Joint contractures is a recurrent clinical feature of individuals with neurodevelopmental disorder due to FOXP1 likely gene disruptive variants.

Haploinsufficiency of FOXP1 gene is responsible for a neurodevelopmental disorder presenting with intellectual disability (ID), autism spectrum disorder (ASD), hypotonia, mild dysmorphic features, and multiple congenital anomalies. Joint contractures are not listed as a major feature of FOXP1-related disorder. We report five unrelated individuals, each harboring likely gene disruptive de novo FOXP1 variants or whole gene microdeletion, who showed multiple joint contractures affecting at least two proximal and/or distal joints. Consistent with the phenotype of FOXP1-related disorder, all five patients showed developmental delay with moderate-to-severe speech delay, ID, ASD, and facial dysmorphic features. FOXP1 is implicated in neuronal differentiation and in organizing motor axon projections, thus providing a potential developmental basis for the joint contractures. The combination of joint contractures and neurodevelopmental disorders supports the clinical suspicion of FOXP1-related phenotype.

Body-Focused Repetitive Behaviors in Patients with FOXP1 Syndrome: An International Cross-Sectional Survey-Based Study.

Introduction: FOXP1 syndrome is a rare neurodevelopmental disorder due to forkhead box protein 1 (FOXP1) gene mutations and is associated with intellectual disability, dysmorphic features, and autism spectrum disorder. We aimed to assess body-focused repetitive behavior (BFRB) prevalence in this patient population using a cross-sectional survey-based study. Methods: A validated survey assessing for BFRBs was administered to parents attending the International FOXP1 Foundation conference on June 21, 2023, and was sent to a FOXP1 syndrome listserv. Results: Excoriation disorder, onychophagia, onychotillomania, and trichotillomania were reported by 58.6%, 38.6%, 29.7%, and 10.0% of subjects, with 63.4%, 59.3%, 54.5%, and 14.3% having moderate to severe disease, respectively. Overall, 28.6%, 30.0%, and 10.0% had one, two, and three BFRBs, respectively. Conclusion: Prevalence of BFRBs is high among FOXP1 syndrome patients surveyed, affecting quality of life for patients and their families and causing significant sequelae.

Case report: FOXP1 syndrome caused by a de novo splicing variant (c.1652+5 G>A) of the FOXP1 gene.

FOXP1 syndrome is a rare neurodevelopmental disorder characterized by global developmental delay, intellectual disability, and language delay, with or without autistic features. Several splicing variants have been reported for this condition, but most of them lack functional evidence, and the actual effects of the sequence changes are still unknown. In this study, a de novo splicing variant (c.1652 + 5 G>A) of the FOXP1 gene was identified in a patient with global developmental delay, mild intellectual disability, speech delay, and autistic features. Assessed by TA-cloning, the variant promoted the skipping of exon 18 and a premature stop codon (p.Asn511*), resulting in a predicted truncated protein. This variant, that is lacking the forkhead-box DNA-binding domain and nuclear localization signal 2, may disrupt the protein function and thus cause FOXP1 syndrome-related symptoms. Our study extends the phenotypic and allelic spectra of the FOXP1 syndrome.

Mitochondrial dysfunction and oxidative stress contribute to cognitive and motor impairment in FOXP1 syndrome.

FOXP1 syndrome caused by haploinsufficiency of the forkhead box protein P1 (FOXP1) gene is a neurodevelopmental disorder that manifests motor dysfunction, intellectual disability, autism, and language impairment. In this study, we used a Foxp1+/- mouse model to address whether cognitive and motor deficits in FOXP1 syndrome are associated with mitochondrial dysfunction and oxidative stress. Here, we show that genes with a role in mitochondrial biogenesis and dynamics (e.g., Foxo1, Pgc-1α, Tfam, Opa1, and Drp1) were dysregulated in the striatum of Foxp1+/- mice at different postnatal stages. Furthermore, these animals exhibit a reduced mitochondrial membrane potential and complex I activity, as well as decreased expression of the antioxidants superoxide dismutase 2 (Sod2) and glutathione (GSH), resulting in increased oxidative stress and lipid peroxidation. These features can explain the reduced neurite branching, learning and memory, endurance, and motor coordination that we observed in these animals. Taken together, we provide strong evidence of mitochondrial dysfunction in Foxp1+/- mice, suggesting that insufficient energy supply and excessive oxidative stress underlie the cognitive and motor impairment in FOXP1 deficiency.

