FOXP2-Related Speech and Language Disorder

Clinical characteristics.

FOXP2-related speech and language disorder (FOXP2-SLD) is caused by heterozygous FOXP2 pathogenic variants (including whole- or partial-gene deletions). The core phenotype of FOXP2-SLD is childhood apraxia of speech (CAS), a disorder of speech motor programming or planning that affects the production, sequencing, timing, and stress of sounds, and the accurate sequencing of speech sounds into syllables and syllables into words. CAS also interferes nonselectively with multiple other aspects of language, including phonology, grammar, and literacy. Additional findings in FOXP2-SLD can include oral-motor dyspraxia (difficulty planning or programming oral movements on command); dysarthria; moderate-to-severe receptive and expressive language disorder; reading and spelling impairments; and fine motor difficulties. Nonverbal (performance) IQ is typically relatively preserved compared to verbal IQ; gross motor skills are normal. Autistic features or a diagnosis of autism spectrum disorder have been reported in some individuals.

Diagnosis/testing.

The diagnosis of FOXP2-SLD is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in FOXP2 identified by molecular genetic testing.

Management.

Treatment of manifestations: There is no cure for FOXP2-SLD. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by speech-language pathologists (to individualize care, which may include use of nonverbal support or alternative means of communication), developmental pediatricians (to help guide parents through appropriate behavior management strategies and individualized education plans), occupational therapists (to address fine motor impairments), and mental health specialists (to address issues such as anxiety and depression, which can occur).

Surveillance: To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended: follow-up evaluations with standardized tests by a speech-language pathologist; review of educational progress/needs; review of mental health if anxiety and/or depression have been issues or have emerged as issues.

Genetic counseling.

FOXP2-SLD is inherited in an autosomal dominant manner. About half of individuals diagnosed with FOXP2-SLD have the disorder as the result of a de novo pathogenic variant. If a parent of the proband has the FOXP2 pathogenic variant identified in the proband, the risk to sibs of inheriting the pathogenic variant is 50%. Once the FOXP2 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

FOXP2-SLD should be suspected in a child with the following clinical findings and family history.

Establishing the Diagnosis

The diagnosis of FOXP2-SLD is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in FOXP2 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous FOXP2 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel, single-gene testing) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires the clinician to determine which gene(s) are likely involved (see Option 1), whereas genomic testing may not (see Option 2).

Clinical Description

Available evidence to date suggests that FOXP2-related speech and language disorder (FOXP2-SLD) is caused by heterozygous FOXP2 pathogenic variants (including whole- or partial-gene deletions). FOXP2-SLD has a core phenotype: childhood apraxia of speech (CAS), a disorder of speech motor programming or planning that affects the production, sequencing, timing, and stress of sounds, and the accurate sequencing of speech sounds into syllables and syllables into words. In addition, CAS interferes nonselectively with multiple other aspects of language, including phonology, grammar, and literacy.

The interactions between these communication disorder subtypes are not well understood. Language and literacy difficulties may be influenced by or even result from CAS, or these phenotypes may actually be features of the same broad communication disorder.

Additional findings in FOXP2-SLD can include oral-motor dyspraxia (difficulty planning or programming oral movements on command); dysarthria (a neuromuscular-based speech disorder that may affect nasal resonance, voice quality, prosody, and breath support for speech); moderate-to-severe receptive and expressive language disorder; reading and spelling impairments; and fine motor difficulties. "Autistic features" or a diagnosis of autism spectrum disorder have been reported in a quarter of affected individuals. Typically mild dysmorphology has been reported in a few individuals.

In FOXP2-SLD nonverbal IQ (performance) is typically relatively preserved compared to verbal IQ; gross motor skills are delayed or impaired in the early years of development.

Sleep issues are present in some.

To date, FOXP2-SLD has been described in approximately 30 families (see Supplementary Table 1 in Morison et al [2022] for a summary of all reported families). The following description is based on the findings in these families.

Childhood apraxia of speech. First words typically appear between ages 18 months and seven years in children with FOXP2-SLD [Vargha-Khadem et al 1995, MacDermot et al 2005, Laffin et al 2012, Reuter et al 2017, Morison et al 2022]. FOXP2-SLD is typically diagnosed around age three to four years, but may be considered earlier when the family history is positive.

In the first decade of life, speech is highly unintelligible, even to close friends and family. Although speech development and intelligibility improve over time, speech never develops to the same level as age-matched peers, and intelligibility may remain reduced in adulthood [Morison et al 2022]. In contrast, for typically developing children, speech sound acquisition is mastered by around age eight years [Dodd et al 2003], with intelligibility as high as 97% as early as age three years [Flipsen 2006].

