Clinical characteristics.

FOXP1 syndrome is characterized by delays in early motor and language milestones, mild-to-severe intellectual deficits, speech and language impairment in all individuals regardless of level of cognitive abilities, and behavior abnormalities (including autism spectrum disorder or autistic features, attention-deficit/hyperactivity disorder, anxiety, repetitive behaviors, sleep disturbances, and sensory symptoms). Other common findings are oromotor dysfunction (contributing to speech and feeding difficulties), refractive errors, strabismus, cardiac abnormalities, renal abnormalities, cryptorchidism, hypertonia, hearing loss, and epilepsy. To date, more than 200 individuals have been identified with FOXP1 syndrome.

Diagnosis/testing.

The diagnosis of FOXP1 syndrome is established in a proband with a heterozygous pathogenic variant in FOXP1 identified by molecular genetic testing and supportive clinical findings.

Management.

Treatment of manifestations: Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in pediatrics, developmental medicine or neurodevelopment, neurology, physiatry, occupational and physical therapy, speech-language pathology, psychiatry, psychology, ophthalmology, and medical genetics.

Surveillance: Regular monitoring by the relevant specialists of existing manifestations, the individual's response to supportive care, and the emergence of new manifestations is recommended.

Genetic counseling.

FOXP1 syndrome is an autosomal dominant disorder typically caused by a de novo pathogenic variant. To date, most probands with FOXP1 syndrome whose parents have undergone molecular genetic testing have the disorder as the result of a de novo FOXP1 pathogenic variant. Rarely, a parent of an individual with FOXP1 syndrome has somatic and germline mosaicism for the FOXP1 pathogenic variant or a complex chromosome arrangement involving FOXP1. Each child of an individual with FOXP1 syndrome has a 50% chance of inheriting the FOXP1 pathogenic variant. Risk to future offspring of the parents of the proband is presumed to be low, as the proband most likely has a de novo FOXP1 pathogenic variant. There is, however, a recurrence risk (~1%) to sibs based on the possibility of parental germline mosaicism; given this risk, prenatal and preimplantation genetic testing may be considered.

Suggestive Findings

FOXP1 syndrome should be considered in a proband with the following clinical findings, imaging findings, and family history.

Clinical findings

• Generalized hypotonia of infancy
• Infant feeding issues
• Mild-to-severe intellectual disability
• Speech and language disorder
• Delays in early motor and language milestones
• Behavior abnormalities:
  • Attention-deficit/hyperactivity disorder
  • Anxiety, combined with other clinical signs
  • Autism spectrum disorder or autistic features
  • Repetitive behaviors
• Strabismus, refractive errors
• Cryptorchidism
• Congenital abnormalities of the heart and/or kidneys

Facial features. Nonspecific dysmorphic facial features include a prominent forehead, ocular hypertelorism, down-slanting palpebral fissures, ptosis, short nose with a broad tip or base, thick vermilion, frontal hair upsweep, and irregular dentition, usually with wide spacing between the front teeth [Sollis et al 2016, Meerschaut et al 2017, Siper et al 2017, Lozano et al 2021, Trelles et al 2021].

Brain MRI findings. Structural brain abnormalities, observed on brain MRI in approximately half of affected individuals, include dilated lateral ventricles, white matter abnormalities, arachnoid cysts, large cisterna magna, corpus callosum defects, moderate frontal atrophy, cerebellar defects (including atrophy), and Chiari I malformation [Meerschaut et al 2017, Lozano et al 2021].

Family history. Because FOXP1 syndrome is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family). Rarely, the family history may suggest autosomal dominant inheritance (e.g., affected males and females in multiple generations).

Establishing the Diagnosis

The diagnosis of FOXP1 syndrome is established in a proband with a heterozygous pathogenic (or likely pathogenic) variant in FOXP1 identified by molecular genetic testing and suggestive findings (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include likely pathogenic variants. (2) Identification of a heterozygous FOXP1 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular testing approaches. Because the phenotype of FOXP1 syndrome is indistinguishable from many other inherited disorders with intellectual disability, recommended molecular genetic testing approaches include use of a multigene panel (see Option 1) or comprehensive genomic testing (see Option 2).

