FOXP1 Syndrome

Neurodevelopmental disorder due to haploinsufficiency of the FOXP1 transcription factor, with global developmental delay, intellectual disability of variable severity, dysarthric speech disorder in all patients, a behavioural profile featuring hyperactivity, anxiety and repetitive behaviours, and cardiac, urogenital, ocular and cerebral malformations in varying proportions.

Literature and regulatory information updated: 9 October 2026.

0. Initial Reference Table

1. Introduction

FOXP1 syndrome is a neurodevelopmental disorder caused by loss of function of one of the two copies of the FOXP1 gene, which encodes a transcription factor of the forkhead box (FOX) family. Its history begins by analogy with the paralogous gene FOXP2, disruption of which in a large British family had been associated with developmental verbal dyspraxia, a disorder of speech motor planning. As the FOXP1 and FOXP2 proteins share the deoxyribonucleic acid (DNA)-binding forkhead domain, a polyglutamine tract and coexpression patterns in brain regions involved in language, several groups sought FOXP1 abnormalities in children with intellectual disability (ID), language disorder and autism [12, 13].

The first report to raise this hypothesis was by Pariani and colleagues in 2009: a child with a 785 kb deletion at 3p14.1p13 encompassing FOXP1, EIF4E3, PROK2 and GPR27, with speech delay, joint contractures, hypertonia and blepharophimosis [13]. In 2010, three publications strengthened the association. Hamdan and colleagues studied 30 patients with sporadic non-syndromic ID and 80 with ASD by array comparative genomic hybridisation and found a de novo intragenic deletion of FOXP1 exons 4 to 14 in a patient with ID and autistic traits; sequencing of the coding exons in 110 patients with ID, 135 with ASD and 570 controls also revealed the de novo nonsense variant c.1573C>T p.(Arg525Ter), located in the forkhead domain, in a patient with ID and autism, with loss of activity in a luciferase assay. Both patients had severe language disorder, mood lability with physical aggression, obsessions and compulsions, leading the authors to conclude that FOXP1 had a more global impact on brain development than FOXP2 [12]. In the same year, Horn and colleagues, in a molecular karyotyping series of 1523 patients with ID, identified three overlapping heterozygous de novo deletions affecting only FOXP1, in patients with moderate ID and marked speech and language impairments; among 4104 controls of similar ancestry, a single large deletion including FOXP1 and other genes was found [14]. Carr and colleagues described a child with FOXP1 haploinsufficiency, Chiari I malformation, gross motor delay, severe speech delay and epileptiform discharges [15].

In subsequent years, exome sequencing studies in sporadic ASD confirmed FOXP1 as a gene with recurrent deleterious de novo variants in autism samples [16, 17], and associations with congenital heart disease [18] and congenital anomalies of the kidney and urinary tract (CAKUT) [19] were described. In 2013, Le Fevre and colleagues proposed a recognisable phenotype, with psychomotor delay, ID, moderate to severe speech delay, a broad forehead, downslanting palpebral fissures, a short nose with a broad tip, relative or true macrocephaly, a frontal hair whorl and prominent finger pads [20]. Sollis and colleagues functionally characterised de novo variants in 2016 and, in 2017, showed that the FOXP1 p.(Arg514His) variant, equivalent to the FOXP2 p.(Arg553His) variant that cosegregates with childhood apraxia of speech, produces similar molecular consequences but a broader and more severe phenotype [21, 22]. The series by Meerschaut and colleagues, with 25 new patients and 23 previously published patients, consolidated the designation of a ‘recognisable entity’ in 2017 [23].

From 2017, the Seaver Autism Center at the Icahn School of Medicine at Mount Sinai (New York) began prospective characterisation using standardised instruments: first in 9 individuals [24], then in a cohort of 22 individuals from the United States and Canada [9] and, in 2025, in 20 adolescents and adults [25]. The same group published a review of 62 individuals with practice parameters for medical assessment and monitoring in 2021 [4], and Braden and colleagues, in Melbourne, defined the speech profile [26]. GeneReviews published the entry ‘FOXP1 Syndrome’ on 21 September 2023, with the alternative designation ‘FOXP1-related neurodevelopmental disorder’, following the dyadic nomenclature proposed by Biesecker and colleagues [1, 3]. Dutch groups subsequently expanded knowledge through parental questionnaires in 40 and 52 individuals [27, 28].

In this article, ‘FOXP1 syndrome’ denotes the condition caused by a heterozygous germline pathogenic or likely pathogenic FOXP1 variant (sequence variants, intragenic deletions or duplications, and structural rearrangements disrupting the gene) and by deletions encompassing FOXP1. Larger 3p deletions, which include other genes, share the core phenotype but add their own manifestations and are treated as a contiguous gene syndrome (sections 2 and 6) [1, 23]. Somatic FOXP1 variants in sporadic tumours and the role of FOXP1 as a fusion partner in mucosa-associated lymphoid tissue (MALT) lymphoma are outside the scope because they do not confer hereditary predisposition [1].

2. Molecular Genetics and Pathophysiology

2.1. The FOXP1 gene and protein

FOXP1 is located on the short arm of chromosome 3 (3p13 in GeneReviews nomenclature; 3p14.1 in some clinical literature) and encodes the FOXP1 protein, a member of the evolutionarily ancient FOX family of transcription factors defined by a highly conserved DNA-binding forkhead domain [1, 4]. The forkhead domain is a winged-helix structure (winged-helix) of approximately 100 amino acids, with helices H1 to H5 and sheets β1 to β3; the recognition helix contacts DNA directly and other regions mediate dimerisation by domain swapping (domain swapping) [24]. FOXP1 acts predominantly as a transcriptional repressor, partly in cooperation with the corepressor CTBP1, and forms homodimers and heterodimers with FOXP2 and FOXP4 [5, 21, 29].

FOXP1 is widely expressed. Developmental studies assign it roles in the brain (particularly the striatum and vocal communication), heart, oesophagus, lung, immune system (B-cell development and T-cell suppression) and columnar organisation of spinal motor neurons [1, 4, 5]. FOXP1 dosage influences the neurodevelopmental trajectory, and partial overlap with FOXP2 suggests shared and distinct pathways through regulation of common and exclusive targets [1, 30].

2.2. Disease mechanism

The established mechanism is loss of function with haploinsufficiency [1]. GeneGuidance records a ClinGen haploinsufficiency score of 3, the sufficient-evidence category [5]. Haploinsufficiency is supported by the phenotypic equivalence between whole-gene deletions, intragenic deletions, truncating variants and balanced rearrangements disrupting the gene [23, 31]. Missense variants (missense) cluster in the forkhead domain and, in functional assays, have effects as severe as truncating variants: loss of transcriptional repression, aberrant subcellular localisation and reduced protein stability [21–23]. As these mutant proteins retain the ability to interact with normal FOXP1 and with FOXP2, an additional dominant-negative effect has been proposed for some missense variants, a hypothesis revisited in subsequent literature but not demonstrated as a distinct clinical mechanism [9, 21]. A molecular dynamics study of six missense variants showed distinct conformational landscapes and reduced interaction with DNA for variants in helix H3, providing a framework for structural interpretation but not clinical validation [32].

Heterozygous mouse models (Foxp1+/−) help explain extraneurological and behavioural manifestations. Fröhlich and colleagues described gastrointestinal dysmotility with achalasia and muscular atrophy of the oesophagus and colon [9, 33]. Wang and colleagues described mitochondrial dysfunction in the striatum, with dysregulation of Foxo1, Pgc-1α, Tfam, Opa1 and Drp1, reduced membrane potential and complex I activity, decreased Sod2 and glutathione, increased oxidative stress and lipid peroxidation, reduced neuritic branching and deficits in learning, memory, endurance and motor coordination [34]. In 2025, the same group described reduced Pde10a in striatal medium spiny neurons, microglial activation and reduced synaptic pruning, with 111 dysregulated inflammatory genes [35]. In Drosophila, loss of FoxP during development in peptidergic neurons fragments and reduces sleep and alters the circadian rhythm, whereas silencing only in adulthood does not affect sleep; common FOXP1 variants are associated with frequent insomnia and short sleep in genome-wide association studies [36].

2.3. Variant spectrum

GeneReviews estimates that sequence variants (small insertions and deletions, missense, nonsense and splice variants) account for approximately 95% of probands with a pathogenic variant and intragenic deletions or duplications for approximately 5%, based on unpublished data from a single laboratory; contiguous gene deletions are not included in these calculations [1]. These proportions describe the distribution of detected variants and not the clinical sensitivity of a test. In the review by Lozano and colleagues, 44 of the 62 individuals had sequence variants detected by next-generation sequencing (NGS) and 18 had deletions detected by CMA, a proportion reflecting the era and diagnostic methods of the included publications [4]. In Braden's speech series of 29 patients, there were 14 truncating variants, 3 missense variants, 3 splice variants, one in-frame deletion and 8 cytogenetic deletions [26]. In the Trelles cohort of 22 individuals, there were 2 deletions (one encompassing approximately 30 genes including the whole of FOXP1, PROK2 and ROBO2; another of 4 exons) and 20 sequence variants (7 missense, 6 frameshift, 5 nonsense and 2 splice variants) [9]. Three complex structural rearrangements (inversions and translocations) disrupting the locus have been described, including a de novo balanced paracentric inversion of 2.1 Mb identified by genome sequencing in a patient with severe ID [31, 37, 38].

