In 1986, Susan and Mark Stodola welcomed their first child, Andy, after an emergency cesarean section during which he did not receive enough oxygen. Their son’s harrowing birth, they believed, caused the developmental delays that led to his diagnosis of “moderate intellectual disability” at age 4.

The Stodolas did not question this explanation for Andy’s limitations, which they managed with help from various therapists and special education teachers. Then, when Andy was 30, a physician suggested they pursue genetic testing — something they had never considered.

“We did the testing and were surprised it came back showing Lamb-Shaffer syndrome (LAMSHF), because nobody else in our families has any special needs,” Susan says. 

Classified as a rare disease in the U.S. because it affects fewer than 200,000 people nationwide, LAMSHF arises when changes to a gene called SOX5, which plays a key role in brain development, prevent the gene from functioning as it should. With under 1,000 known cases worldwide, LAMSHF draws little attention from academic and pharmaceutical industry researchers. One of few experts in the condition, Véronique Lefebvre, PhD, leads a laboratory at Children’s Hospital of Philadelphia (CHOP), where — fueled by philanthropic support from families affected by LAMSHF, such as the Stodolas — she studies SOX5 deficiencies.

“Federal funding for rare disease research is tough to get. The generosity of these families has changed the course of my work,” Lefebvre says. “They really want to understand this syndrome and find a cure, and so do I. Together, we are getting closer.” 

A deep dive into SOX5

Lefebvre began studying SOX genes, initially focusing on their involvement in skeletal formation, in the 1990s. About a decade ago, she received an email from Megan and Michael Yockey, a couple from Austin, Texas, whose 3-year-old daughter, Harper, had LAMSHF. They had heard Lefebvre researched SOX genes and implored her to investigate the obscure syndrome.

“There was almost no information available to us — our geneticist didn’t even call the condition by name and just referred to it as a ‘deletion’ or a ‘mutation,’” Megan recalls. “We pretty much begged Véronique to help us get some answers, and luckily, she said ‘yes.’”

After connecting with Lefebvre, Megan and Michael founded a nonprofit organization called Harper’s Quest so they could fundraise for her lab. Along with a handful of other affected families, they also created a parent support group on Facebook. Word of Lefebvre’s interest spread among the group members, many of whom began sending donations. Amplifying a pilot grant she received from the Cleveland Clinic, where she worked before joining CHOP in 2018, this funding enabled her to kickstart a LAMSHF research program.

To develop typically, people need two functional copies of the SOX5 gene. If either of those copies is missing or mutated, an individual will face lifelong challenges with learning, speaking, socializing and muscle coordination.

“The description sounds like autism spectrum disorder [ASD], and Lamb-Shaffer indeed is now considered one of the many syndromes within the large ASD family. But there is a different explanation for each type of ASD, and Lamb-Shaffer has a distinct genetic cause,” says Lefebvre, who has also received funding from the Eagles Autism Foundation. 

Lefebvre and her team have two main goals for their LAMSHF research program: to define what goes wrong when SOX5 mutations or deletions occur and to design a gene therapy to correct such defects.

In pursuit of the first goal, they are studying mouse models as well as human brain models generated from patient-derived stem cells. The mice demonstrate what happens in a brain that lacks the SOX5 gene and how that deficiency influences behavior, while the organ model indicates whether SOX5 functions similarly or differently in humans than in rodents.

Simultaneously, they are exploring the possibility of treating LAMSHF with the use of adeno-associated viruses, which deliver agents that can fix or compensate for gene defects. 

“When you add up all the rare diseases, they really are not rare. They affect lots of people,” Lefebvre says. “This research is helping us understand brain development, which gives us a better understanding of Lamb-Shaffer but also applies to many other poorly understood neurodevelopmental conditions.” 

Strength in numbers

Because there are so many rare diseases — an estimated 10,000 — and because they affect small populations compared to more widespread diagnoses, pharmaceutical companies and government agencies do not prioritize their study, and research funding is scarce.

“I understand why more common diseases get more attention — but my kid matters, too,” says Elizabeth Foor, mom of 12-year-old Isaac and founder of Raising a Rare, an advocacy and fundraising organization that supports Lefebvre’s work. “Children with Lamb-Shaffer don’t deserve less just because most people aren’t familiar with the syndrome.”

Susan and Mark Stodola have been supporting Lefebvre’s work since they traveled to CHOP from their home in Arizona to meet her five years ago.

“We realize it takes a long time to do research and develop treatments, and even if a cure is found, it might never benefit Andy, since he’s already an adult,” Mark says. “But making a financial commitment to CHOP and to Véronique means we can help other families facing Lamb-Shaffer down the road.”

Andy Stodola is the oldest person with a confirmed LAMSHF diagnosis, uniquely positioning Susan and Mark to answer questions from and provide reassurance to parents of younger children with the syndrome — parents like Jennifer and Matt Venuto, whose daughter Stella received her diagnosis in 2017 at age 2. Jennifer and Matt also learned of Lefebvre’s work through the LAMSHF Facebook group, and in 2018, they traveled from their home in Orange County, Calif., with family to tour her lab in Philadelphia. The visit spurred their creation of a community fundraising page that has since drawn more than $250,000 for the LAMSHF Research Fund at CHOP. 

The LAMSHF community continues to grow and inspire donations from around the world; recently, Lefebvre received a significant gift from a family in Ecuador, and a family in the Netherlands contributes through the Venutos’ fundraising page every month.

“Véronique is a blessing and a champion,” Jennifer says. “What she studies is so specific and so rare — but it impacts our lives on a daily basis. If her work can help the next generation of kids and provide some light at the end of this tunnel for other families in the future, to me, it’s all worth it.”