Note: Single-gene testing (sequence analysis of FOXP1, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

Clinical Description

FOXP1 syndrome is characterized by mild-to-severe intellectual disability, speech and language impairment in all individuals despite level of cognitive abilities, behavior abnormalities (including autism spectrum disorder or autistic features, attention-deficit/hyperactivity disorder, anxiety, repetitive behaviors, and sensory symptoms), and dysmorphic features.

To date, more than 200 individuals have been identified with a pathogenic variant in FOXP1 [Carr et al 2010, Hamdan et al 2010, O'Roak et al 2011, Chang et al 2013, Le Fevre et al 2013, Iossifov et al 2014, Srivastava et al 2014, Lozano et al 2015, Sollis et al 2016, Bekheirnia et al 2017, Meerschaut et al 2017, Siper et al 2017, Braden et al 2021, Lozano et al 2021] (see also FOXP1 Foundation). The following description of the phenotypic features associated with this condition is based on these reports.

Developmental delay (DD) and intellectual disability (ID). Common neurologic features include global developmental delay (i.e., language, motor, cognitive) in young children and, with time, mild-to-severe intellectual disability. While intellectual disability is mild to moderate in the majority of individuals, several individuals have borderline to average cognitive functioning. Importantly, even in individuals who do not have intellectual disability, other persistent issues are likely to include learning disabilities, motor problems, and speech and language deficits.

Motor delays. Impairments in both gross and fine motor skills have been identified. Despite motor delays and hypotonia, individuals with FOXP1 syndrome learn to walk (range: age 13-38 months (21.75 ± 5.49); a subset of individuals display gait abnormalities and the majority of individuals display deficits in motor coordination and visual-motor integration [Trelles et al 2021]. Fine motor weakness can affect handwriting and written expression.

Speech deficits. Dysarthria, the most common speech disorder, is a defining feature of FOXP1 syndrome. Apraxic features and phonologic deficits may also co-occur [Braden et al 2021].

The speech difficulties lead listeners to presume expression of language (vocabulary, grammar) is more affected than understanding, but this is not the case.

Language deficits. While all individuals have language deficits to various degrees, language ability ranges from no words to fluent, complex sentences. While language impairment generally persists beyond early childhood, the majority of individuals do develop some expressive language. While language is typically low for most individuals, expressive language (i.e., the ability to express vocabulary and grammar) is a relative strength compared to receptive language (the understanding of vocabulary and grammar) [Braden et al 2021].

Oromotor dysfunction, likely due to poor motor planning and the presence of hypotonia, can contribute to speech and feeding difficulties. Excessive drooling is present until late childhood in around 30% of individuals [Braden et al 2021].

Autism spectrum disorder and other behavioral issues. Although autistic features occur in the majority of individuals, only about 25% meet DSM-5 criteria for autism spectrum disorder (ASD), based on clinical judgement due to strengths in social reciprocity and nonverbal communication (i.e., gestures, eye contact, facial expression).

Development and maintenance of friendships is an area of particular challenge.

Despite certain social communication strengths, repetitive behaviors, restricted interests, and sensory symptoms are highly prevalent even in those who do not meet DSM-5 criteria for ASD. Specifically, long-standing restricted interests are common and can be all encompassing in their intensity (e.g., collecting objects of interest).

Sensory manifestations are characterized by frequent sensory seeking (finger picking is also common), tactile hyporeactivity (i.e., high pain threshold), and auditory hyperreactvity. Repetitive behaviors and sensory manifestations are present in the majority of individuals with FOXP1 syndrome regardless of the diagnosis of ASD.

Behavioral problems include hyperactivity, attention problems, impulsivity, aggression, anxiety, mood lability, obsessions, and compulsions. Attention-deficit/hyperactivity disorder (ADHD) is present in the majority of individuals, often combined with hyperactivity and inattention.

Aggressive behavior is common, often emerging during early childhood and likely due to low frustration tolerance and communication challenges. In most individuals, hyperactivity and aggressive behavior appear to improve with age.

