Kleefstra syndrome (KS) is a rare genetic disorder caused by either a pathogenic variant in the EHMT1 gene or a deletion of the long arm of chromosome 9 (9q34.3) where EHMT1 is located. Patients with KS have intellectual disabilities and developmental delays, often accompanied by an autism spectrum disorder and specific facial dysmorphisms. A significant portion of KS patients develop a psychotic symptoms, followed by a severe decline in their adaptive functioning, leading to a dramatic reduction in their quality of life, which currently is untreatable. More knowledge about the natural course of KS and the effects of anti-psychotic drugs on these associated psychotic episodes is essential for understanding and treating this issue. To prevent general developmental regression in patients with the KS syndrome, and to develop a follow-up strategy for KS patients with special attention to psychotic disorders and behavioral changes, a prospective cohort open label follow-up study was set up as a collaboration between Radboud University Medical Center in the Netherlands and Boston Children's Hospital in the United States of America.

KS patients aged 12 and above were visited at home or in clinics, assessing cognitive and adaptive functioning and psychiatric symptoms using various instruments (e.g., VABS, Mini PAS-ADD, and PANSS). Additionally, data regarding age, sex, genotype, and medication use were recorded.

Between 12-20 of age, 6/19 (32.6%) of participants had experienced developmental regression and/or psychotic symptoms. Whereas this is 9/20 (45.0%) between 21-30 years and 14/15 (93.3%) aged 31 years or older. After onset of psychotic symptoms and developmental regression, 7/8 of KS patients treated with either olanzapine or clozapine showed a relative improvement on adaptive functioning according to the VABS.

KS is highly associated with the lifetime prevalence of developmental regression and psychotic symptoms. Atypical antipsychotic drugs have positive effects on levels of adaptive functioning after regression.