Kennedy Krieger used innovative genetic sequencing technology to diagnose two brothers who were “undiagnosable” for more than 20 years, leading the way for other families to find answers.
For nearly 25 years, Cathy Rzepkowski blamed herself for her two younger sons’ severe intellectual disabilities. Maybe there was some noxious chemical in the carpet she had installed when she was pregnant, or some toxin she breathed while working for a defense contractor. Or maybe the learning disability she had as a child had somehow morphed into something much more severe when she passed it on to her sons. She played the what-if game constantly and racked her mind with guilt. It was hard not to feel guilty when no one could tell her exactly what was wrong with her sons.
When her third child, Kevin, was a baby, Cathy noticed he was slower to develop than her other two children. At 7 months old, he wasn’t rolling over, which some babies do when they are only a few weeks old, and he seemed listless. She took her concerns to the pediatrician, who after several months told her he had a severe developmental delay, but couldn’t tell her why. She was then pregnant with her fourth child, Keith, and doctors said her new baby could have the same delay.
When Keith was born, he developed quickly at first. But one day Cathy noticed his head lolling backward in his walker—he was unable to hold up his head. She had Keith assessed, and later, both boys were found to have profound intellectual disability, autism, and cerebral palsy, the cause of which was unknown. Kevin could walk and use some words at age 5, but then regressed. Keith’s disabilities were more severe, and he could neither walk nor talk. Both boys had self-injurious behaviors from an early age.
As they grew older, the boys became aggressive and would bite others, in addition to their self-injurious behaviors, so Cathy sought treatment for them at Kennedy Krieger’s neurobehavioral unit. “I didn’t understand why they were hurting themselves,” says Cathy. “I was told I was depressed, and I lost weight. My husband and I went through hell, not understanding why this was happening. It took such a toll on our family.”
Cathy sought counseling, and after much personal turmoil, she and her husband, Ken, decided to seek foster care for the boys. Keith and Kevin were placed with a loving foster mother who cared for the boys and continued to seek treatment for them at Kennedy Krieger. Kevin’s gait was worsening and he fell frequently, but doctors couldn’t explain why. The boys underwent brain MRIs, EEGs for seizures, tissue biopsies, and numerous laboratory tests, but nothing turned up, and Cathy gave up hope of ever finding a cause.
For many years, the family took a break from seeking answers, but in 2009, they decided it was time to try again. They scheduled an appointment in the neurology clinic at Kennedy Krieger to see Ali Fatemi, MD, a pediatric neurologist with expertise in genetic disorders of the brain, and Julie Cohen, a genetic counselor. Kevin and Keith underwent updated genetic and metabolic testing, but still everything came back negative. Then in the fall of 2011, Cathy received a call from Cohen telling her about a new genetic testing method known as exome sequencing, which had recently become available as a diagnostic tool. Exome sequencing allows clinicians to read information on thousands of genes all at once with a single test, casting a much wider net than the traditional method of testing for a single disease, then moving on to the next one by trial and error. “With exome sequencing, we have 25,000 times more data than before,” explains Dr. Fatemi.
Cohen had been anxiously awaiting the availability of exome sequencing as a diagnostic tool, knowing that it had the potential to provide answers for many patients at the Institute, including the Rzepkowski brothers. With the family’s permission, they drew blood samples from Keith and Kevin, and from their parents, sister, and brother.
When Cohen and Dr. Fatemi looked at the results, they found that the brothers had a mutation in a gene that had been discovered to be responsible for intellectual disability, in a study published just one month earlier in the journal Nature Genetics. “The timing was incredible,” says Cohen.
Cathy was at work when she got the phone call from Cohen, who told her, “We found something.” What Cathy previously assumed was a disorder that she had caused was actually a recessive disorder, meaning that both she and her husband were carriers of the gene mutation. It was not her fault—it was, in fact, no one’s fault. For Cathy, knowing that she didn’t cause her sons’ disabilities meant that a burden of guilt had been lifted.
For Cathy’s daughter, Chrissy, it meant she could now pursue having children of her own without needless worry—there is less than a 1 percent chance of her having children with this genetic mutation.
“It was such a long journey for the family, and to finally have an answer is incredible for them and for us,” says Cohen. “It was very moving for me and Dr. Fatemi.”
The Rzepkowskis were the first family at the Institute to find answers through exome sequencing, but the test has the potential to benefit many more. In the neurogenetics clinic, only 10 to 20 percent of patients are currently able to be diagnosed with a genetic cause. “There are thousands more at Kennedy Krieger to whom this test could be applied,” says Dr. Fatemi.
Exome sequencing can not only help families find diagnoses, but it also paves the way for researchers to gain a broader understanding of the causes of developmental disability. In order to develop a treatment for a disorder, you need to first understand the cause.
“Exome sequencing is going to revolutionize our approach for diagnosing patients with genetic disorders,” says Cohen. “This technology is a major advancement in medical genetics and neurogenetics, and will result in many, many more patients and families getting answers.”
Today both brothers are in wheelchairs and live together with their foster mother on the Eastern Shore. They have little understanding of the world around them, but can still experience happiness and express love, always giving Cathy hugs and kisses whenever she visits. Kevin, now 25, loves airplanes, trucks, and motorcycles, while Keith, 23, loves being outside.
There is no known treatment for the brothers’ disorder, but with the family’s permission, Dr. Fatemi and Cohen will publish a case study about Kevin and Keith so others in the medical community can learn from them and help others with similar disorders.
“All those years, I blamed myself for my sons’ disabilities,” says Cathy. “Now that we have an answer, a burden has been lifted. For us, it means closure.”
With exome sequencing, we have 25,000 times more data than before.
Exome sequencing is going to revolutionize our approach for diagnosing patients with genetic disorders. This technology is a major advancement in medical genetics and neurogenetics, and will result in many, many more patients and families getting answers.
Julie Cohen, ScM, CGC, genetic counselor in Kennedy Krieger’s Genetic Counseling program