Reviewing the literature up to 2017, Siper and colleagues counted 7 recurrent and 34 private variants. Recurrent variants included c.975-2A>G and c.975-2A>C, c.974+1G>C, p.Tyr439Ter, p.Arg503Ter, p.Arg525Ter and missense variants at codons Pro466, Arg514 and Ala532; FOXP1 p.Pro466Leu corresponds to FOXP2 p.Pro505Leu and p.Arg514His corresponds to FOXP2 p.Arg553His [24]. The Trelles cohort added recurrences of p.Leu414AspfsTer26, p.Arg525Gln, p.Arg514His and p.Arg503Ter [9]. In December 2025, ClinVar contained 186 short variants (fewer than 50 bp) classified as pathogenic or likely pathogenic [39]; the search on 9 October 2026 returned 1186 records for the gene, 240 pathogenic or likely pathogenic and 391 of uncertain significance (VUS), numbers which include CNVs encompassing the gene and do not correspond to patients [40].

2.4. Variant nomenclature and normalisation

The MANE Select transcript is NM_001349338.3 (protein NP_001336267.1), whereas most clinical literature uses NM_032682.5 or NM_032682.6 (NP_116071.2, canonical UniProt Q9H334-1 isoform). For the variants checked in VariantValidator (GRCh38, 9 October 2026), c. numbering is identical in both transcripts (table) [6]. The remaining variants cited in this article retain the transcript from the source article.

The nine variants in Siper's prospective series (NM_032682.5, GRCh37) illustrate the spectrum: c.975-2A>C (exon 8 skipping, p.Lys325AsnfsTer12), c.1267_1268delGT p.(Val423HisfsTer37), c.1333_1335delinsAA p.(Val445AsnfsTer29), c.1393A>G p.(Arg465Gly), c.1506C>G p.(Phe502Leu), c.1014dupA p.(Ala339SerfsTer4), c.1240delC p.(Leu414Ter), c.1409A>G p.(Tyr470Cys) and c.1590_1601del12 p.(Gly531_Trp534del); all were de novo except c.1240delC, of unknown inheritance, and the p.(Tyr470Cys) variant was present in a gnomAD control, a reminder that presence in a population database neither excludes pathogenicity in a gene with de novo variants nor confirms it. A seventh individual, with a large duplication encompassing FOXP1, was excluded following conservative interpretation as being of uncertain significance [24].

2.5. Non-coding variants and the role of RNA

Two publications in 2026 show that some pathogenic variants escape conventional analysis. Planté-Bordeneuve and colleagues (Lille) identified a de novo 17 bp intronic deletion, c.1531-31_1531-15del, upstream of the exon 18 acceptor by trio genome sequencing, initially classified as a VUS; SpliceAI predicted acceptor loss (Δ 0.76), the minigene assay produced aberrant transcripts, and long-read sequencing of blood complementary DNA (69 reads) showed 51% canonical transcript, 20% with exon 18 skipping, 6% with exons 18 and 19 skipping, 21% with partial intron 17 retention and 2% with use of a cryptic acceptor, allowing application of the PS3 criterion and reclassification of the variant. FOXP1 expression in blood (4.6 transcripts per million in the GTEx tissue expression database) is sufficient for this type of analysis [7]. Xiang and colleagues described four Chinese children with de novo variants (NM_001349338.3): c.1909dup p.(Glu637GlyfsTer10), c.1568T>C p.(Phe523Ser), c.1541G>T p.(Arg514Leu) and the intronic deletion c.1653-34_1653-25delTTTAACTTTG, which causes skipping of exons 18 and 19 with an in-frame deletion of 64 amino acids p.(Asn511_Gln574del), demonstrated by RNA sequencing and RT-PCR [39]. Urreizti and colleagues had already demonstrated by minigene assay that the splice variant c.1428+1G>A causes exon 16 skipping (p.Ala450GlyfsTer13) [41].

2.6. Genotype–phenotype correlations

No robust genotype–phenotype correlations have been identified [1]. In the Meerschaut series, deletions, truncating variants and missense variants did not differ significantly in the severity of delay [4, 23], and the recurrent p.(Arg525Ter) variant is associated with different phenotypes in different patients [4]. The practical exception concerns larger 3p deletions including other genes: in the 14 patients with an interstitial deletion in the Meerschaut series, ID and neuromotor delay were more severe and sensorineural hearing loss and feeding difficulties more frequent than in the 34 patients with a monogenic FOXP1 defect [23]. In the speech series, relative preservation of expression compared with comprehension was observed in the 21 patients with truncating variants, splice variants or small deletions [26]. Cohorts are small and missense variants rarely have functional studies, limiting any conclusions [9].

2.7. Penetrance, expressivity, allelic disorders and contiguous genes

Pathogenic FOXP1 variants have apparently complete penetrance for neurodevelopmental delay and speech disorder, but highly variable expressivity for cognitive severity, behaviour and malformations [1, 4]. GeneReviews does not recognise another phenotype associated with heterozygous germline FOXP1 variants [1]. Subsequent publications have expanded the spectrum of organs involved: a family with a recurrent nonsense allele in a series of colobomatous microphthalmia [42]; a critical region for congenital diaphragmatic hernia (CDH) at 3p13 including FOXP1 and four other genes, with two patients with de novo variants predicted to trigger nonsense-mediated decay and CDH, leading the authors to treat FOXP1 as a susceptibility factor because not all carriers of loss-of-function variants have CDH [29]; and multiple joint contractures in 5 individuals with de novo variants or a microdeletion [43].

Contiguous gene deletions encompassing FOXP1 and neighbouring genes cause generally more severe ID, neuromotor delay, sensorineural hearing loss, feeding difficulties, growth restriction and facial dysmorphism [1, 44]. Hearing loss is more frequent in extensive 3p deletions including MITF, haploinsufficiency of which causes Waardenburg syndrome type 2A (OMIM 193510) [1]. Other genes in the region have their own consequences: PROK2 (hypogonadotropic hypogonadism type 4) and ROBO2 (vesicoureteric reflux type 2), both included in a deletion of approximately 30 genes in the Trelles cohort [9]. A deletion report must therefore be read according to its boundaries rather than the name FOXP1 alone [5].

3. Clinical Spectrum and Manifestations by System

3.1. Data sources and what each cohort measures

Knowledge of natural history rests on three types of data, which measure different things. The review by Lozano and colleagues assembled 62 independent individuals from 21 publications (March 2009 to July 2020), 41 male and 21 female, aged between 4 months and 31 years (mean 11.4 years); as an unreported feature was counted as absent, percentages are probably underestimated, and denominators range from 41 (male sex) to 62 [4]. The prospective Seaver Autism Center cohorts administered standardised batteries to 9 individuals aged 5 to 17 years [24], to 22 individuals aged 2 to 33 years assessed between October 2016 and February 2020 (81% Caucasian, 14% Asian, 5% Hispanic) [9] and to 20 adolescents and adults aged 13 to 35 years, the latter through remote caregiver interviews [25]. Koene's Dutch and international studies used parental questionnaires in 40 individuals (2 to 54 years, 7 adults), diagnosed predominantly by exome sequencing for neurodevelopmental delay, and in 52 individuals for activities of daily living [27, 28]. Clinical cohorts overlap partially (Seaver individuals appear in more than one publication), have small samples and are biased by recruitment through family organisations and autism centres; none of these numbers is a population estimate.

The following table reproduces the frequencies compiled by GeneReviews from Meerschaut 2017, Lozano 2021 and Trelles 2021, alongside the denominators of the source cohorts where available.

Sources: GeneReviews [1]; review of 62 individuals [4]; prospective cohorts [9, 24].

Discrepancies between columns have methodological explanations. Hypotonia appears in 29% when its recording in the published clinical history is counted, ‘in half’ in the GeneReviews text and in 89–95% when a neurologist examines all individuals using the same protocol [1, 4, 9, 24]. For ADHD and anxiety in the Trelles cohort, the article abstract and GeneReviews table report 75% and 38% according to criteria in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5), whereas the article body reports 15/21 (71%) with ADHD by clinical consensus and 10/21 (47%) with anxiety, a difference resulting from different denominators and definitions [1, 9]. Congenital heart disease ranges from 47% in older series to 14% in the Trelles cohort, with approximately 25% in the GeneReviews text and 30% in its table [1].

