NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

FOXP2-Related Speech and Language Disorders

, BSpPath (Aud Hons), PhD, , DPhil, , MBBS, PhD, FRACP, FAA, and , PhD.

Author Information

Initial Posting: ; Last Revision: February 2, 2017.

Estimated reading time: 29 minutes

Summary

Clinical characteristics.

All FOXP2-related speech and language disorders, regardless of the underlying genetic alteration, have 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, syllables, and words. All individuals with CAS – whether caused by an alteration of FOXP2 or of an unknown cause – have difficulties in automatically and accurately sequencing speech sounds into syllables, syllables into words, and words into sentences with the correct prosody. Additional findings in FOXP2-related speech and language disorders 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; and reading and spelling impairments.

The underlying genetic cause of FOXP2-related speech and language disorders is either disruption of FOXP2 only (referred to in this GeneReview as FOXP2-only-related speech and language disorder) or large copy number variants (i.e., contiguous gene deletions), structural variants (i.e., chromosome translocation or inversion), or maternal uniparental disomy of chromosome 7 (UPD7) involving FOXP2 (here referred to as FOXP2-plus speech and language disorders). The genetic alteration determines if only speech and language problems are present (FOXP2-only-related speech and language disorder) or if more global developmental and behavioral issues are likely to be present as well (FOXP2-plus speech and language disorder). In FOXP2-only-related disorders, nonverbal (performance) IQ is typically more preserved compared to verbal IQ. Fine motor skills may be impaired (e.g., buttoning clothes, tying shoelaces), yet gross motor skills are normal. Autistic features and dysmorphic findings have been reported in a few affected individuals. In FOXP2-plus-related disorders oral motor deficits, global developmental delay, and autism spectrum disorder are common.

Diagnosis/testing.

The diagnosis of a FOXP2-related speech and language disorder is established in a proband by detection of one of the following:

Management.

Treatment of manifestations: Optimally management of the speech and/or language disorder is determined by a speech pathologist based on the individual's findings (typically: presence and severity of CAS, dysarthria, language deficits, and literacy impairments). A clinical psychologist or neuropsychologist may provide strategies to help manage deficits in specific cognitive domains and an occupational therapist and physiotherapist can provide strategies to help with fine and gross motor deficits, respectively.

Surveillance: Follow-up evaluations with standardized tests by a speech and language pathologist.

Evaluation of relatives at risk: Clarification of the genetic status of pre-symptomatic relatives at risk identifies as early as possible those who would benefit from prompt evaluation for speech and language disorders and initiation of treatment.

Genetic counseling.

Recurrence risk for sibs of proband with a FOXP2-related speech and language disorder depends on the genetic alteration:

Non-recurrent contiguous gene deletions (80% are de novo and the remainder are inherited in an autosomal dominant manner)

FOXP2 sequence variants (~70% are de novo and the remainder are inherited in an autosomal dominant manner)

Maternal UPD7 (no increased risk to sibs)

A structural variant (e.g., chromosome translocation, inversion. If one parent has a structural variant, the risk to sibs is increased and depends on the specific structural variant.)

Prenatal testing and preimplantation genetic diagnosis are possible if the causative genetic alteration has been identified in an affected family member.

GeneReview Scope

FOXP2-Related Speech and Language Disorders: Included Phenotypes
  • FOXP2-only-related disorders
  • FOXP2-plus-related disorders

For synonyms and outdated names see Nomenclature.

Diagnosis

Suggestive Findings

A FOXP2-related speech and language disorder should be suspected in a child with childhood apraxia of speech (CAS) [American Speech-Language-Hearing Association 2007] (also known as developmental verbal dyspraxia, verbal dyspraxia, or speech dyspraxia) and additional clinical findings.

CAS

  • Children with CAS have difficulties in automatically and accurately sequencing speech sounds into syllables, syllables into words, and words into sentences.
  • The diagnosis of CAS is made by assessment by a speech-language pathologist (also known as a speech and language therapist in the UK). CAS is challenging to diagnose in a child younger than age three years: speech development is delayed in these children, and thus key manifestations are typically not seen or able to be elicited until the child has acquired sufficient speech to complete the verbal assessment tasks.