Although CAS comprises certain core features, it is important to note that the severity and features of CAS change across the life span [Royal College of Speech and Language Therapists 2011], and while referred to as "core" features, they are not necessarily present in all individuals with CAS [American Speech-Language-Hearing Association 2007]. Core features, agreed upon by a consensus panel, include the following:

• Inconsistent speech errors (e.g., producing the same syllable or word differently across repetitions of the same word, such as "ubella," "umbrella," and "umbarella" for umbrella)
• Lengthened and disrupted coarticulatory transitions (e.g., oral groping behaviors during speech; difficulty sequencing phonemes and syllables; difficulty maintaining syllable integrity; hypernasality, thought to be due to incoordination of the velum for denoting oral-nasal contrasts; slowed and disrupted diadochokinetic sequences, e.g., when asked to repeat "pa-ta-ka")
• Inappropriate prosody (e.g., lexical stress errors, equal stress across words giving a robotic-sounding presentation)

In addition, children with CAS tend to lag behind their peers in acquiring the sounds of their language system; hence, their phonetic inventory may be reduced for the child's age. Children with CAS may use a more restricted range of consonants and vowels than age-matched peers. For example, they will simplify syllable shapes, reducing a consonant-consonant-vowel (CCV) shape (e.g., "sta") or a consonant-consonant-consonant-vowel (CCCV) shape ("stra") to a consonant-vowel (CV) shape ("sa").

Although CAS is distinct from other speech disorders (e.g., stuttering, phonologic disorder) and language disorders (e.g., developmental language disorder), these additional diagnoses can co-occur with CAS [Morison et al 2022].

Additional common speech- and language-related comorbidities in FOXP2-SLD can include the following, irrespective of underlying genetic alteration:

• Oral-motor dyspraxia, an inability or difficulty in planning or programming of oral movements on command, including single movements in isolation (e.g., commands such as "blow," "bite," "stick out your tongue") or sequences of oral movements (e.g., commands such as "bite and blow," "touch your bottom lip with your tongue and then blow a kiss"). Both oral dyspraxia [Vargha-Khadem et al 1998, Alcock et al 2000, Lai et al 2000, MacDermot et al 2005, Turner et al 2013] and more general oral-motor deficits (e.g., difficulty performing isolated tongue movements) have been reported in FOXP2-SLD [Morison et al 2022].
• Dysarthria is infrequent relative to CAS and phonologic errors [Morison et al 2022]. Typical dysarthric features include hypernasality, impaired laryngeal quality, and difficulties modulating pitch and loudness [Turner et al 2013, Morison et al 2022].
• Moderate-to-severe receptive and expressive language disorder [Vargha-Khadem et al 1995, Morison et al 2022]. Expressive language is usually poorer than receptive language, with expressive language likely confounded by the presence of CAS. Impaired performance across both semantic and syntactic language domains has been reported in FOXP2-SLD [Watkins et al 2002, Vargha-Khadem et al 2005, Turner et al 2013, Morison et al 2022]. Affected semantic domains include naming accuracy and lexical decision making; affected syntactic domains include past tense production for regular and irregular verbs.
• Reading and spelling impairments are typically evident once literacy develops [Vargha-Khadem et al 2005]. Difficulties with real word and nonword reading, spelling, and phonologic awareness skills are common in FOXP2-SLD [Watkins et al 2002, Turner et al 2013, Morison et al 2022].

Other features of FOXP2-SLD

• IQ. Generally stronger nonverbal (performance) IQ compared to verbal IQ [Vargha-Khadem et al 1995, Watkins et al 2002, Turner et al 2013, Reuter et al 2017, Morison et al 2022], although both verbal and nonverbal (performance) IQ may be impaired [Watkins et al 2002, Reuter et al 2017, Morison et al 2022].
• Fine or gross motor impairments are highly prevalent in the early years of life but typically improve and even resolve with physiotherapy and occupational therapy input. These motor impairments are relatively mild compared to the marked speech production deficits [Lai et al 2000, Morison et al 2022].
• Autism spectrum disorder or features of autism have been observed in about 25% of affected individuals [Reuter et al 2017, Morison et al 2022].
• Mental health. Some individuals report anxiety and depression, but it is not clear whether this is part of FOXP2-SLD or occurs secondary to the other communication and developmental challenges [Morison et al 2022].
• Mild physical features or dysmorphology have been reported in a small number of individuals, although no clear pattern has been identified [Morison et al 2022]. Physical features have included: high-arched palate; horizontal eyebrows; ear features (i.e., simply folded ears, prominent ears, anteverted ears); periorbital fullness; nasal features (i.e., upturned nose, prominent nose, hypoplastic alae nasi, high nasal root, rounded, fleshy, or prominent nasal tip); short/flat philtrum; prominent eyes; retrognathia; full lips or thin upper lip [Reuter et al 2017, Morison et al 2022]. In individual instances, mild finger pads, tapering fingers, single palmar crease, and clinodactyly were also noted [Morison et al 2022]. Submucous cleft palate was reported in one individual [Liégeois et al 2016].