3.2. Cognitive and adaptive development

Global developmental delay manifests in early childhood and evolves over time into mild to severe ID, predominantly mild to moderate; several individuals have borderline or average cognitive functioning and, even without ID, learning, motor, speech and language difficulties persist [1]. In the review of 62 individuals, full-scale intelligence quotient (IQ) ranged from 20 to 93, with a mean of 50 [4]. In the Siper series, the full-scale IQ of the 7 individuals with deviation IQ scores ranged from 42 to 93 (mean 62.7 ± 16.5); 7/9 had ID, one had borderline functioning and one child, the youngest and with an early truncating variant, had average functioning [24]. In the Trelles cohort, full-scale IQ or developmental quotient ranged from 14.6 to 93.0 (mean 55.2 ± 18.9); verbal IQ was lower than non-verbal IQ in 77% (p<0.01); 13 of the 17 individuals older than 5 years had ID; there was no correlation between age and performance; and adaptive behaviour, measured by the Vineland-3 (composite 32 to 80), showed communication below socialisation and daily living, with individual discrepancies between IQ and adaptive functioning (for example, IQ 93 with an adaptive composite of 69) [9].

3.3. Speech, language and oromotor function

Speech and language disorder is present in all individuals, regardless of cognitive level [1]. In Braden's series (29 patients, 17 female and 12 male, mean age 9 years and 6 months, range 2 years and 7 months to 33 years; 28/29 de novo), speech was atypical in all: 21 were verbal and 8 minimally verbal; all verbal patients had dysarthria and apraxic features, and 14 of 16 assessed had phonological deficits; none was receiving therapy targeting dysarthria [26]. Dysarthria, a disorder of speech motor execution, is thus the defining feature and may coexist with apraxic (planning) and phonological components [1, 26].

Evidence on the relationship between expression and comprehension is conflicting. Parental reports from the earliest series suggested greater expressive impairment [4, 20]. Speech severity leads communication partners to assume that expression is more affected than comprehension, but standardised tests showed the opposite in the Siper series: expressive vocabulary (EVT-2, n=7; 69.4 ± 17.5) exceeded receptive vocabulary (PPVT-4, n=8; 55.8 ± 25.9) in all individuals [1, 24]. In the Trelles cohort there was no difference between the two tests (p=0.51) and, on the Vineland-3, receptive language exceeded expressive language in 9/16 (56%) [9]. In Braden's series, relatively preserved expression compared with comprehension was confined to patients with loss-of-function variants [26]. The practical conclusion is that the profile must be measured in each patient rather than assumed.

First words emerged between 14 and 42 months (mean 26.8 months) and first phrases between 24 and 96 months (mean 53 months) in the Siper series [24]; in Lozano's review, mean age at first word was 33 months [4]; in the Trelles cohort, the means were 29 months for first word and 44 months for first phrase, and the only individual without words was 25 months old, suggesting that language develops in almost everyone, more slowly [9]. Among the 20 adolescents and adults, all had at least single words, 19 used phrases and 11 complex sentences; fluent speech emerged at a mean age of 7 years and language continued to improve after puberty, although Vineland-3 age equivalents were approximately 3 to 4 years for language and 7 years for writing [25].

Oromotor dysfunction, due to impaired motor planning and hypotonia, contributes to speech and feeding difficulties; excessive drooling persists into late childhood in approximately 30% [1, 26].

3.4. Motor development, tone and gait

Motor deficits involve both gross and fine skills. All individuals eventually walk: in the Trelles cohort, independent walking emerged between 13 and 38 months (mean 21.75 ± 5.49), sitting between 5 and 18 months and crawling between 9 and 25 months [1, 9]; in the Siper series, walking emerged between 18 and 33 months (mean 22.3) [24]; in Lozano's review, the mean was 24.4 months (16 to 48) [4]; and all 20 adolescents and adults walked by 2 and a half years [25]. Most have developmental coordination disorder: all individuals in the two prospective cohorts had difficulties on the coordination questionnaire (DCDQ), and visual–motor integration (VMI) was impaired in 5/7 and in 33%, respectively [9, 24]. Fine motor weakness compromises handwriting and written expression [1].

Tone is heterogeneous. Generalised or axial hypotonia is the most common abnormality; some individuals have peripheral hypertonia with axial hypotonia, in which case the gait disorder may include spastic contractures; muscle spasms have been described [1]. In Lozano's review, hypertonia or spasms occurred in 34% and spasticity or contractures in 16/56 (29%) [4]. On neurological examination in the Trelles cohort, all had hypotonia, gait abnormalities and dysarthria [9]. Peduto and colleagues described contractures of at least two proximal or distal joints in 5 unrelated individuals, all with moderate to severe speech delay, ID, ASD and dysmorphic features, and linked them to FOXP1's role in organising motor axonal projections [43]. In 3 children studied by gait analysis, there was toe walking with increased plantar flexion and knee and hip flexion in mid-stance, premature gastrocnemius activation in all and gastrocnemius spasticity with ankle or knee contractures in 2/3 [45].

3.5. Behaviour, autism and sensory profile

Autistic traits are present in most individuals, but only approximately a quarter meet DSM-5 criteria for ASD by clinical judgement, because social reciprocity and non-verbal communication (gestures, eye contact, facial expression) are relatively preserved [1]. In the Siper series, the ADOS-2 scale (Autism Diagnostic Observation Schedule, 2nd edition) was positive in 4/8 and the ADI-R interview (Autism Diagnostic Interview–Revised) in 4/9, but a consensus diagnosis of ASD was made in only 2/8, both with limited language; all had autistic symptoms [24]. In the Trelles cohort, ADOS-2 classified 10/21 as autism and 2/21 as spectrum, ADI-R was positive in all domains in 10/21, but DSM-5 consensus confirmed ASD in 5/21 (24%), almost always because criterion A (social communication) was not met; 4 of the 5 were girls, with no significant difference by sex (p=0.62), and social motivation measured by SRS-2 (Social Responsiveness Scale) was typical [9]. The scoping review by Stewart and Cho (15 studies, 103 participants) found diagnosed ASD in 30/76 (39%) of those with diagnostic information and restricted and repetitive behaviours in 33/37 (89%) of those with symptom-level data [46]. Among Levy's adolescents and adults, ASD was diagnosed in 40%, with an atypical presentation due to preserved social interest [25].

Repetitive behaviours and restricted interests (lasting, sometimes absorbing, such as collecting objects) occur in approximately 95%, with or without ASD [1, 9]. Sensory symptoms are highly prevalent: in the Trelles cohort, compared with 54 controls, sensory seeking predominated (including picking and pulling skin from the fingers), with tactile hyporeactivity (high pain threshold) and auditory hyperreactivity [1, 9]. Body-focused repetitive behaviours are frequent and sometimes severe: in an international survey by the International FOXP1 Foundation, dermatillomania (compulsive skin picking) was reported in 58.6%, onychophagia in 38.6%, onychotillomania in 29.7% and trichotillomania in 10.0%, with moderate to severe intensity in 63.4%, 59.3%, 54.5% and 14.3%, respectively; the abstract does not specify the denominator [47]. In the Siper series, 5/9 had compulsive skin or nail picking and 5/9 self-injury [24].

Hyperactivity, inattention, impulsivity, aggression, anxiety, mood lability, obsessions and compulsions make up the behavioural profile [1]. In the Siper series, all had ADHD symptoms and compulsions (including hoarding small objects), 8/9 anxiety, irritability and mood lability, and 7/9 aggression [24]. In the Trelles cohort, consensus ADHD was of the combined type in 13 of the 15 cases; aggression (9/21) almost always arose in association with low frustration tolerance; the BRIEF executive function inventory showed inhibition and working memory deficits close to those of combined ADHD, with typical emotional control; the Child Behavior Checklist (CBCL) captured anxiety poorly; and only 5/21 were receiving treatment for ADHD or anxiety, interpreted by the authors as community underdiagnosis and undertreatment [9]. Aggression emerges in early childhood and, like hyperactivity, tends to diminish with age [1].

Among Levy's adolescents and adults, 17/20 had anxiety symptoms (more than half with a formal diagnosis), 1/20 depression, and aggression or irritability diminished or resolved in 10 of 15; when persistent, it is often severe, posing a risk to safety at home [25]. Two girls had a first psychotic episode at 13–14 years, one diagnosed with bipolar disorder, corresponding to 10% with suspected or diagnosed bipolar symptoms, compared with approximately 3–4% in the United States population; the cohort lacks power to demonstrate an increased risk, and both had greater adaptive and language skills [25]. There was no loss of skills (defined as loss of a skill used for at least 3 months), catatonia or neuropsychiatric decompensation [25]. A French observational study by Assistance Publique–Hôpitaux de Paris (AP-HP), at Necker Hospital, was designed precisely because the child psychiatry service had observed psychotic disorders and families reported methylphenidate inefficacy and poor tolerability; it ended in July 2025 and has no results published in the registry, nor were any found in the literature [10].

