To document the clinical phenotypes and identify the genetic causes of four unrelated children with intellectual disability and speech impairment. Trio-based whole exome sequencing (Trios) was performed for four probands and their parents. Identified variants underwent pathogenicity assessment utilizing in silico protein structure prediction and RNA analysis. Trios revealed four novel de novo heterozygous FOXP1 variants: a frameshift variant c.1909dup (p.Glu637Glyfs*10), two missense variants c.1568T>C (p.Phe523Ser) and c.1541G>T (p.Arg514Leu), and a splicing variant c.1653-34_1653-25delTTTAACTTTG, all confirmed by Sanger sequencing. Protein structure analysis predicted that the missense variants, located within the forkhead box (FOX) domain, are likely to impair protein function. RNA analysis demonstrated that the splicing variant c.1653-34_1653-25delTTTAACTTTG induced skipping of exons 18 and 19, resulting in an in-frame deletion of 64 amino acids (p.Asn511_Gln574del). Our findings expand the mutational spectrum of FOXP1 and underscore the utility of in silico protein structure prediction and RNA analysis in the classification of variants of uncertain significance.

FOXP1 syndrome caused by FOXP1 haploinsufficiency is characterized by intellectual disability, speech, and language impairment, autistic features, and neuropsychiatric abnormalities such as anxiety and hyperactivity. Behavioral changes in patients are mirrored in Foxp1± mice. It is shown that decreased Foxp1 in the Foxp1± striatum results in a significant decrease in phosphodiesterase 10a (Pde10a). Predominantly expressed in medium spiny neurons (MSNs), Pde10a modulates basal ganglia circuitry. Furthermore, the Foxp1± striatum exhibits microglial activation, reduced synaptic pruning, and dysregulation of 111 inflammatory genes. These include the downregulated P2ry12 and Fcrls, markers of homeostatic microglia, and upregulated Cd74, a marker of reactive microglia, suggesting that neuroinflammation contributes to the observed deficits. Interestingly, treatment of Foxp1± mice with the PDE10A antagonist MP-10 (PF-2545920) immediately after birth not only corrects behavioral abnormalities, including decreased ultrasonic vocalization, hyperactivity, and anxiety but also normalizes changes in microglia morphology and synaptic pruning. Transcriptomic analysis with a neuroinflammation-specific gene panel reveals nominal gene expression changes after MP-10 treatment, including Bdnf upregulation and enrichment of neurotrophin signaling. Since FOXP1 and its signaling pathway are highly conserved, administration of MP-10 or other Pde10a antagonists may also alleviate the neurological dysfunction seen in humans with FOXP1 syndrome.

FOXP1 syndrome is a rare neurodevelopmental disorder associated with a range of cognitive, behavioural, and physical consequences, including autism spectrum disorder and associated symptomatology. This scoping review aims to explore the prevalence and characteristics of autism and autism-like features in individuals with FOXP1 syndrome. A comprehensive literature search identified 15 studies encompassing 103 participants. Of these, 13 studies (n = 76 participants) detailed autism spectrum disorder diagnostic information, and 13 studies (n = 37 participants) detailed information at the symptom level. Autism spectrum disorder was diagnosed in 39 % (n = 30) of cases, with repetitive and restrictive behaviours being the most commonly reported feature, observed in 89 % (n = 33) of patients. However, significant heterogeneity in study methodologies and diagnostic criteria prevented direct comparisons and may have led to an underestimation of certain symptoms. Additionally, inconsistencies in symptom reporting across studies further limited the accuracy of conclusions. Overall, findings highlight the need for more standardized and detailed assessments of autism-like features in FOXP1 syndrome to improve differential diagnosis and inform targeted intervention strategies. Future research should address these gaps to enhance understanding and clinical management of individuals with FOXP1 syndrome.

Forkhead box protein P1 (FOXP1), a transcription factor enriched in the neocortex, is associated with autism spectrum disorders (ASDs) and FOXP1 syndrome. Emx1Cre/+;Foxp1fl/fl conditional deletion (Foxp1 conditional knockout [cKO]) in the mouse cortex leads to overall reduced cortex thickness, alterations in cortical lamination, and changes in the relative thickness of cortical layers. However, the developmental and cell-type-specific mechanisms underlying these changes remained unclear. We find that Foxp1 deletion results in accelerated pseudo-age during early neurogenesis, increased cell cycle exit during late neurogenesis, altered gene expression and chromatin accessibility, and selective migration deficits in a subset of upper-layer neurons. These data explain the postnatal differences observed in cortical layers and relative cortical thickness. We also highlight genes regulated by FOXP1 and their enrichment with high-confidence ASD or synaptic genes. Together, these results underscore a network of neurodevelopmental-disorder-related genes that may serve as potential modulatory targets for postnatal modification relevant to ASDs and FOXP1 syndrome.

Parents perceive a lack of prognostic information among the most challenging consequences of having a child with a rare disease. Although the medical phenotype of FOXP1 syndrome, including neurodevelopmental delay, speech impairment, psychiatric problems and congenital malformations is becoming clearer, there is little detailed information about the acquisition of activities of daily living. This study aimed to provide a detailed picture of practical and daily social skills development in individuals with FOXP1 syndrome. In this cross-sectional study, parents were invited to complete an online questionnaire about the medical issues, milestones and practical abilities of their child with FOXP1 syndrome (n = 52, age 2-54 years). We found that individuals with FOXP1 syndrome have great difficulties with both basic and instrumental activities of daily living, but continue to develop their skills into adulthood. Although most individuals learn to perform some basic daily living tasks independently, the majority heavily rely on their parents, many needing 24-7 supervision to support many aspects of daily life up to adulthood. The results of this study can be used to counsel parents after a diagnosis of FOXP1. We include a visual representation of the results for parents in the Supplementary file.