Disrupted Mitochondrial Network Drives Deficits of Learning and Memory in a Mouse Model of FOXP1 Haploinsufficiency.

Reduced cognitive flexibility, characterized by restricted interests and repetitive behavior, is associated with atypical memory performance in autism spectrum disorder (ASD), suggesting hippocampal dysfunction. FOXP1 syndrome is a neurodevelopmental disorder characterized by ASD, language deficits, global developmental delay, and mild to moderate intellectual disability. Strongly reduced Foxp1 expression has been detected in the hippocampus of Foxp1+/- mice, a brain region required for learning and memory. To investigate learning and memory performance in these animals, fear conditioning tests were carried out, which showed impaired associative learning compared with wild type (WT) animals. To shed light on the underlying mechanism, we analyzed various components of the mitochondrial network in the hippocampus. Several proteins regulating mitochondrial biogenesis (e.g., Foxo1, Pgc-1α, Tfam) and dynamics (Mfn1, Opa1, Drp1 and Fis1) were significantly dysregulated, which may explain the increased mitophagy observed in the Foxp1+/- hippocampus. The reduced activity of complex I and decreased expression of Sod2 most likely increase the production of reactive oxygen species and the expression of the pre-apoptotic proteins Bcl-2 and Bax in this tissue. In conclusion, we provide evidence that a disrupted mitochondrial network and the resulting oxidative stress in the hippocampus contribute to the altered learning and cognitive impairment in Foxp1+/- mice, suggesting that similar alterations also play a major role in patients with FOXP1 syndrome.

Individuals with FOXP1 syndrome present with a complex neurobehavioral profile with high rates of ADHD, anxiety, repetitive behaviors, and sensory symptoms.

BACKGROUND: FOXP1 syndrome is an autosomal dominant neurodevelopmental disorder characterized by intellectual disability, developmental delay, speech and language delays, and externalizing behaviors. We previously evaluated nine children and adolescents with FOXP1 syndrome to better characterize its phenotype. We identified specific areas of interest to be further explored, namely autism spectrum disorder (ASD) and internalizing and externalizing behaviors. METHODS: Here, we assess a prospective cohort of additional 17 individuals to expand our initial analyses and focus on these areas of interest. An interdisciplinary group of clinicians evaluated neurodevelopmental, behavioral, and medical features in participants. We report results from this cohort both alone, and in combination with the previous cohort, where possible. RESULTS: Previous observations of intellectual disability, motor delays, and language deficits were confirmed. In addition, 24% of the cohort met criteria for ASD. Seventy-five percent of individuals met DSM-5 criteria for attention-deficit/hyperactivity disorder and 38% for an anxiety disorder. Repetitive behaviors were almost universally present (95%) even without a diagnosis of ASD. Sensory symptoms, in particular sensory seeking, were common. LIMITATIONS: As FOXP1 syndrome is a rare disorder, sample size is limited. CONCLUSIONS: These findings have important implications for the treatment and care of individuals with FOXP1 syndrome. Notably, standardized testing for ASD showed high sensitivity, but low specificity, when compared to expert consensus diagnosis. Furthermore, many individuals in our cohort who received diagnoses of attention-deficit/hyperactivity disorder or anxiety disorder were not being treated for these symptoms; therefore, our findings suggest that there may be immediate areas for improvements in treatment for some individuals.

FOXP1 syndrome: a review of the literature and practice parameters for medical assessment and monitoring.

FOXP1 syndrome is a neurodevelopmental disorder caused by mutations or deletions that disrupt the forkhead box protein 1 (FOXP1) gene, which encodes a transcription factor important for the early development of many organ systems, including the brain. Numerous clinical studies have elucidated the role of FOXP1 in neurodevelopment and have characterized a phenotype. FOXP1 syndrome is associated with intellectual disability, language deficits, autism spectrum disorder, hypotonia, and congenital anomalies, including mild dysmorphic features, and brain, cardiac, and urogenital abnormalities. Here, we present a review of human studies summarizing the clinical features of individuals with FOXP1 syndrome and enlist a multidisciplinary group of clinicians (pediatrics, genetics, psychiatry, neurology, cardiology, endocrinology, nephrology, and psychology) to provide recommendations for the assessment of FOXP1 syndrome.