3.6. Sleep

Sleep disorders were recorded in only 3/60 (5%) in Lozano's review, but in 4/9 (44%) in the Siper series (sleep onset and awakenings) and in approximately 45% in Koene's survey [4, 24, 27, 36]. Coll-Tané and colleagues showed that the phenotype is predominantly sleep maintenance insomnia. Among 6 individuals with loss-of-function variants in the Simons Simplex Collection and a National Institute of Mental Health (NIMH) study, 4/6 had frequent night awakenings, 3/6 sleep onset problems and 3/6 daytime complaints, rates similar to idiopathic ASD (n=2509) and other loss-of-function variants (n=372). In a Dutch cohort of 9 individuals with previous complaints, assessed by questionnaire and a two-week sleep diary, 7/9 had current problems, with early waking before 5 o'clock in 5/7, night awakenings in 4/7, increased wake time after sleep onset in 5/7, prolonged latency in 5 and efficiency below 85% in approximately half; approximately 80% of relatives had their own sleep disrupted. The authors concluded that insomnia is an intrinsic feature of the syndrome and that the 5% estimate was an underestimate, and proposed actigraphy or polysomnography to quantify it [36]. A report of severe obstructive sleep apnoea syndrome (OSAS) has also been published [48], and OSAS was recorded in 2/60 in the review and 1/22 in the Trelles cohort [4, 9].

3.7. Epilepsy and brain imaging

Epilepsy occurs in approximately 12%, with heterogeneous semiology (absences, febrile seizures, tonic–clonic seizures) and variable age at onset [1, 4]. In the review, only 4 of the 7 patients with seizures had an abnormal electroencephalogram (EEG); in the Siper series, 2/4 had an abnormal EEG without clinical seizures and none had epilepsy [4, 24]. Most respond to usual antiseizure medications, and refractory seizures appear rare, based on anecdotal evidence [1].

Structural abnormalities on brain magnetic resonance imaging (MRI) occur in approximately half of patients (29/58 in the review, of whom only 45 had explicitly reported imaging): dilated lateral ventricles, white matter abnormalities, arachnoid cysts, enlarged cisterna magna, corpus callosum defects, moderate frontal atrophy, cerebellar abnormalities and Chiari I malformation, with isolated cases of polymicrogyria, schizogyria and periventricular heterotopia [1, 4]. In the Siper series, 6/7 MRI scans were abnormal and one patient had a tethered cord with the conus at L3 [24]; in the Trelles cohort, 5/19 [9]. A Chinese child with polymicrogyria at 7 months and a thin corpus callosum at 2 years was labelled as having cerebral palsy at 3 years before the molecular diagnosis [39].

3.8. Eyes and hearing

Refractive errors (hypermetropia and myopia) occur in approximately 50% and strabismus (including esotropia) in 18–45% [1, 4, 9]. In the Trelles cohort, 17/22 had an ocular anomaly, including nystagmus and amblyopia in 3/22 each [9]. Hypermetropia is among the most prevalent signs in Koene's survey [27]. Central vision loss, developmental defects of the iris (coloboma, aniridia), optic nerve hypoplasia, microphthalmia, retinitis pigmentosa and cortical visual impairment may occur in isolated individuals [1, 4], and the family with colobomatous microphthalmia reinforces ocular involvement [42]. Hearing impairment was recorded in 8/48 (17%) in the review, without consistent characterisation of the type [1, 4]; it is more frequent in extensive 3p deletions, particularly when they include MITF [1, 23]. Recurrent otitis occurred in 12% in the review but in 6/9 and 11/22 in the prospective cohorts [4, 9, 24].

3.9. Heart, lungs and infections

Congenital heart disease occurs in approximately 25–30% of review series [1, 4]. Atrial septal defect is the most common lesion; patent ductus arteriosus (PDA), patent foramen ovale (PFO) and pulmonary stenosis follow [1]. Chang and colleagues described a patient with an atrioventricular septal defect (AVSD) and a hypoplastic left ventricle with FOXP1 deletion and, among 82 patients with AVSD or hypoplastic left heart syndrome, found 2 with FOXP1 variants (hypoplastic left ventricle with mitral and aortic atresia; AVSD with pulmonary atresia and a single ventricle in heterotaxy) [4, 18]. In the prospective cohorts, lesions were mild: pulmonary valve stenosis and PDA with spontaneous resolution at 14 months in the Siper series [24]; PDA with an atrial septal defect, atrial septal defect with PFO, and atrial septal defect with pulmonary stenosis and right ventricular dilatation in the Trelles cohort, the latter with a concurrent pathogenic KCNQ1 variant [9].

Pulmonary hypertension was recorded in 4/60 in the review, and one patient in the Siper series had neuroendocrine cell hyperplasia of infancy with pulmonary hypertension, receiving continuous oxygen until 3 years and nocturnal oxygen until 5 [4, 24]. Recurrent respiratory infections are among the most prevalent signs in Koene's survey and occurred in 9/22 in the Trelles cohort, which recorded recurrent infections of any type in 17/22 [9, 27]. The authors suggest a link with FOXP1's role in B-cell development and T-cell suppression, an unproven hypothesis [4].

3.10. Feeding and the digestive system

Feeding problems may be present from birth, with difficulty latching on [1]. Constipation and gastro-oesophageal reflux disease (GORD) are the most frequently reported gastrointestinal problems and are often overlooked; infantile reflux resolves in some individuals [1]. Constipation, recorded in only 5/60 in the review, occurred in 4/9 in the Siper series, and the review authors acknowledge that constipation, sleep disorders and infections are probably underreported [4, 24]. Swallowing difficulties may result from oesophageal achalasia [1, 49], consistent with oesophageal and colonic dysmotility in heterozygous mice [33]. Isolated cases of intestinal atresia, absent gallbladder, liver and biliary tract abnormalities, oesophageal dysmotility and anal malformation have been described [1, 4]. In the Trelles cohort, 7/22 had neonatal problems (neonatal intensive care admission in 4, meconium aspiration in 3, hyperbilirubinaemia in 2) [9].

3.11. Urogenital system, continence and growth

Cryptorchidism (22%) and micropenis (7%) occur in males; whether genital abnormalities occur in females is unknown [1, 4]. CAKUT occur in approximately 7%: unilateral renal agenesis, hydronephrosis, collecting system duplication and horseshoe kidney [1, 4]. In Bekheirnia's CAKUT exome series, 4 of 8 individuals with de novo FOXP1 variants had genitourinary anomalies, including hypospadias [4, 19]. Acquisition of bladder control is delayed: all individuals in the Siper series had difficulty, 3/9 had enuresis [24], delayed bladder control was the most prevalent sign in Koene's survey [27] and, among Levy's adolescents and adults, toilet training was difficult in all but one, with persistent accidents in young adults [25]. Incontinence may last longer than cognitive level would predict [1].

In the review, 13% had short stature, 5% obesity, 3% hypothyroidism and 2% type 2 diabetes [4]. In the Siper series, 2/8 had height below the 3rd centile and 2/8 body mass index (BMI) above the 80th centile; hypothyroidism and type 2 diabetes occurred in the same patient; and 2/9 had iron deficiency, one with restless legs syndrome [24]. Macrocephaly was recorded in 15% in the review and in 4/8 (head circumference above the 99th centile) in the Siper series [4, 24].

3.12. Dysmorphism

Dysmorphism is non-specific: prominent forehead, hypertelorism, downslanting palpebral fissures, ptosis, short nose with a broad tip or base, thick vermilion, frontal hair whorl (frontal hair upsweep) and irregular dentition, usually with an incisor diastema [1]. Orphanet adds relative or true macrocephaly and a broad, open mouth with downturned corners [2]. The table presents frequencies from Lozano's review (N=59 unless otherwise stated), which counted each unreported feature as absent [4].

In the prospective cohorts, examined by geneticists using the same protocol, frequencies are higher: a broad nasal bridge in 95% and bulbous nose in 90% in the Trelles cohort, which also recorded malocclusion in 63%, hypoplastic or dysplastic nails in 55% and high palate in 53% [9]; in the Siper series, each individual had 3 to 13 dysmorphic features (mean 7.9), none specific, including pectus excavatum in 2/8 and scoliosis in 1/8 [24]. Sacral dimple is among the most prevalent signs in Koene's survey [27]. Published photographs show a prominent forehead, broad nasal bridge with a broad tip, downslanting fissures, mild ptosis, thick vermilion and diastemata [4].