Motor impairments involve both gross and fine motor skills. Despite motor delays and hypotonia, individuals with FOXP1 syndrome learn to walk; some display gait abnormalities, and the majority display deficits in motor coordination and visual-motor integration. Fine motor weakness can affect handwriting and written expression.

Hypotonia, seen in half of affected individuals, can be either generalized or axial. Some individuals have peripheral hypertonia and axial hypertonia. In the latter instance, movement disorder / gait disturbance can include the presence of spastic contractures. Muscle spasms have also been reported.

Ophthalmologic involvement, common in FOXP1 syndrome, includes refractive errors (hypermetropia and myopia) and strabismus (including esotropia). Central vision loss may be present. Although nystagmus has been reported, no specific information is available on the age of onset or cause. Developmental defects of the iris (coloboma, aniridia) and optic nerve hypoplasia have been reported in single individuals.

Cardiac. Congenital heart defects are present in approximately 25% of individuals [Lozano et al 2021], with rates ranging from 14% [Trelles et al 2021] to 47% in older studies [Meerschaut et al 2017]. Atrial septal defects are most common. Patent ductus arteriosus, patent foramen ovale, and pulmonary stenosis are less common. In individual case reports heart defects included hypoplastic left ventricle with atrioventricular septal defect, hypoplastic left ventricle with mitral valve and aortic valve atresia, atrioventricular septal defect, and pulmonary atresia with a single ventricle in the presence of heterotaxy syndrome.

Feeding difficulties. Some feeding problems may be present at birth (e.g., difficulty latching).

Gastrointestinal problems. Constipation and gastroesophageal reflux disease (GERD), the most commonly reported gastrointestinal problems, are frequently overlooked. GERD that emerged during infancy resolved in some individuals.

Swallowing problems may also result from esophageal achalasia, resulting from failure of the lower esophageal sphincter to relax after swallowing [Myers et al 2017].

Hearing impairment. Although reported occasionally, little is known about the specific type of loss (e.g., sensorineural vs conductive). Twelve percent of individuals had frequent ear infections.

Epilepsy. The semiology of seizures in FOXP1 syndrome is highly heterogeneous; to date no pattern specific to FOXP1 syndrome has emerged. Likewise, age of onset of seizures is variable. Anecdotally, most affected individuals respond to standard anti-seizure medications; treatment-refractory seizures appear to be rare.

Other associated features

• Gastrointestinal. There are individual reports of gut atresia (no information available on location or length), hepatic and bile duct abnormality (no other details available), esophageal dysmotility, and anal malformation.
• Genital abnormalities in males include cryptorchidism and micropenis. It is unknown if genital abnormalities occur in females.
• CAKUT (congenital anomalies of the kidney and urinary tract) have been reported in ~7% of individuals. Upper and lower urinary tract defects represent the majority of the detected abnormalities, including unilateral renal agenesis, hydronephrosis, and duplicated renal collecting system.
• Incontinence may be present for a longer duration than expected based on cognitive development.

Prognosis. Based on current data, life span is not limited in FOXP1 syndrome [Palumbo et al 2013, Song et al 2015]. Progression of neurologic findings in adulthood has not been described. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with FOXP1 syndrome are underrecognized and underreported.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Nomenclature

FOXP1 syndrome may be referred to as "FOXP1-related neurodevelopmental disorder" based on the dyadic naming approach proposed by Biesecker et al [2021] to delineate mendelian genetic disorders.

Prevalence

FOXP1 syndrome is considered rare. Approximately 200 individuals have been identified in the medical literature and by the FOXP1 Foundation.

According to the SFARI Gene database, FOXP1 is among the most common genes causing autism spectrum disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with FOXP1 syndrome, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for FOXP1 syndrome.

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in pediatrics, developmental medicine or neurodevelopment, neurology, physiatry, occupational and physical therapy, speech-language pathology, psychiatry, psychology, ophthalmology, and medical genetics (see Table 4).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Icahn School of Medicine at Mount Sinai is currently recruiting for an observational clinical trial on FOXP1 syndrome (NCT03718923).

Mode of Inheritance

FOXP1 syndrome is an autosomal dominant disorder typically caused by a de novo FOXP1 pathogenic variant.

