A study co-led by IDIBGI identifies the origin of sleep disorders in FOXP1 syndrome

An international study co-led by the Girona Biomedical Research Institute (IDIBGI) and Radboud University Medical Center (Nijmegen, the Netherlands) has identified the biological mechanisms that explain sleep disorders associated with FOXP1 syndrome, a neurodevelopmental disorder of genetic origin. The work provides new evidence on the key role of FOXP family genes in sleep regulation and opens new avenues for the development of treatments.

Sleep is essential for proper brain function, as it supports key processes such as memory consolidation, learning, emotional regulation, and the maintenance of neuronal function. In this context, FOXP1 syndrome is a rare genetic disease caused by alterations in the FOXP1 gene, a transcription factor essential for the development of the nervous system. This condition is characterized by intellectual disability, language difficulties, and traits associated with autism spectrum disorder. The study shows that children with FOXP1 syndrome very frequently experience sleep problems, to the extent that these constitute one of the most prevalent symptoms of the disorder. Despite this, these alterations have so far received little attention, despite their significant impact on the quality of life of patients and their families. Specifically, researchers have identified a characteristic pattern of insomnia that prevents sleep maintenance in affected individuals, resulting in frequent nighttime awakenings and very early waking. “For years they have been considered a secondary or less relevant symptom, but our results indicate that they are part of the core of the disorder,” explains Dr. Anna Castells, researcher at IDIBGI and co-author of the study.

The study goes beyond this clinical observation in patients with FOXP1 syndrome. By analyzing common variants of the FOXP1, FOXP2, and FOXP4 genes in the general population using large genetic databases, researchers observed an association between certain variants of these genes and insomnia symptoms, as well as shorter sleep duration. These results reinforce the idea that the FOXP family, previously known mainly for its key role in neuronal development, also plays a fundamental role in sleep regulation.

To confirm the involvement of FOXP proteins in sleep regulation and further investigate the underlying biological mechanisms, the team led by Dr. Castells used the animal model Drosophila melanogaster (fruit fly), an organism particularly effective for studying sleep patterns. The results show that loss of function of the FoxP gene in this organism reproduces phenotypes similar to those observed in humans, such as severe sleep fragmentation and alterations in circadian rhythms. In this context, researchers demonstrated that this gene is essential during nervous system development to ensure a normal sleep pattern in adulthood. In particular, it was observed that its alteration affects specific neurons in the brain responsible for sleep regulation through the release of signaling molecules called neuropeptides, and disrupts neuronal plasticity in circuits involved in the control of sleep and biological rhythms.

A new perspective on therapeutic opportunities

This study expands knowledge of the genetic mechanisms that regulate sleep and highlights the fundamental role of these processes during neurodevelopment. The results indicate that sleep disorders in FOXP1 syndrome are not a secondary consequence, but rather a core feature of the disorder. This paradigm shift is key to improving both diagnosis and clinical management of patients.

According to the researchers, one of the next steps will be to study whether other conditions associated with alterations in FOXP genes also present sleep problems. Sleep is an essential biological function for physical and mental health, especially during childhood, when it is crucial for brain development, learning, memory, and emotional well-being. In this sense, improving sleep quality could have a positive impact on other manifestations of the disorder. “More attention should be paid to sleep problems in these patients, as they may contribute to worsening the overall condition. If we can improve sleep, we may also improve other aspects of the disorder,” notes Dr. Castells.

In addition, the study identifies new mechanisms of communication at the brain level that could in the future be used as potential therapeutic targets. Although this field is still in its early stages, it may open new strategies to address not only sleep disorders but also other symptoms associated with neurodevelopmental disorders. However, further studies will be needed to validate these approaches and explore their clinical potential.

Reference article: Coll-Tané M, Eidhof I, Han J, Raun N, van Renssen LV, Fisher SE, Kayser MS, Kleefstra T, Pillen S, Hudac CM, Mayneris-Perxachs J, Klein M, Koene S, Castells-Nobau A, Schenck A. Conserved sleep disturbances in FOXP1 syndrome originate from developmental dysregulation of peptidergic signaling. J Clin Invest. 2026 Apr 1;136(7):e193475. doi: 10.1172/JCI193475. PMID: 41919501; PMCID: PMC13038207.