Neuroimaging. Routine clinical brain MRIs of individuals with FOXP2-SLD typically appear normal on visual inspection [Vargha-Khadem et al 1998].

Genotype-Phenotype Correlations

The specific genetic alteration responsible for FOXP2-SLD does not predict clinical severity.

Of note, large copy number abnormalities and more complex variants (including deletions, translocations, and inversions) affecting one allele also lead to speech and language issues as well as other features similar to FOXP2-plus-related disorder (see Genetically Related Disorders).

Penetrance

The penetrance for FOXP2-SLD is high – close to 100% – based on the findings in individuals reported to date [Morison et al 2022].

Nomenclature

Prior to the discovery of causative pathogenic variants in FOXP2, the locus "speech language disorder-1 (SPCH1)" was assigned to the chromosome region linked to the CAS phenotype [Fisher et al 1998].

FOXP2-SLD may also be referred to as "FOXP2-only speech and language disorder" to distinguish the condition from FOXP2-plus-related disorder (a generally more severe phenotype associated with large copy number variants, structural variants, or maternal uniparental disomy of chromosome 7 involving FOXP2 and additional adjacent genes; see Genetically Related Disorders).

"Speech and language impairment" is a synonymous term for "speech and language disorder." The term "speech and language delay" should be avoided unless there is a clear clinical justification for use of this term, which implies a child will "catch up" to peers.

Prevalence

The population prevalence of CAS has not been determined by any epidemiologic study. The most commonly referenced estimate of prevalence is 1-2:1,000 [Shriberg et al 1997].

In a cohort with a severe speech disorder, one of 49 individuals had a confirmed FOXP2 pathogenic variant [MacDermot et al 2005].

Three recent studies performed molecular genetic testing on probands clinically diagnosed with CAS [Eising et al 2019, Hildebrand et al 2020, Kaspi et al 2022]. Within these three cohorts (total: 121 individuals), none of the probands had a pathogenic FOXP2 variant. Hence, pathogenic FOXP2 variants are rare, even in cohorts selected for CAS.

Evaluations Following Initial Diagnosis

To establish the extent of disease and management needs for an individual with FOXP2-SLD, the following evaluations conducted by a trained and specialized speech-language pathologist are recommended:

• Detailed developmental history including early oral-motor and feeding abilities, speech sound development, motor milestones, and cognitive development
• Family history of speech disorder
• Oral-facial structural examination to determine if any structural abnormalities are present
• Speech sound assessment including a test of single words, sounds in isolation, and connected speech to determine the child's phonetic inventory (i.e., has the child acquired age-appropriate speech sounds) and to determine if the child has phonologic errors, apraxic errors, dysfluency (stuttering), dysarthric errors, or a combination of these speech disorder diagnoses. The presence of resonance or nasality deficits signals the need to consider whether structurally based velopharyngeal port incompetence is present by referral to an ear, nose, and throat specialist and possibly videopalatography.
• Assessment of oral-motor function including:
  • Examination of facial asymmetry, reduced or increased oral-facial tone, and/or poor coordination of neuromuscular oral movements (e.g., "try to lick your nose with your tongue," "move your tongue quickly side to side," "blow a kiss" [lip protrusion], "smile" [lip retraction], etc.)
  • Examination for evidence of oral-motor dyspraxia (i.e., can the individual perform oral movements on command in isolation [e.g., "bite" or "blow"] or in sequence [e.g., "kiss and blow"; "kiss, blow, and bite"])
• Language assessment to determine the presence of receptive and/or expressive language impairments across the domains of semantics, syntax, and morphology
• Literacy assessment or preliteracy (phonologic awareness) for evidence of reading and spelling difficulties so that appropriate support can be arranged

Additional evaluations include the following:

• Referral to a neuropsychologist or clinical psychologist to determine the extent of any coexisting cognitive and learning impairments and to assess for the presence of behaviors associated with autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety, or depression
• Referral to a physical therapist if gross motor movement difficulties are reported and to an occupational therapist if fine motor movement difficulties are observed
• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of FOXP2-SLD to facilitate medical and personal decision making
• Assessment of the need for family support (see Resources and Parent to Parent)

Treatment of Manifestations

There is no cure for FOXP2-SLD.

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields.

Speech and language disorder. A speech-language pathologist will utilize treatments targeted to the specific findings in an affected individual; thus, a thorough initial assessment to establish the extent of the condition and management needs for an individual is important.

No single recommended treatment exists. The optimal approach should be determined based on the individual's presentation, but guidance on CAS therapies is as follows [American Speech-Language-Hearing Association 2007, Royal College of Speech and Language Therapists 2011, Murray et al 2014, Murray et al 2015, Morgan et al 2018].

