q11.2 region resulted in loss of approximately 50 genes, including important developmental drivers such as TBX1, now known to be the main cause of congenital heart disease, immunodeficiency, and hypocalcemia.

Following the introduction of FISH studies, McDonald-McGinn reported findings on 181 patients with 22q11.2DS evaluated at CHOP – the largest series to date. As a result, she was invited to present as the inaugural keynote speaker at the first International 22q11.2 Scientific Conference in Strasbourg, France in 1998, kickstarting a lifelong commitment to studying associated findings in patients with 22q11.2DS and supporting comprehensive coordinated multidisciplinary care with her newfound colleagues across the globe.

McDonald-McGinn organized the 2^nd International Conference in 2000 in Philadelphia, expanding the meeting's scope to include families. The group has gone on to assemble biennially, with McDonald-McGinn ultimately establishing the 22q11.2 Society as a scientific body working to advance the study of chromosome 22q11.2 differences, including genes within the region, modifier genes outside of the region, and the underlying biology. Members include healthcare providers, clinical and basic science researchers, educators, and family advocates.

Similarly, McDonald-McGinn joined families in establishing the International 22q11.2 Foundation to support the needs of families and individuals affected by chromosome 22q11.2 differences by promoting awareness, state-of-the-art clinical care, cutting-edge research endeavors, and solidarity with related associations around the globe.

McDonald-McGinn and her colleagues continued to learn that 22q11.2DS is common – with an estimated prevalence of 1 in 1,000 pregnancies, 1 in 1,500 miscarriages, and 1 in 2,000 livebirths, making it more common than other well-known conditions such as cystic fibrosis. They also learned that the severity of associated features varies from patient to patient, that 22q11.2DS is the most common cause of syndromic palatal anomalies and schizophrenia, and that it is the second most common cause of congenital heart disease and developmental differences after Down syndrome.

Much of the work also focused on families. Recognizing that not every patient with 22q11.2DS could travel to Philadelphia for treatment, McDonald-McGinn collaborated with an international team to produce pediatric, adult and fetal healthcare guidelines, sifting through more than 6,000 publications to develop practical recommendations to be used by clinicians and families around the globe. In 2023, the most recent version of the pediatric review was selected as the Top Editor's Choice paper by Genetics in Medicine.

Today, McDonald-McGinn and her colleagues are investigating the importance of genes within the chromosome 22q11.2 region, as well as associated features, always with an eye toward improving surveillance and long-term outcome.

"We have identified the importance of genes within the 22q11.2 deletion incrementally and we're still learning," McDonald-McGinn said.

22q and the Brain

One such important area under investigation by McDonald-McGinn and her colleagues is the increased risk for developing neuropsychiatric phenotypes in individuals with 22q11.2DS. These include anxiety, autism spectrum disorder, attention-deficit/hyperactivity disorder, and psychosis. Given 22q11.2DS provides such a unique window into understanding these conditions, the National Institutes of Mental Health awarded McDonald-McGinn and Raquel Gur, MD, PhD, Director of the Lifespan Brain Institute (LiBi), a grant to conduct a large-scale study using a "genetics-first" approach.

"This study specifically examines changes over time, because the brain is an organ like any other organ and is therefore treatable, so the earlier you observe a difference and make a diagnosis the sooner you can implement care, which we hope will lead to better outcomes," McDonald-McGinn said.

McDonald-McGinn and Gur previously worked together on multiple initiatives including leading the International 22q Brain and Behavior Consortium, a group of 22 clinical and five genomic sites worldwide. Now, they will follow a cohort of approximately 300 CHOP patients with 22q11.2DS from school-age to adulthood, observing developmental milestones, neuroimaging, and potential environmental factors that may contribute to developing psychosis. The study also will examine existing genomic data, while contributing to national phenomic and genomic resources established for data sharing.

Moving forward, McDonald-McGinn hopes to bring personalized medicine to patients with 22q11.2DS. Concentrating on the specifics of each person's chromosomal difference, including the size of the deletion and changes in important genes on the non-deleted chromosome 22, as well as in genes on other chromosomes across the genome. This can inform the risk of developing problems related to the chromosome 22q11.2 deletion, as well as those genome-wide changes unrelated to the deletion.

"Nobody has a crystal ball with any child, and we have to remind families of that, but it is natural that they want, and need, some inkling of what might happen down the road," McDonald-McGinn said. "Is my child going to be independent? Will they reproduce and, if so, do they need to be concerned about the 50% chance of passing on 22q11.2DS to a child who may be more significantly affected?"

Despite these unknowns, one thing is certain: McDonald-McGinn will always keep her patients, and their stories, top of mind.

Learn more about CHOP's internationally recognized 22q and You Center, the largest program in the country dedicated to the diagnosis and treatment of children with chromosome 22q11.2 differences.