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

Lozano, Reymundo; Gbekie, Catherine; Siper, Paige M.; Srivastava, Shubhika; Saland, Jeffrey M.; Sethuram, Swathi; Tang, Lara; Drapeau, Elodie; Frank, Yitzchak; Buxbaum, Joseph D.; Kolevzon, Alexander

doi:10.1186/s11689-021-09358-1

Cited by 35 publications

(35 citation statements)

References 39 publications

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“…Disruption of the FOXP1 locus results in a collection of cognitive and neurodevelopmental symptoms known as FOXP1 syndrome (Lozano et al ., 2021; Siper et al, 2017). The individuals diagnosed with this disorder have loss of function mutations such as deletions, frameshifts or de novo point mutations in one copy of FOXP1 (Siper et al, 2017; Urreizti et al, 2018).…”

Section: Resultsmentioning

confidence: 99%

“…A crucial regulator of the molecular mechanisms underlying cortical development is the transcription factor (TF) Forkhead Box P1 (FOXP1). FOXP1 has been linked to neurodevelopmental disorders, such as autism spectrum disorder (ASD) and intellectual disability (ID) (Co et al, 2020; Lozano et al, 2021). Previous studies have shown that either knockdown (KD) or knockout (KO) of FOXP1 leads to varying phenotypes reflecting abnormal neurogenesis in the cortex (Braccioli et al, 2017; Li et al, 2015; Pearson et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

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FOXP1 orchestrates neurogenesis in human cortical basal radial glial cells

Park

Kulkarni

Konopka

2022

Preprint

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During cortical development, human basal radial glial cells (bRGCs) are highly capable of sustained self-renewal and neurogenesis. Selective pressures on this cell type may have contributed to the evolution of the human neocortex, leading to an increase in cortical size. bRGCs have enriched expression for Forkhead Box P1 (FOXP1), a transcription factor implicated in neurodevelopmental disorders such as autism spectrum disorder. However, the cell type-specific roles of FOXP1 in bRGCs during cortical development remain unexplored. Here, we examine the requirement for FOXP1 gene expression regulation underlying the production of bRGCs using human brain organoids. We examine a developmental time point when FOXP1 expression is highest in the cortical progenitors, and the bRGCs, in particular, begin to actively produce neurons. With the loss of FOXP1, we show a reduction in the number of bRGCs, as well as reduced proliferation and differentiation of the remaining bRGCs, all of which lead to reduced numbers of excitatory cortical neurons over time. Using single-nuclei RNA sequencing and cell trajectory analysis, we uncover a role for FOXP1 in directing cortical progenitor proliferation and differentiation by regulating key signaling pathways related to neurogenesis and neurodevelopmental disorders. Together, these results demonstrate that FOXP1 regulates human-specific features in early cortical development.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

FOXP1 orchestrates neurogenesis in human cortical basal radial glial cells

Park

Kulkarni

Konopka

2022

Preprint

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“…Children and adults with FOXP1 syndrome present with behavioral symptoms that often include externalizing behaviors (i.e., hyperactivity or impulsivity), anxiety, and autistic traits. FOXP1 syndrome is also associated with medical problems such as heart defects (22–40%), recurrent infections (e.g., sino-respiratory infections, skin infections) (33–67%), genitourinary abnormalities (13–42%), gastrointestinal problems (44–73%), and ocular defects (56–75%) [ 11 , 29 , 30 ]. Neurological abnormalities can include dysarthria, hypotonia, gait problems, feeding issues, atypical neuroimaging findings, and seizures [ 11 , 29 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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“…ERK activation through downstream signaling guides to changes in the cytoskeletal organization, which ultimately leads to the stimulation of neurite outgrowth [ 62 , 63 ]. The FOXP1 gene, which was hypomethylated in FXSA, compared to TD, encodes for a transcription factor important for early brain development and, interestingly, variants, deletions, missense mutations FOXP1 are causative for severe forms of ASD, often comorbid with intellectual disability, language deficits, and congenital anomalies, including mild dysmorphic features, and brain, cardiac, and urogenital abnormalities [ 64 ].…”

Section: Discussionmentioning

confidence: 99%

Profiling Genome-Wide DNA Methylation in Children with Autism Spectrum Disorder and in Children with Fragile X Syndrome

Jasoliya

AlOlaby

et al. 2022

Genes

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Autism spectrum disorder (ASD) is an early onset, developmental disorder whose genetic cause is heterogeneous and complex. In total, 70% of ASD cases are due to an unknown etiology. Among the monogenic causes of ASD, fragile X syndrome (FXS) accounts for 2–4% of ASD cases, and 60% of individuals with FXS present with ASD. Epigenetic changes, specifically DNA methylation, which modulates gene expression levels, play a significant role in the pathogenesis of both disorders. Thus, in this study, using the Human Methylation EPIC Bead Chip, we examined the global DNA methylation profiles of biological samples derived from 57 age-matched male participants (2–6 years old), including 23 subjects with ASD, 23 subjects with FXS with ASD (FXSA) and 11 typical developing (TD) children. After controlling for technical variation and white blood cell composition, using the conservatory threshold of the false discovery rate (FDR ≤ 0.05), in the three comparison groups, TD vs. AD, TD vs. FXSA and ASD vs. FXSA, we identified 156, 79 and 3100 differentially methylated sites (DMS), and 14, 13 and 263 differential methylation regions (DMRs). Interestingly, several genes differentially methylated among the three groups were among those listed in the SFARI Gene database, including the PAK2, GTF2I and FOXP1 genes important for brain development. Further, enrichment analyses identified pathways involved in several functions, including synaptic plasticity. Our preliminary study identified a significant role of altered DNA methylation in the pathology of ASD and FXS, suggesting that the characterization of a DNA methylation signature may help to unravel the pathogenicity of FXS and ASD and may help the development of an improved diagnostic classification of children with ASD and FXSA. In addition, it may pave the way for developing therapeutic interventions that could reverse the altered methylome profile in children with neurodevelopmental disorders.

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

Cited by 35 publications

References 39 publications

FOXP1 orchestrates neurogenesis in human cortical basal radial glial cells

FOXP1 orchestrates neurogenesis in human cortical basal radial glial cells

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

Profiling Genome-Wide DNA Methylation in Children with Autism Spectrum Disorder and in Children with Fragile X Syndrome

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