• Consider evaluation for nonverbal support or alternative means of communication (e.g., augmentative and alternative communication [AAC]) for individuals with severe speech and expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication.
  AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.
• In terms of verbal development, difficulties with motor planning (apraxia) are severe in the early years of life, and intensive evidence-based motor speech therapies should be applied [Morgan et al 2018]. Early phonologic awareness tasks should be implemented to support speech and later literacy development. Therapies addressing both receptive and expressive semantics and grammar are also recommended. The optimal intervention will be tailored to the child's specific profile as it changes during development.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended:

• Routine care by a general pediatrician
• Follow-up evaluations with standardized tests by a speech-language pathologist
• Review educational progress/needs
• Review mental health if anxiety and/or depression have been issues or have emerged as issues

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic sibs of an affected individual by molecular genetic testing for the FOXP2 pathogenic variant in the family to identify as early as possible those who would benefit from prompt evaluation by a speech-language pathologist and initiation of treatment.

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. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

FOXP2-related speech and language disorder (FOXP2-SLD) is caused by a heterozygous pathogenic variant in FOXP2 and inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• About half of individuals diagnosed with FOXP2-SLD have the disorder as the result of a de novo pathogenic variant. In a cohort of 17 families with FOXP2-SLD, eight individuals represented simplex cases (i.e., the only affected family member) and had the disorder as the result of a de novo pathogenic variant [Morison et al 2022].
• About half of individuals diagnosed with FOXP2-SLD have an affected parent [Morison et al 2022].
• If the proband appears to be the only affected family member, 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 pathogenic variant identified in the proband is not identified in either parent 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 a proband depends on the genetic status of the proband's parents:

• If a parent of the proband has the FOXP2 pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• The penetrance of FOXP2-SLD in heterozygous family members approaches 100% [Morison et al 2022]. Although interfamilial variability is observed in FOXP2-SLD, minimal clinical variability is observed among affected family members [Morison et al 2022].
• If the FOXP2 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental mosaicism [Morison et al 2022].

Offspring of a proband. Each child of an individual with FOXP2-SLD has a 50% chance of inheriting the FOXP2 pathogenic variant.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

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 young adults who are affected or at risk of having a child with FOXP2-SLD.

Prenatal Testing and Preimplantation Genetic Testing

Once the FOXP2 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

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

FOXP2 encodes the Forkhead box protein P2, a transcription factor with zinc finger (residues 346 to 371) and DNA-binding (residues 504 to 594) functional domains. FOXP2 is thought to form homodimers (and heterodimers with FOXP1 or FOXP4) via a protein region that includes a leucine zipper and zinc finger. Forkhead box proteins are transcription factors that likely regulate hundreds of downstream target genes, some of which will be critical for development of speech and language. FOXP2 pathogenic missense variants, including those that disrupt the DNA-binding domain (e.g., p.Arg553His [Vernes et al 2006]), produce abnormal gene products that cannot bind DNA targets properly, as shown by functional studies of some variants that cause FOXP2-related speech and language disorder [Deriziotis et al 2014, Estruch et al 2018, Hickey et al 2019, den Hoed et al 2021].

Other pathogenic missense variants may be associated with dominant-negative effects, which to date have not been demonstrated in published reports.

Mechanism of disease causation. Loss of function, haploinsufficiency

FOXP2-specific laboratory technical considerations. Missense variants that directly affect the DNA-binding domain are likely to be pathogenic, while missense variants outside this domain are unlikely to be pathogenic.

Author Notes

Angela T Morgan is a speech pathologist with more than 25 years of experience in speech phenotyping in genetic conditions. She works closely with the coauthors of this review both in identifying genes that cause severe speech disorder and in characterizing speech and language in known genetic conditions.

• University of Melbourne profile
• Murdoch Children's Research Institute profile and publications

Prof Morgan ([email protected]) is actively involved in clinical research regarding individuals with speech disorder. She would be happy to communicate with persons who have any questions regarding diagnosis of genetic conditions related to severe speech presentations.

Prof Morgan ([email protected]) is also interested in hearing from clinicians treating families affected by severe speech disorder or speech apraxia in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Contact Dr Simon Fisher ([email protected]) to inquire about review of FOXP2 variants of uncertain significance.

Acknowledgments

Thank you sincerely to the families who have taken part in our research. Thank you to Dr Christiane Zweier and Prof Faraneh Vargha-Khadem for past collaborative work in phenotyping individuals with FOXP2-related speech and language disorder. AM, IS, MH, and SF received funding from the National Health and Medical Research Council Centre of Research Excellence (APP1116976).

Revision History

• 26 January 2023 (bp) Comprehensive update posted live
• 2 February 2017 (am) Revision: based on Reuter et al [2017]
• 23 June 2016 (bp) Review posted live
• 4 August 2015 (am, msh) Original submission

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