New Study on Kleefstra Syndrome Offers Hope for Better Care and Future Treatments

We have excellent news to kick off 2025! A team of researchers led by Boston Children’s Hospital has published a paper in the prestigious international journal, Clinical Genetics, describing the first 65 individuals seen in its IDefine-funded Kleefstra Clinic.

The paper, “Identifying novel phenotypes and genotype-phenotype correlations in a large clinical cohort of Patients with Kleefstra Syndrome,” is significant because it allows researchers to better understand the complex relationship between genetic variations and observable traits, leading to improved diagnosis, risk stratification, and ultimately, better patient care.

IDefine Chief Scientific Officer Eric Scheeff said the paper underscores the importance of having a clinic dedicated to KS.

“Because Kleefstra syndrome is rare, we are still learning about the many ways it manifests in patients,” said Scheeff. “This study provides new insights, made possible by the large pool of patients seen at the Kleefstra Clinic at BCH. It is so exciting to see the seed we in the KS community planted years ago now yielding so many benefits to both science and patients!”

Research Findings

Researchers reviewed medical records of 65 patients with KS (40 girls and 25 boys, average age 9.3 years). They found that:

• 17% had large 9q34 deletions, 29% had small 9q34 deletions, and 54% had other genetic changes (sequence variants).
• Most patients (77%) had developmental delays or intellectual disabilities.
• Behavioral issues, including autism, were common (38%).
• Epilepsy was seen in 15% of patients.
• Other health issues included heart defects (40%), hearing loss (32%), and constipation (31%).
• Some rare features included severe motor problems (24%), hard-to-treat epilepsy (9%), unusual eye movements (2 cases), low platelet levels (2 cases), brain shrinkage (1 case), and adrenal cancer (1 case).

The study also found that patients with 9q34 deletions had higher rates of developmental delays, motor problems, epilepsy, and vision issues compared to those with sequence variants.

Future Implications

Zoe Frazier, a genetic counselor at BCH who has worked with most of the KS families, is the lead author of the article.

“We hope this paper will be a beneficial contribution to the body of KS literature, especially as we move toward a natural history and eventual interventional trials,” said Frazier

IDefine CEO Geoff Rhyne reiterated that KS community made this research and paper possible through its support of the BCH Kleefstra Clinic, and by families traveling to be seen at it.

“We are still learning more about KS, and the clinic is a huge part of it,” said Rhyne. “We will continue to build on these findings, and I am very excited about the additional fruit they will bear.”

The journal article concludes by stating, “By characterizing this cohort data, we aim to further define the KLEFS genotype–phenotype correlation to improve clinical care and contribute to future research and therapeutic initiatives.”