Additional clinical findings

  • Delayed speech development
  • Poor oral motor function (e.g., excessive drooling, early feeding difficulties)
  • Oral motor difficulties and/or oral motor dyspraxia
  • Dysarthria
  • Receptive and expressive language impairment
  • Low average IQ, typically with poorer verbal IQ compared to nonverbal IQ (and average nonverbal IQ reported in some)
  • Mild dysmorphology may rarely be present
  • Autistic features may rarely be present
  • Reading and spelling impairment
  • Fine and gross motor impairment

Establishing the Diagnosis

The diagnosis of a FOXP2-related speech and language disorder is established in a proband by detection of ONE of the following (see Table 1):

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel or single-gene testing) and genomic testing (chromosomal microarray [CMA] and comprehensive genomic sequencing) depending on the phenotype.

Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing may not. Because the phenotype of FOXP2-related speech and language disorders is broad, children with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas a more severe phenotype that includes developmental delay (DD)/intellectual disability (ID) may be indistinguishable from many other inherited disorders with DD/ID and is more likely to be diagnosed using genomic testing (see Option 2).

Option 1. Gene-targeted testing. When the clinical findings suggest the diagnosis of a FOXP2-related speech and language disorder, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

  • Single-gene testing. Sequence analysis of FOXP2 is performed first, followed by gene-targeted deletion/duplication analysis.
  • A multigene panel that includes FOXP2 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel provides the best opportunity to identify the genetic cause of condition at the most reasonable cost while limiting secondary findings. However, because of the rarity of FOXP2-related speech and language disorders, many panels for inherited disorders with developmental delay/intellectual disability may not include this gene. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Methylation testing for maternal uniparental disomy (UPD) of chromosome 7 should be considered in individuals with verbal dyspraxia and features suggestive of Russell-Silver syndrome, since UPD accounted for about 12% of cases in one study [Feuk et al 2006].

Note: FOXP2 has not been demonstrated to be an imprinted gene. Although FOXP2 is located on chromosome 7, the mechanistic relationship between UPD7 and FOXP2 function has not been established.

Option 2. Genomic testing. When the phenotype is indistinguishable from many other inherited disorders with language delay and developmental delay/intellectual disability, molecular genetic testing approaches can include genomic testing (CMA, comprehensive genomic sequencing, and karyotype):

  • CMA should be the first genetic test as about 52% of FOXP2-related speech and language disorders are caused by large non-recurrent deletions that encompass FOXP2 and flanking DNA.
  • Further testing to consider:
    • Comprehensive genomic sequencing (when clinically available) includes exome sequencing and genome sequencing. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
    • Karyotype. An apparently balanced translocation or pericentromeric inversion involving 7q31.1, the FOXP2 locus, has been observed in about 8% of FOXP2-plus-related disorders and FOXP2-only-related disorders.
    Note: A multigene panel for inherited disorders of speech delay and developmental delay/intellectual disability may be considered.

Table 1.

Molecular Genetic Testing Used in FOXP2-Related Speech and Language Disorders

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
FOXP2-plusFOXP2-only
FOXP2CMA 3, 434/65 (52%) 5, 6NA
Sequence analysis 7NA19/65 (29%) 8
Methylation testing (to detect UPD)7/65 (~11%) 9NA
Karyotype (to detect structural variants)5/65 (~8%) 10NA
Gene-targeted deletion/duplication analysis 11Unknown
1.
2.

See Molecular Genetics and Table 3 for information on reported genetic alterations and phenotypes.

3.

Deletion/duplication analysis (genomic approach) detects deletion of FOXP2 and other contiguous genes using a chromosomal microarray (CMA) that specifically includes this gene/chromosome segment.

4.

ClinGen-19248. Standardized clinical annotation and interpretation for genomic variants from the Clinical Genome Resource (ClinGen) project (formerly the International Standards for Cytogenomic Arrays [ISCA] Consortium).

5.
6.

One affected individual had mosaicism for a large deletion [Palka et al 2012].

7.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice-site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

8.
9.
10.
11.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

Clinical Characteristics

Clinical Description

FOXP2-related speech and language disorders – regardless of the underlying genetic alteration – have 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, syllables, and words. Individuals with CAS (whether caused by an alteration of FOXP2 or of an unknown cause) have difficulties in automatically and accurately sequencing speech sounds into syllables, syllables into words, and words into sentences with the correct prosody. Additional findings in FOXP2-related speech disorders 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; more preserved non-verbal IQ compared to verbal IQ; and fine motor difficulties. "Autistic features" or a diagnosis of autism spectrum disorder (ASD) has been reported in some, but not all cases. Similarly typically mild dysmorphology has been reported in a few cases only.

The underlying genetic alteration of FOXP2-related speech and language disorders is one of the following:

  • Disruption of FOXP2 only – here referred to as FOXP2-only-related speech and language disorders
  • Large copy number variants (i.e., contiguous gene deletions) or structural variants (i.e., translocation or inversion) involving FOXP2 – here referred to as FOXP2-plus speech and language disorders

The genetic alteration determines if only speech and language problems are present (FOXP2-only-related speech and language disorder) or if more global developmental and behavioral issues are likely to be present as well (FOXP2-plus speech and language disorder).

