Genetic Testing Provides Long-Sought Diagnosis of Ultra Rare Disease

When Tammy Flynn gave birth to her son Marcus in 1997, she was thrown into a world of medical uncertainty.

From infancy, Marcus experienced significant feeding challenges, recurrent sinus and ear infections, and chronic gastrointestinal issues. His growth and muscle development also differed from typical patterns – he exhibited low muscle tone in his upper body, increased tone in his legs, and unusually small feet.

In addition to these medical concerns, Marcus showed notable developmental delays. By the time he was one year old, assessments indicated that he was functioning at roughly a one-month developmental level, prompting early intervention and a comprehensive medical evaluation.

Physicians suspected a genetic condition, but when Flynn was approached about genetic testing in the early 2000s, the field was still in its infancy. At that time, the discussion centered on whether testing would alter Marcus’s current medical care or therapies. After careful consideration with his care team, Flynn concluded that it would not.

As Marcus grew into adolescence and adulthood, his medical complexities became increasingly significant. He was diagnosed with a connective tissue disorder; Scheuermann’s kyphosis with secondary scoliosis; an enlarged spleen and prostate; a thyroid nodule; Factor XIII Deficiency, a rare genetic bleeding disorder; and cerebral palsy.

In 2022, as Marcus’s health continued to evolve, the family transitioned to Froedtert & the Medical College of Wisconsin, where they worked with the genetics team to pursue genetic testing once more. After decades of searching, Marcus and his mother finally received a diagnosis: SETD1B-related disorder, a genetic condition so rare that he was only the 41st person in the world to be identified with it.

“For many families of children or adults with complex medical needs, receiving a diagnosis can open doors to more effective treatment, support, and services – and can also drive awareness and research,” says Flynn. “For my family, having this final piece of the puzzle come together after nearly three decades has been incredibly meaningful.”

Providing Answers for Patients with Genetic Diseases

The Froedtert & the Medical College of Wisconsin Genetic Counseling Program provides genetic testing for people who are at risk for certain diseases or conditions. At the clinic, people who have been referred from their physician receive personalized consultations from genetic counselors – health professionals who have graduate degrees in medical genetics and counseling.

Many of the program’s patients are adults like Marcus who have developmental delays or chronic conditions that were never identified. Counselors like Samantha Sandlow Mackman, MS, CGC, work with physicians to review patients’ medical history and discuss their concerns and motivations.

“We want to make sure patients understand what could be found and aren’t taken by surprise,” she says. “A lot of times these families are coming in with incredible stories, but really great challenges, too, and so sometimes having a diagnosis helps.”

After the individual provides a DNA sample (usually saliva or blood), the sample undergoes a genetic test. For some patients like Marcus, this may be whole exome sequencing, which can analyze the entirety of a patient's DNA. That’s important for patients like Marcus, who have symptoms that could be attributed to a wide range of conditions.

Helping Others Understand This Rare Condition

SETD1B-related disorder is a rare neurodevelopmental and genetic condition characterized by global developmental delays, intellectual disability, speech impairment, low muscle tone, and distinctive facial characteristics. Many individuals with the condition also experience seizures – though Marcus does not, which highlights how symptoms can vary from person to person.

Because so few people have been diagnosed, much remains unknown about the disorder. Flynn has made it her mission to connect with others affected by SETD1B-related disorder and to help bridge the gap between families and the broader medical community.

She is currently developing a U.S.-based website to make information about the disorder more accessible – not only for newly diagnosed families, but also for physicians outside of genetics who may be caring for patients with the condition.

She is collaborating with MCW genetic counseling student Ashlyn Arneson, who is helping to develop clear, family- and clinician-friendly educational materials for the upcoming website.

“The information that is out there about SETD1B is in scientific literature, and it’s not accessible for families,” Arneson says. “As a genetic counselor, I want to put my knowledge towards empowering patients and their health and wellness. This is just one way to do that. We want to create patient-facing information that will also hopefully get more resources for research.”

While much of the research on the disorder is currently being conducted in Canada and the Netherlands, Flynn hopes this project will help expand awareness and research efforts in the United States. She is currently in touch with several researchers around the world who are studying SETD1B-related disorder and hopes that expanding educational access in the U.S. will help build stronger collaboration across countries.

Tammy and Marcus continue to visit the genetic counseling program annually, checking in with Sandlow Mackman and bringing new questions that arise throughout their care journey.

“I always bring my list of questions,” Flynn says. “The team has been so wonderful in helping us closely follow Marcus’s health and in supporting our ongoing efforts to learn more and contribute to future research.”