3.13. Adolescence, adulthood and independence

Data on adults are scarce and probably underestimate their frequency because many adults with disability have never undergone comprehensive genetic testing [1]. In Levy's cohort, approximately half attended mainstream preschool, but by the end of the first stage of primary education all were in special education or had an adapted curriculum; 5 of the 20 had paid employment, none was self-sufficient, and those neither working nor studying needed substantial support [25]. Caregiver concerns change with age: in childhood they focus on speech, language and cognition; in adolescence and adulthood, on independence, socialisation, housing and safety, and behavioural problems become more concerning [25]. In Koene's study of 52 individuals (2 to 54 years), difficulties with basic and instrumental activities of daily living were substantial; skills continued to develop in adulthood and most learned some basic tasks independently but depended heavily on parents, many requiring constant supervision into adulthood [28]. In the survey of 40 individuals, the complaints parents considered most burdensome were ID, communication, behaviour, lack of independence, attention, anxiety, incontinence, obsessions and sensory profile [27].

4. Clinical Recognition and Warning Signs

4.1. When to suspect the condition, by age

In infancy, the combination of generalised hypotonia, feeding difficulties (poor latch, reflux, dysphagia), strabismus and possibly mild congenital heart disease (atrial septal defect, PDA, pulmonary stenosis), a renal anomaly or cryptorchidism should prompt inclusion of FOXP1 in the genetic investigation of developmental delay [1, 4]. Between 12 and 36 months, the most characteristic sign is the contrast between moderate motor delay (independent walking on average at approximately 22 months) and disproportionate speech delay, with first words on average after 2 years and imprecise articulation [9, 24]. At preschool and school age, suspicion rests on dysarthric speech with apraxic features, combined-type ADHD, anxiety, repetitive behaviours and sensory seeking, with autistic traits but relatively preserved social interest and non-verbal communication [1, 9, 26]. In adolescents and adults with unexplained ID, anxiety, aggression and body-focused repetitive behaviours, the absence of previous genetic testing is itself a reason to perform exome or genome sequencing [1, 25].

GeneReviews lists as suggestive findings generalised infantile hypotonia, infantile feeding problems, mild to severe ID, speech and language disorder, delayed motor and language milestones, behavioural abnormalities (ADHD, anxiety combined with other signs, ASD or autistic traits, repetitive behaviours), strabismus and refractive errors, cryptorchidism, congenital heart or kidney anomalies, facial dysmorphism, brain MRI abnormalities and a usually negative family history (simplex cases), rarely with an autosomal dominant pattern across several generations [1].

4.2. Combinations that should raise suspicion

Some presentations have led to incorrect initial diagnoses. A child with polymicrogyria and hypertonia was labelled as having cerebral palsy [39]; multiple joint contractures with speech delay and ID should raise suspicion of FOXP1 [43]; toe walking with gastrocnemius spasticity mimics spastic diplegia [45]; and a patient with trigonocephaly was initially diagnosed with Opitz C syndrome [41]. A child with ASD and severe dysarthric speech disorder, particularly when ADOS-2 is positive but social reciprocity appears preserved, should be investigated for FOXP1 [9, 26].

4.3. Warning signs and emergencies

There are no metabolic crises or acute decompensations specific to the syndrome. Signs requiring targeted assessment are: new epileptic seizures or a change in seizure pattern, behavioural changes or new neurological signs (indication for EEG and MRI) [4]; excessive head circumference growth (indication for repeat brain imaging) [4]; coughing, choking or recurrent respiratory infections during feeding (aspiration risk) [1]; urinary tract infection or voiding dysfunction (indication for renal ultrasound) [4]; severe constipation, particularly if the patient is taking anticholinergics [50]; snoring with respiratory pauses (OSAS) [48]; and, in adolescence, psychotic or mood symptoms, which emerged at 13–14 years in the Levy cohort [25]. Severe persistent aggression or severe self-injury (headbanging, skin picking, nail pulling) may require urgent specialist intervention and a safety plan [1, 47, 51].

4.4. Newborn screening

There is no newborn screening for FOXP1 syndrome, which has no biochemical biomarker [5].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

No consensus clinical diagnostic criteria have been published [1]. Diagnosis is established in a proband with suggestive findings by identifying a heterozygous pathogenic or likely pathogenic FOXP1 variant (the two classes are equivalent for clinical decisions under the American College of Medical Genetics and Genomics and Association for Molecular Pathology guidelines, ACMG/AMP) [1, 52]. A FOXP1 VUS neither establishes nor excludes the diagnosis [1]. No non-molecular test confirms it [5].

5.2. Test selection

As the phenotype is indistinguishable from many other forms of ID, GeneReviews recommends one of two approaches: a multigene ID panel including FOXP1 and other relevant genes, which limits identification of VUS and non-explanatory variants but whose content, sensitivity and methods (sequencing, deletion and duplication analysis) vary between laboratories; or comprehensive genomic testing, usually exome and increasingly genome sequencing. Single-gene testing (sequencing followed by targeted deletion and duplication analysis) is rarely useful and is generally not recommended [1]. The Seaver practice parameters propose CMA for the proband, a first-line test in ID, ASD and global developmental delay that detects 3p13–p14 deletions, and NGS (ASD or ID panels, exome or genome sequencing) for sequence variants, noting that many neurodevelopmental panels include FOXP1 [4]. The two sources converge in practice when exome or genome sequencing includes CNV analysis [5].

5.3. Test yield and limitations

These proportions describe the distribution of variants among already diagnosed patients and not the clinical sensitivity of each test, which has not been estimated. Four limitations have practical consequences. First, CMA analysis using usual thresholds may miss small intragenic deletions: reanalysis of 131 patients with a threshold of 25 kb and 25 probes revealed an 89.1 kb intragenic FOXP1 deletion [53]. Second, deep or non-canonical intronic variants are detected only by genome sequencing (or by exome sequencing if within the covered region) and can be classified only with RNA studies (minigene, RT-PCR, RNA sequencing or long-read sequencing of blood complementary DNA) [7, 39]. Third, CMA does not detect balanced rearrangements, necessitating karyotyping and, if required, metaphase fluorescence in situ hybridisation (FISH) when investigating recurrence risk [4]. Fourth, segregation in parental blood does not exclude gonadal mosaicism [8]. A negative result does not exclude the diagnosis in a suggestive presentation; in that situation, data reanalysis or progression to genome sequencing is justified.

5.4. Report content and VUS interpretation

The report should state the gene, transcript and version (preferably MANE Select NM_001349338.3, with equivalence to NM_032682.5 or NM_032682.6 in the literature), HGVS c. and p. nomenclature, genomic coordinate with assembly, zygosity, ACMG/AMP classification with the criteria applied and, for CNVs, genomic boundaries and included genes [5, 6, 52]. VUS interpretation relies on confirmation of de novo occurrence by parental testing (criterion PS2 or PM6), location within the forkhead domain for missense variants, comparison with equivalent FOXP2 variants and, for splice variants, RNA studies, which allowed two intronic variants to be reclassified in 2026 [7, 22, 24, 39]. GeneReviews names Dr Saskia Koene, of Leiden University Medical Center, as a contact for review of FOXP1 VUS [1].

5.5. Clinical assessment complementary to diagnosis

Standardised ASD instruments (ADOS-2 and ADI-R) have high sensitivity but low specificity in this syndrome: in the Trelles cohort, approximately 60% exceeded the cut-offs and only 24% received the diagnosis by multidisciplinary consensus [1, 9]. Formal speech assessment should distinguish dysarthria, apraxic and phonological components, and separate expressive and receptive language, because this guides therapy [5, 26]. The neurologist should distinguish speech delay due to oromotor hypotonia from language impairment due to cognitive deficit, which may coexist [4].

5.6. Practical algorithm

5.7. Prenatal and preimplantation diagnosis

There are no characteristic prenatal ultrasound signs; a cardiac defect, renal anomaly or CDH detected during pregnancy may rarely lead to diagnosis by fetal exome sequencing, but the sources consulted do not describe prenatal series [29]. In families with a known variant, prenatal diagnosis (chorionic villus sampling or amniocentesis) and preimplantation genetic testing are options discussed in section 8 [1, 8].

6. Differential Diagnosis

The features of FOXP1 syndrome are insufficient to distinguish it clinically from other causes of ID, so all forms of ID without distinctive findings enter the differential, including the OMIM phenotypic series for autosomal dominant, autosomal recessive, X-linked non-syndromic and syndromic ID [1]. The most useful differentials in practice are those sharing speech disorder, motor disorder or malformations.

The paralogue FOXP2 is the most conceptually instructive differential. The two proteins form heterodimers and regulate common and exclusive targets, and the same arginine substitution in the recognition helix produces similar molecular consequences in both (aberrant subcellular localisation, loss of activity and altered interactions), but the FOXP2 phenotype is essentially confined to speech apraxia, whereas the FOXP1 phenotype includes global delay, ID, behaviour and malformations [22, 30]. Clinically, FOXP1 speech disorder is predominantly dysarthric, with apraxic features, rather than isolated apraxia [26].