In FOXP2-only-related disorders nonverbal (performance) IQ is typically relatively preserved compared to verbal IQ and gross motor skills are normal. In FOXP2-plus-related disorders oral motor deficits, global developmental delay, and autism spectrum disorders are commonly seen.

To date, available evidence suggests that heterozygous pathogenic variants in FOXP2 (including whole- or partial-gene deletions) cause the motor speech disorder known as childhood apraxia of speech (CAS) which interferes non-selectively with multiple 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.

Childhood apraxia of speech (CAS), a disorder of speech motor planning/programming, is the core phenotype of FOXP2-related speech and language disorders [Watkins et al 2002, Laffin et al 2012, Turner et al 2013].

CAS affects the production, sequencing, timing, and stress of sounds, syllables, and words [American Speech-Language-Hearing Association 2007]; thus, children with CAS have difficulties in automatically and accurately sequencing speech sounds into syllables, syllables into words, and words into sentences with appropriate prosody.

First words are reported to appear between ages 18 months and seven years in children with FOXP2-only-related disorders [Vargha-Khadem et al 1995, MacDermot et al 2005, Laffin et al 2012, Reuter et al 2017] and FOXP2-plus-related disorders [Feuk et al 2006, Zeesman et al 2006, Lennon et al 2007, Zilina et al 2012, Rice et al 2012]. FOXP2-related speech and language disorders are 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; intelligibility may remain reduced even in the third and fourth decades of life [Fee 1995, Shriberg et al 2006]. Note: The Fee [1995] study of members of the KE family was conducted prior to the identification of a causative FOXP2 heterozygous pathogenic variant in affected family members by Lai et al [2001].

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," "umbarella" for umbrella)
  • Lengthened and disrupted co-articulatory 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 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 shape (CCV) (e.g., "sta") or a 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., specific language impairment), these additional diagnoses can technically co-occur with CAS.

Additional common speech- and language-related comorbidities in FOXP2-related speech and language disorders 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 your top lip"). Oral dyspraxia has been more commonly reported than oral motor deficits per se in FOXP2-only-related disorders [Vargha-Khadem et al 1998, Alcock et al 2000, Lai et al 2000, MacDermot et al 2005, Turner et al 2013], in contrast to FOXP2-plus-related disorders [Zeesman et al 2006, Feuk et al 2006].
  • Dysarthria, which is typically classified as spastic [Shriberg et al 2006, Morgan et al 2010, Turner et al 2013]. Typical dysarthric features include hypernasality, impaired laryngeal quality, and difficulties modulating pitch and loudness.
  • Moderate to severe receptive and expressive language disorder [Vargha-Khadem et al 1995, Zeesman et al 2006, Tomblin et al 2009]. 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-related speech and language disorders [Watkins et al 2002, Vargha-Khadem et al 2005, Turner et al 2013]. 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, which are evident once literacy develops [Vargha-Khadem et al 2005]. Difficulties with real word and non-word reading, spelling, and phonologic awareness skills have been noted in some individuals with FOXP2-related speech and language disorders [Watkins et al 2002, Turner et al 2013]. Of note, the literacy skills of affected individuals have rarely been discussed in case reports and – given the link between speech and literacy disorders – deficits are likely to be underrecognized.

Other features of FOXP2-only-related disorders

  • 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] and compared to children with FOXP2-plus-related disorders [Tomblin et al 2009, Rice et al 2012]. Based on data from the largest family reported to date (which also has the most comprehensive IQ phenotyping available), it appears that in addition to lower verbal IQ (presumably affected by CAS and comorbid expressive language deficits), nonverbal (performance) IQ may also be lower than average in some areas (e.g., coding subtest; see Watkins et al [2002). Further, relative strengths in nonverbal IQ have been previously reported in block design and object assembly subtests of IQ measures [Watkins et al 2002], notably tasks relying on visual processing.
  • Normal fine and gross motor skills are seen in some affected individuals [Lai et al 2001, Watkins et al 2002, MacDermot et al 2005] but others with FOXP2-only disorders [Reuter et al 2017], or FOXP2-plus-related disorders [Rice et al 2012] have fine motor deficits. Fine or gross motor impairments are reported as relatively mild compared to the marked speech production deficits [Lai et al 2000]. Overall however, relatively little attention has been given in the literature to the possible presence of general motor deficits.
  • Some features of ASD have been observed and formal diagnoses of ASD have been made in a small number of recently reported individuals; however, the data suggest that these behavioral issues are not a core feature [Reuter et al 2017].
  • Mild dysmorphology reported in a small number of individuals, included high arch palate, horizontal eyebrows, simply folded ears [Reuter et al 2017] submucous cleft palate was reported in one individual [Liégeois et al 2016]

Other features of FOXP2-plus-related disorders

Neuroimaging

Clinical brain MRIs of individuals with a FOXP2-related speech and language disorder reportedly appear normal on visual inspection [Vargha-Khadem et al 1998].