Risk to Family Members

Parents of a proband

• Most probands reported to date with FOXP1 syndrome whose parents have undergone molecular genetic testing have the disorder as the result of a de novo FOXP1 pathogenic variant.
• Rarely, a parent of an individual with FOXP1 syndrome has somatic and germline mosaicism for the FOXP1 pathogenic variant or a complex chromosome arrangement involving FOXP1. In one family, an affected parent with a complex inversion disrupting FOXP1 transmitted the rearrangement to an affected child [Schluth-Bolard et al 2019]. In another family, an unaffected parent carrying a (balanced) intrachromosomal 3p insertion transmitted a 3p deletion including FOXP1 to an affected child [Lloveras et al 2014].
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the proband has a complex chromosomal rearrangement involving FOXP1, testing for a chromosome rearrangement in the parents is also recommended.
• If the proband has a genetic alteration involving FOXP1 that is not identified in either parent, neither parent has a chromosome alteration, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is known to have the FOXP1 pathogenic variant identified in the proband, the risk to the sibs of inheriting the variant is 50%.
• If one of the parents has a chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement and the possibility of other variables.
• If the FOXP1 genetic alteration found in the proband cannot be detected in the leukocyte DNA of either parent and neither parent has a chromosome alteration, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].

Offspring of a proband. Each child of an individual with FOXP1 syndrome has a 50% chance of inheriting the FOXP1 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the FOXP1 genetic alteration, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Risk to future offspring of the parents of the proband is presumed to be low, as the proband most likely has a de novo FOXP1 pathogenic variant. There is, however, a recurrence risk (~1%) to sibs based on the possibility of parental germline mosaicism. Given this risk, prenatal and preimplantation genetic testing may be considered.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

FOXP1 syndrome is caused by defects in FOXP1, which encodes FOXP1, part of the Forkhead box (FOX) group of proteins, an evolutionarily ancient family of transcription factors characterized by a highly conserved forkhead DNA-binding domain. FOXP1 has been associated with a wide range of functions including development of the brain, heart, esophagus, lung, immune system, and spinal motor neurons. Disruption of FOXP1 function is predicted to impair mitochondrial function and lead to oxidative stress, thereby contributing to cognitive and motor impairment [Fröhlich et al 2019].

The phenotypic spectra of FOXP1 and FOXP2 disruptions suggest that these closely related transcription factors are involved in both shared and distinct neurodevelopmental pathways underlying cognitive diseases through the regulation of common and exclusive targets [Bacon & Rappold 2012].

Mechanism of disease causation. Loss of function

Author Notes

Prof Gudrun Rappold (grebledieh-inu.dem@dloppar.nurdug) is actively involved in basic and clinical research regarding individuals with FOXP1 syndrome. Dr Alexander Kolevozn (ude.mssm@nozvelok.rednaxela), Dr Paige Siper (de.mssm@repis.egiap), and Dr Ana Kostic (ude.mssm@citsok.ana) are actively involved in clinical research and drug discovery in FOXP1 syndrome.

Dr Saskia Koene (ln.cmul@eneok.s) is actively involved in clinical research regarding individuals with FOXP1 syndrome. She would be happy to communicate with persons who have any questions regarding FOXP1 syndrome.

Dr Ruth Braden (ua.ude.bleminu@r.nedarb) and Professor Angela Morgan (ua.ude.ircm@nagrom.alegna) are actively involved in research investigating speech and language abilities in individuals with FOXP1 syndrome. More information about our work, and how to get involved in studies, is available at www.geneticsofspeech.org.au.

Contact Dr Saskia Koene (ln.cmul@eneok.s) to inquire about review of FOXP1 variants of uncertain significance.

Acknowledgments

We acknowledge the involvement of Dr Henning Fröhlich and Prof Maja Hempel in this project. Research support is from the Deutsche Forschungsgemeinschaft and the Medical Faculty of the University of Heidelberg.

We acknowledge individuals with FOXP1 syndrome and their families for their generous contributions to our research, and the FOXP1 Foundation for their ongoing support.

Revision History

• 21 September 2023 (bp) Review posted live
• 26 August 2022 (gr) Original submission

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