The distinction between FOXP1 syndrome due to an intragenic variant and a larger 3p deletion has implications for surveillance: a deletion including MITF requires particularly careful hearing assessment, one including PROK2 attention to puberty and one including ROBO2 surveillance for vesicoureteric reflux [1, 9]. Proximal 3p deletion may result from a balanced intrachromosomal insertion in a healthy parent, which may also give rise to the reciprocal duplication in a sibling [54].

7. Treatments and Risk Management Strategies

7.1. Principles and reference documents

There is no cure or treatment targeting the mechanism. Management is symptomatic and multidisciplinary, involving paediatrics, developmental or neurodevelopmental medicine, neurology, physical and rehabilitation medicine, occupational therapy, physiotherapy, speech and language therapy, psychiatry, psychology, ophthalmology and medical genetics [1]. There are no clinical practice guidelines from scientific societies: GeneReviews bases its recommendations on the literature and the authors' experience [1], and the Seaver Autism Center practice parameters derive from a literature review and the opinion of a multidisciplinary group at a single centre, without formal evidence grading [4]. The search for more recent consensus documents found no replacement document, which does not prove that none exists.

The two sources agree on almost everything and differ in details that warrant attention. Both recommend an echocardiogram and electrocardiogram (ECG) for everyone at diagnosis, and both reserve renal ultrasound for symptomatic patients (urinary tract infection, voiding dysfunction) or those with an external genital abnormality, despite CAKUT prevalence of approximately 7% [1, 4]. Seaver recommends brain imaging at initial assessment for everyone and universal hearing and vision assessment, whereas GeneReviews indicates neurological assessment with MRI when examination reveals focal abnormalities and EEG when seizures are suspected [1, 4]. Seaver alone proposes a numerical interval, comprehensive neuropsychological reassessment at least every 3 years [4]. The prevalence of sleep disorders, estimated at 5% in the Seaver review, has been revised by subsequent data to approximately 45% [4, 36].

7.2. Treatment of manifestations

Source: GeneReviews treatment of manifestations table, with the note on sensory integration based on the American Academy of Pediatrics position [1, 55].

7.3. Neurodevelopmental and educational intervention

All children are candidates for early intervention, and therapies should begin as soon as possible, ideally before milestones are missed in cases diagnosed early [4]. GeneReviews describes the United States model: from 0 to 3 years, a federal home-based early intervention programme with occupational therapy, physiotherapy, speech and language and feeding therapy, infant mental health and special education; from 3 to 5 years, developmental preschool through the school district; and at all ages an individualised education programme (IEP) reviewed annually, with vision and hearing consultants when needed, a transition plan in adolescence, school services until 21 years and early vocational rehabilitation [1]. Equivalent services vary between countries; the transferable principle is early assessment, intensive intervention and a periodically reviewed individualised education plan.

The Seaver parameters recommend a comprehensive neuropsychological assessment for everyone by a psychologist experienced in neurodevelopment, including cognition, adaptive behaviour, ASD symptoms, expressive and receptive language, visual–motor integration, academic performance, executive functions and overall behaviour, using clinician-administered instruments and caregiver questionnaires, repeated at least every 3 years and sooner if expected progress is not occurring [4]. Speech and language therapy, occupational therapy and behavioural therapy are critical components, and applied behaviour analysis (ABA) is recommended for communication, social skills, attention, learning, activities of daily living and challenging behaviour [1, 4].

7.4. Speech, language, augmentative communication and feeding

Dysarthria is rarely treated: none of the 29 patients in Braden's series was receiving therapy targeting dysarthria [26]. Assessment should differentiate dysarthria, apraxia and phonological deficits because intervention differs [5, 26]. In severe apraxia (planning) or dysarthria (execution) in the early years, GeneReviews recommends intensive evidence-based motor speech therapies, referring to the Cochrane review of interventions for childhood apraxia of speech [1, 56]. It also recommends early phonological awareness tasks for speech and literacy, therapies for receptive and expressive semantics and grammar, and intervention adapted to the profile as it changes [1]. AAC (from low technology, such as picture exchange, to high technology, such as speech-generating devices) should be assessed in all non-verbal or minimally verbal patients; AAC does not delay oral speech and supports communication development [1, 4].

Feeding therapy, delivered by a speech and language therapist or occupational therapist, uses postural modification and alteration of food and liquid consistency, based on the Cochrane review of interventions for oropharyngeal dysphagia in children with neurological disease [1, 57]. In the first weeks and months, a lactation consultant can support breastfeeding [1]. Assessment should consider aspiration risk and nutritional status, and the team should have a low threshold for intervention [1].

7.5. Motor function and rehabilitation

Occupational therapy addresses fine motor skills (self-feeding, hygiene, dressing and writing), and physiotherapy crawling, walking, running and strength, particularly in hypotonia [1]. The neurologist or developmental paediatrician assesses tone, joint mobility, fine and gross motor skills, gait, cranial nerves and reflexes and refers to rehabilitation medicine and orthopaedics when needed, for physiotherapy, occupational therapy, feeding therapy, orthoses and splints [4]. Stretching aims to prevent contractures and falls [1]. Toe walking with gastrocnemius spasticity and ankle or knee contractures benefits from instrumental gait analysis before deciding between orthoses and other interventions [45].

7.6. Behaviour and psychopharmacology

ADHD, anxiety, irritability and aggression should be treated by a child psychiatrist, developmental paediatrician, paediatric neurologist or geneticist experienced in neurodevelopmental psychopharmacology [4]. Neither GeneReviews nor the Seaver parameters specify particular drugs or doses [1, 4]. The Trelles cohort showed undertreatment: only 5/21 were receiving treatment for ADHD or anxiety, and the authors interpreted aggression as secondary, at least in part, to untreated ADHD and anxiety and to language limitations [9].

The only data on specific drugs are observational. In Levy's adolescent and adult cohort, more than half were taking or had taken psychotropic drugs for anxiety, mood, behaviour or ADHD, with mixed effects and many changes due to adverse effects; fluoxetine was the only mood medication that none of the 3 patients discontinued because of adverse effects, and guanfacine (n=5) and clonidine (n=3) were used for ADHD with benefit and no reported adverse effects [25]. These data rely on caregiver recall, do not include doses and are insufficient for recommendations; use of these drugs follows approved indications for ADHD or depression generally rather than a syndrome-specific indication [25]. The rationale for the French Necker study refers to family reports of methylphenidate inefficacy and poor tolerability, an observation still without published results [10]. In the absence of specific data, selection and dosing of each psychotropic follow general guidance for ADHD, anxiety or depression in ID, with slow titration and monitoring for adverse effects.

A 2026 case report described a 9-year-old girl with a de novo in-frame FOXP1 deletion, severe psychomotor delay and ASD, with severe headbanging since 2 years of age, progressive and refractory to multidisciplinary behavioural strategies and several drugs. Levodopa/carbidopa, started at 7 years for progressive foot dystonia and contractures, had no clear benefit for dystonia but immediately improved headbanging, with an effect sustained for more than 19 months; the authors relate this to FOXP1's role in midbrain dopaminergic neuron differentiation through PITX3 [51]. This is a single patient, without a dose reported in the abstract, and does not constitute a recommendation.

For body-focused repetitive behaviours, frequent and sometimes moderate to severe, the sources consulted describe no interventions tested in this syndrome [47]. For severe aggression or destructive behaviour, GeneReviews recommends referral to a neurologist, developmental paediatrician, psychologist or psychiatrist [1].

7.7. Epilepsy and imaging

EEG is performed when there is clinical suspicion, preferably overnight video-EEG with the 10–20 system and automated spike and seizure detection; sedation is generally not recommended for EEG [4]. Antiseizure medications are those used in epilepsy generally; there are no data indicating superiority of any drug or on seizure severity, and most patients respond to usual treatments [1, 4]. The threshold for repeating EEG should be low when there are new seizures, a change in pattern, behavioural changes or new neurological signs [4]. Brain MRI frequently requires sedation, and the risks and benefits should be weighed individually [4].

7.8. Drooling: oral glycopyrronium

GeneReviews states that some patients with excessive drooling are treated with glycopyrronium (glycopyrrolate) and refers to NICE (the United Kingdom National Institute for Health and Care Excellence) guidance on oral glycopyrronium [1]. There are no efficacy data in FOXP1 syndrome; the approved indication in the United States and European Union covers severe chronic drooling in children with neurological disorders, a category that includes these patients [50, 58]. Glycopyrronium is an anticholinergic that reduces salivary secretion [50].

Sources: Cuvposa® FDA label [50]; Sialanar® summary of product characteristics (SmPC) [58].