In contrast, sophisticated quantitative MRI data acquisition and analysis techniques suggest that bilateral subcortical volume reductions are strong markers of FOXP2 disruption in childhood based on findings in (1) members of the KE family with the FOXP2 pathogenic variant p.Arg553His compared to unaffected family members [Vargha-Khadem et al 2005] and (2) one individual with the FOXP2 pathogenic variant Gln415ValfsTer5 [Turner et al 2013, Liégeois et al 2016]. Because data are limited further studies are required to understand the generalizability of this finding.

Click here (pdf) for detailed information on neuroimaging findings in the KE family, the first (and largest) family for which published imaging data are reported.

Genotype-Phenotype Correlations

The specific genetic alteration responsible for a FOXP2-related speech and language disorder does not predict clinical severity. However, the phenotype of FOXP2-plus-related disorders tends to be more severe overall (given the increased risk for the additional clinical features of global developmental delay and a formal diagnosis of autism spectrum disorder) compared to the phenotype of FOXP2-only-related disorders. See Table 3 for reported genetic alterations and phenotypes.

Penetrance

The penetrance for this severe speech and language disorder is high, close to 100% based on reported cases.

Nomenclature

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

Prevalence

The population prevalence of childhood apraxia of speech (CAS) has not been determined by any epidemiologic study. The most commonly referenced estimate of prevalence is 1-2:1000 population [Shriberg et al 1997]. Of note, no data are available to determine what proportion of CAS is caused by disruption of FOXP2 only or large copy number variants or structural variants involving FOXP2.

In a cohort with a severe speech disorder, one of 49 individuals had a confirmed FOXP2-related speech and language disorder, whereas a previously unreported FOXP2 variant of uncertain clinical significance was detected in two additional unrelated individuals [MacDermot et al 2005].

In an independent cohort with a CAS diagnosis, a previously unreported FOXP2 variant of uncertain clinical significance was detected in one of 24 individuals [Laffin et al 2012].

Of note, beyond these studies of CAS, other studies of cohorts with different disorders of speech and language development have not reported individuals with pathogenic FOXP2 coding variants (e.g., see Han et al [2014] for a study of developmental stuttering, Gauthier et al [2003] for a study of autistic disorder, and Newbury et al [2002] for a study of autism and specific language impairment).

Differential Diagnosis

The prelinguistic developmental history of children with childhood apraxia of speech (CAS) (e.g., restricted babbling or feeding difficulties) is very similar to that seen in other neurodevelopmental speech or language conditions (e.g., specific language impairment, phonologic disorder) or even other neurodevelopmental disorders in which language impairment may occur such as autism spectrum disorders (ASDs). Hence, early signs are not usually sufficiently discriminating to enable a differential diagnosis prior to a child gaining some speech production abilities.

The primary feature of the FOXP2-related speech and language disorders is CAS, a rare diagnosis. Other developmental speech and language disorders, such as stuttering and phonologic production disorder, are distinguishable on a speech and language assessment.

While CAS is rare, it may also be observed in a range of other conditions. The following may be considered in the differential diagnosis.

Unknown cause of CAS. Although the clinical manifestations and developmental history of children with CAS of unknown cause is almost indistinguishable from that of children with FOXP2-related CAS, speech prognosis appears poorer for individuals with FOXP2-related CAS. No studies have systematically compared the two populations.

Known causes of CAS. Disorders to consider in the differential diagnosis of FOXP2-related speech and language disorders are listed in Table 2. The clinical features of these disorders vary; most can be diagnosed by chromosomal microarray (CMA).

Table 2.