In practice, the difference in units is the main source of error: the American label expresses the dose as glycopyrrolate (salt) and the European label as glycopyrronium (cation), with the bromide equivalent stated in parentheses [50, 58]. As constipation is already frequent in FOXP1 syndrome and intestinal dysmotility has a biological basis in the mouse model, bowel monitoring during treatment is particularly relevant [24, 33, 50].

7.9. Other manifestations

Congenital heart defects are usually mild and may or may not require medical or surgical intervention, as directed by the cardiologist [4]. Refractive errors and strabismus should be corrected promptly [1, 4]. For recurrent otitis, insertion of tympanostomy tubes should be considered [4]. Cryptorchidism follows paediatric urology guidance [1]. Endocrine assessment is performed as in the general population, with emphasis on nutrition (restrictive diets and feeding difficulties) and clinical assessment of puberty, and attention to pituitary deficiencies when corpus callosum abnormalities or ventriculomegaly are present [4]. Constipation, sleep, infections and gastro-oesophageal reflux should be monitored in primary care, with referral to gastroenterology and sleep medicine; routine dental care is justified by the high palate and malocclusion [4]. For sleep maintenance insomnia, the sources consulted describe no interventions tested in the syndrome; Coll-Tané and colleagues recommend quantifying sleep by actigraphy or polysomnography [36].

7.10. Regulatory status

No medicine is authorised by the Food and Drug Administration (FDA) or the European Medicines Agency (EMA) for FOXP1 syndrome, and there is no orphan drug designation or registered interventional trial for this indication in the sources consulted [10]. The only drug named by management sources is glycopyrronium for drooling, whose regulatory status is summarised in the table.

Sources: Drugs@FDA and Cuvposa® label [50]; Sialanar® EPAR [58]. The sources consulted do not include data on national reimbursement in Portugal or Brazil.

7.11. Trials and clinical studies

The glycopyrronium trials were conducted in mixed neurological populations and cannot estimate the effect in FOXP1 syndrome; the response rate should be read alongside the 11–18% placebo rate and anticholinergic effects, frequent in the active group, and there are no controlled data beyond 8 weeks [50, 58]. Syndrome-specific studies are all observational; there are no negative or positive therapeutic trials, and the absence of registered interventional trials in the search performed does not prove that programmes at the preregistration stage do not exist. The Seaver authors state that outcomes for future trials should prioritise instruments sensitive to the syndrome's profile: the ABC scale (Aberrant Behavior Checklist) and the Vineland-3 maladaptive behaviour scale proved more useful than the CBCL/ABCL, which captures only externalising behaviour [25].

7.12. Developments in the last twelve months and research

Preclinical studies suggest two targets, mitochondrial dysfunction and oxidative stress in the striatum and the PDE10A pathway with microglial activation, but neither has reached human studies [34, 35]. The Drosophila and MP-10 data, both showing effects dependent on early intervention, suggest developmental windows, a relevant hypothesis for future trial design [35, 36]. Three GeneReviews authors from the Seaver Autism Center declare involvement in drug discovery research for FOXP1 syndrome [1].

7.13. Special populations, agents to avoid and transition

The sources consulted describe no pregnancies in women with FOXP1 syndrome or specific anaesthetic or perioperative complications. Sedation is frequently necessary for MRI and should be considered individually; for EEG, it is generally not recommended [4]. Hypotonia, dysphagia with aspiration risk and OSAS described in some patients are factors to consider in pre-anaesthetic assessment [1, 48]. Sialanar® is contraindicated in pregnancy and breastfeeding [58]. No drugs specifically contraindicated by the syndrome have been described; anticholinergics require additional caution because of frequent constipation [24, 50]. Transition to adult care should be prepared in adolescence, with an educational and vocational transition plan [1], attention to anxiety, mood and psychotic symptoms [25], continence and the need for continuous supervision [28], and guidance on housing and safety, families' main concerns at this stage [25].

8. Reproductive Options and Family Counselling

8.1. Inheritance and origin of variants

FOXP1 syndrome is inherited in an autosomal dominant manner, but almost all cases result from de novo variants: most probands whose parents have been tested have a de novo variant [1], 28 of the 29 patients in Braden's series were de novo [26] and, up to 2017, all published variants were de novo except one of unknown inheritance [24]. As ID affects reproduction, vertical transmission of a sequence variant is not described in the sources consulted; known familial cases result from chromosomal rearrangements or parental mosaicism [1, 8].

8.2. Familial transmission scenarios

GeneReviews and the Seaver parameters describe two scenarios involving structural rearrangements. In the first, an affected parent carrying a complex inversion with a breakpoint disrupting FOXP1 transmitted it to an affected child [1, 38]. In the second, an unaffected parent carrying a balanced intrachromosomal insertion at 3p transmitted the 3p deletion including FOXP1 to a child; in the family described by Lloveras, two siblings inherited the reciprocal deletion and duplication, respectively [1, 54]. The third scenario is gonadal mosaicism: Zsigmond and colleagues described two Hungarian siblings with the same p.(Arg514His) variant, absent from both parents' blood (case in section 10) [8].

8.3. Recurrence risks

The approximately 1% risk is a theoretical estimate derived from the frequency of germline mosaicism in germline mutation studies, rather than an observed rate in families with FOXP1 syndrome [1, 60]. Zsigmond and colleagues point out that gonadal mosaicism may make the risk higher or lower than this value and that de novo single-nucleotide variants arise 3 to 4 times more often in the paternal germline, increasing with paternal age; in their reported case, the father was 41 and 45 years old at the two births [8]. The risk to other relatives depends on parental status [1].

8.4. Testing parents and siblings

Molecular testing of parents is recommended to confirm de novo origin [1, 4]. If the proband has a deletion or complex rearrangement, parents should undergo karyotyping and, when indicated, metaphase FISH, because CMA does not detect balanced inversions or insertions [1, 4]. Parental leucocyte DNA does not detect all somatic mosaicism or exclusively germline mosaicism [1, 8]. Siblings with signs of developmental delay should be tested when relevant [4]. There is no specific presymptomatic surveillance for at-risk relatives [1]. Therefore, in an asymptomatic sibling with normal development, testing has no direct clinical utility and discussion belongs primarily in the reproductive context in adulthood.

8.5. Prenatal diagnosis and preimplantation genetic testing

The ideal time to determine genetic risk and discuss prenatal or preimplantation testing is before pregnancy, and counselling should be offered to parents of affected children [1]. Given the approximately 1% risk, prenatal diagnosis and preimplantation genetic testing may be considered when the proband's variant is known [1]. Perspectives on prenatal diagnosis differ between professionals and families, and most centres consider it a personal decision [1]. In the Hungarian siblings' case, preimplantation testing and prenatal diagnosis were offered for future pregnancies [8]. An adult with FOXP1 syndrome has a 50% transmission risk in each pregnancy, and counselling should be adapted to their level of understanding [1].

8.6. Counselling content

Counselling should explain the nature of the syndrome, mode of transmission, usual de novo origin, residual risk of mosaicism and limitations of testing parental blood [1, 8]. It should also convey what is known about functional prognosis: walking is practically universal, language develops slowly and continues to progress in adolescence, no regression has been described, and most adults need substantial support [25, 28]. The visual representation of daily living skills published by Koene and colleagues was designed for this purpose [28]. Parents should receive information on patient organisations and registries (section 9) [1].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each number measures

There is no validated population estimate of the prevalence or incidence of FOXP1 syndrome. Available numbers are counts of known cases. GeneReviews reports more than 200 individuals identified in the literature and by the International FOXP1 Foundation in 2023 [1]; Lozano's review counted more than 100 individuals published in more than 30 reports and series up to 2020 [4]; the foundation refers to ‘several hundred’ cases worldwide, a patient organisation figure rather than an epidemiological one [61]; and Orphanet assigns a prevalence class below 1/1 000,000, with 48 cases counted, a count preceding the more recent cohorts [2, 5]. None of these values can be converted into a rate per 100,000 inhabitants. In the SFARI database, FOXP1 is among the genes most frequently implicated in ASD, reflecting the frequency of de novo variants in autism cohorts rather than syndrome prevalence [1, 17]. Adults are probably underrepresented because many have never undergone comprehensive genetic testing [1].

9.2. Geography, ancestry and sex

Published cohorts come predominantly from the United States and Canada (Seaver, 22 individuals in the prospective cohort and 20 adolescents and adults) [9, 25], the Netherlands with international recruitment (40 and 52 individuals) [27, 28], Australia with international recruitment (29 patients) [26] and Belgium and other European countries (48 patients) [23]. There are reports from France [7], Hungary [8], Japan [62] and China [39], and the Necker study (Paris) included 25 individuals, without published results [10]. The sources consulted contain no data from Portugal or Brazil, which does not demonstrate an absence of patients or publications in those countries. As almost all cases are de novo, no founder effect or populations with increased frequency have been described. The Trelles cohort was 81% Caucasian, 14% Asian and 5% Hispanic, limiting the description of facial phenotype in other ancestries [9]. Regarding sex, Lozano's review counted 41 male and 21 female individuals, possibly owing to diagnostic or publication bias, whereas Koene's survey included 20 of each sex [4, 27]. In the Trelles cohort, ASD diagnosis did not differ by sex [9].

9.3. Special populations

Adults are the least studied population, with data from 20 individuals aged 13 to 35 years and 7 adults in Koene's survey [25, 27]. The oldest adult included in the parental studies was 54 years old [27, 28], and one report describes an adult with a de novo 3p14.1 microdeletion, autism, severe speech delay and impaired motor coordination [63]. There are no data on pregnancy in affected women or on ageing. In non-verbal or minimally verbal people, pain, gastrointestinal discomfort, constipation and sleep disorders may manifest as behavioural changes, and a high pain threshold may delay identification of injuries [4, 9].

9.4. Reference networks and patient organisations

In Europe, the relevant reference network is ERN ITHACA (European Reference Network on Rare Malformation Syndromes, Intellectual and Other Neurodevelopmental Disorders) [11]. The International FOXP1 Foundation, based in the United States and founded in 2020 from the RareConnect community, organises family conferences (United States in 2023, Netherlands in June 2025) and a data collection programme with RARE-X [61]. Simons Searchlight maintains an online registry including FOXP1 [10, 59]. GeneReviews also lists AAIDD (American Association on Intellectual and Developmental Disabilities), Apraxia Kids, MedlinePlus, VOR and the Melbourne speech genetics research group (geneticsofspeech.org.au) [1]. The Seaver Autism Center (Mount Sinai, New York) and Necker Hospital (AP-HP, Paris) conduct phenotyping studies [10].

10. Illustrative Clinical Case

Zsigmond and colleagues, from Pécs (Hungary), described two siblings with the same FOXP1 variant in 2024 and the first case of suspected gonadal mosaicism in this syndrome [8].

Patient 1 was a boy, his father's first child (41 years) and his mother's second (31 years), with no consanguinity and a negative family history (a healthy maternal half-sister). He was born by caesarean section at 41 weeks, weighing 3600 g (50–75th centile), with normal adaptation. He rolled over and crawled at 10 months and walked independently at 2 and a half years, with marked expressive language delay. He was referred to the genetics clinic at 18 months: weight at the 10–25th centile, length at the 50–75th centile and head circumference at the 10–25th centile; he had mild axial hypotonia, convergent strabismus, dyskinetic movements and subtle dysmorphic features (prominent forehead, frontal hair whorl, broad nasal bridge with a broad tip, hypertelorism); he was not walking and only babbled. On the Bayley-III scale, cognitive, language and motor quotients were 60, 56 and 55 at 28 months and 65, 54 and 58 at 42 months. Metabolic investigations (urinary organic acids, serum amino acids, thyroid function) and EEG were normal; brain MRI showed smaller basal ganglia and predominantly frontotemporal cerebral atrophy (Figure 2 of Zsigmond et al., 2024). Karyotype (46,XY in 100 cells), FISH for Angelman syndrome and array comparative genomic hybridisation (array-CGH) were normal. Exome sequencing identified the heterozygous variant NM_032682.6:c.1541G>A p.(Arg514His), equivalent to NM_001349338.3:c.1541G>A in the MANE transcript [6], located in the DNA recognition helix of the forkhead domain, predicted as probably damaging by PolyPhen-2 and with previous functional data showing aberrant subcellular localisation and loss of transcriptional repression [22]. Later, the boy had moderate ID, autistic traits and absent expressive speech, with ASD assessment ongoing [8].

His sister was born after a pregnancy termination for prenatally diagnosed trisomy 21. She was born by caesarean section at 39 weeks, weighing 3630 g (95th centile), and had moderate generalised hypotonia from birth. She was referred at 8 months for feeding difficulties, with weight at the 3–10th centile, length and head circumference at the 25–50th centile, generalised hypotonia and bilateral convergent strabismus; she neither crawled nor sat, did not reach for toys, had poor visual attention and did not babble. At 14 months, Bayley-III quotients were 75 (cognitive), 74 (language) and 61 (motor). Targeted testing identified the same variant. The variant was not detected in either parent's blood, leading to the hypothesis of gonadal mosaicism; the father declined sperm testing, and parental origin remained undetermined. Photographs of the siblings show a prominent forehead, frontal hair whorl, hypertelorism, broad nasal bridge with a broad tip and convergent strabismus (Figure 3 of Zsigmond et al., 2024) [8].

Counselling explained the limitations of blood segregation studies and offered preimplantation genetic testing or prenatal diagnosis in future pregnancies [8]. The case illustrates four points of this article: hypotonia, strabismus and feeding difficulties as infantile signs; motor delay followed by independent walking; disproportionate expressive language disorder; and the need to discuss a recurrence risk above the residual risk when two siblings are affected, even with parents testing negative in blood [1, 8]. The p.(Arg514His) variant is recurrent, described de novo in three unrelated patients and equivalent to FOXP2 p.(Arg553His) [22].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Based on current data, life expectancy is not reduced, although adult data are limited [1, 62, 63]. No neurological progression or loss of skills has been described: in the cohort of 20 adolescents and adults, no one lost skills acquired in childhood, adolescence or adulthood, no one had catatonia, and adaptive and language skills continued to progress after puberty [25]. All individuals in the cohorts eventually walk [9, 25], most develop some expressive language, with fluent speech at a mean age of 7 years in the adolescents and adults studied [1, 25], and hyperactivity and aggression tend to decrease with age, although persistent aggression is often severe [1, 25]. Anxiety is highly prevalent in adulthood (17/20), and the occurrence of psychosis in 2/20 warrants surveillance in adolescence, without an increased risk having been demonstrated [25].

Independence is the main determinant of functional prognosis. Most adults remain dependent, many with constant supervision, although they continue to acquire skills [28]; among Levy's adults, 5 of 20 had paid employment, none was self-sufficient, and continence was incomplete in many young adults [25]. Heterogeneity is considerable, ranging from average cognitive functioning to severe ID [1, 9], and there are no reliable genetic predictors [1]. There is no ClinGen actionability assertion for FOXP1 [5]. The value of diagnosis lies in ending the diagnostic odyssey, directing speech and language therapy towards the dysarthric profile, initiating cardiac, renal, ophthalmological and behavioural assessments and enabling recurrence counselling [5].

11.2. Initial assessment after diagnosis

11.3. Surveillance

Except for neuropsychological reassessment and glycopyrronium reassessment, the sources do not propose numerical surveillance intervals, and all frequencies are defined by the responsible specialist [1, 4].

12. Summary and Final Considerations

FOXP1 syndrome is a monogenic cause of global developmental delay and ID, caused by haploinsufficiency of a forkhead transcription factor with functions in the brain, heart, digestive system, lungs, immune system and motor neurons. It almost always results from a de novo variant (sequence variant, intragenic or whole-gene deletion, structural rearrangement), and larger 3p deletions add manifestations dependent on other genes, such as MITF, PROK2 and ROBO2. The most constant feature is a dysarthric speech disorder, with apraxic and phonological components, present in all patients and disproportionate to motor delay; the behavioural profile combines ADHD, anxiety, repetitive behaviours, sensory seeking and frustration-related aggression, with frequent autistic traits but ASD criteria met only in a minority because social interest and non-verbal communication are relatively preserved. Hypotonia, refractive errors, strabismus, mild congenital heart defects, urogenital anomalies, structural brain MRI abnormalities, constipation and sleep maintenance insomnia complete the picture.

Diagnosis is molecular, without consensus clinical criteria, and is made by exome or genome sequencing with CNV analysis, or an ID panel complemented by CMA. A negative test does not exclude the diagnosis in a suggestive presentation because small intragenic deletions, deep intronic variants and balanced rearrangements escape conventional analyses; blood RNA studies have become a tool for reclassifying splice variants. Recurrence risk for parents of a proband with a de novo variant is approximately 1%, increased when there is a parental balanced rearrangement or gonadal mosaicism, as in the case of two affected siblings with parents testing negative in blood.

There is no targeted treatment. Management rests on speech and language therapy targeting dysarthria, AAC, physiotherapy and occupational therapy, behavioural intervention, treatment of psychiatric comorbidities (undertreated in published cohorts), visual correction, universal cardiac assessment and surveillance of sleep, constipation, infections and mental health in adolescence. Oral glycopyrronium is the only medication named by management sources, for drooling, with American and European labels differing in units, age and duration. Preclinical research points to mitochondrial function, PDE10A and developmental windows, without human studies. Life expectancy is not reduced, no regression has been described and skills continue to progress in adulthood, but most adults remain substantially dependent, making transition planning and family support central components of follow-up.

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