Disorders to Consider in the Differential Diagnosis of FOXP2-Related Speech and Language Disorders

Disease NameGene or Critical RegionMOICASOverlapping Clinical Features
(in addition to CAS)
Distinguishing Clinical Features
16p11.2 microdeletionAUTS14AD 1, 2+
  • Intellectual disability
  • Autism spectrum disorder
  • Developmental delay
  • Expressive language skills more severely impaired than receptive language
  • Epilepsy or recurrent seizures
  • Dysmorphic features (e.g., low-set ears, partial syndactyly)
7q11.23 duplication syndromeWBSCRAD3
  • Developmental delay
  • Appropriate nonverbal pragmatic abilities in socially comfortable situations
  • Oral apraxia
  • Phonologic disorder
  • Expressive language disorder
  • Hypotonia
  • Dysmorphic features (brachycephaly, broad forehead, straight eyebrows, broad nasal tip, low insertion of the columella, short philtrum, thin upper lip, minor ear anomalies, facial asymmetry)
  • Social anxiety
  • Developmental coordination disorder
  • In some:
  • Macrocephaly
  • Visually detectable MRI abnormalities (e.g., vermis hypoplastic, ventriculomegaly, vermis hypoplasia)
  • Signs of cerebellar dysfunction
KANSL1-related intellectual disability syndromeKANSL1AD 1+
  • Early oral motor and feeding difficulties
  • Developmental delay
  • Oral dyspraxia
  • Expressive language abilities better than receptive language
  • Literacy problems
  • Intellectual disability
  • Hypotonia
  • Dysmorphic features (elongated face, bulbous nasal tip)
  • Seizures
  • Visual and/or hearing deficits
  • Heart problems
GRIN2A-related disorders 4
OMIM
GRIN2AAD±
  • Oral dyspraxia
  • Dysarthria
  • Aphasia
  • Epilepsy
Worster-Drought syndrome 5
OMIM
AD
  • Cerebral palsy 6
  • Oral dyspraxia
  • Dysarthria
  • Mild fine and gross movement difficulties
  • Epilepsy
  • Moderate learning difficulties
  • Club feet
  • Restricted joint movement
Floating-Harbor syndrome 7SRCAPAD 17
  • Dysarthria
  • Hypernasality
  • Severe expressive & receptive language & literacy impairments
  • Short stature
  • Delayed bone age
  • Characteristic facies
  • Aggression in childhood
Galactosemia 8GALTAR9
  • Expressive/receptive language impairments
  • Typical or borderline-low IQ to more severe IQ depending on type of galactosemia 10
  • Dysarthria
  • Movement coordination disorder, primarily affecting balance & manual dexterity
  • Voice dysfunction
  • Liver function issues

CAS = childhood apraxia of speech

1.

Most pathogenic variants are de novo in the proband.

2.
3.
4.

Landau Kleffner syndrome and epilepsy-aphasia syndromes

5.
6.

Cerebral palsy may be associated with brain damage or malformation such as bilateral perisylvian polymicrogyria (excessive and small gyri).

7.
8.

The prevalence of motor speech disorder in this group is high; in one study ~25% of children had CAS [Shriberg et al 2011].

9.
10.

Individuals with the Gln188Arg/Gln188Arg genotype may be at increased risk for cognitive and language impairments.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and management needs for an individual with a FOXP2-related speech and language disorder, 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
  • Assessment of oral motor function including:
    • Examination of cranial nerve function for evidence of asymmetry, reduced or increased tone, and/or poor coordination of neuromuscular movements
    • Examination for evidence of oral motor dyspraxia (e.g., can the patient perform oral movements on command in isolation [e.g., "bite" or "blow"] or in sequence [e.g., "kiss and blow"; "kiss, blow, and bite"])
  • 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 articulation errors, phonologic errors, apraxic errors, dysarthric errors, or a combination of these errors. The presence of resonance or nasality deficits signals the need to consider whether such structurally based velopharyngeal port incompetence is present by referral to an ear, nose, and throat specialist and possibly videopalatography.
  • Language assessment to determine the presence of receptive and/or expressive language impairments across the domains of semantics, syntax, and morphology
  • Literacy assessment or pre-literacy (phonologic awareness) for evidence of reading and spelling difficulties
  • Social skills assessment for the presence of autistic features

Additional evaluations:

  • Referral to a neuropsychologist or clinical psychologist to determine the extent of any coexisting cognitive and learning impairments and to examine for the presence of behaviors associated with autism spectrum disorder
  • Referral to a physiotherapist if gross motor movement difficulties are reported and an occupational therapist if fine motor movement difficulties are observed
  • Consideration of MRI to evaluate for the presence of a neurologic lesion if indicated
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Speech and language deficits. A speech pathologist will utilize treatments targeted to the specific findings in an affected individual; hence, the importance of a thorough initial assessment to establish the extent of disease and management needs for an individual. No single recommended treatment exists.

The optimal approach should be determined based on the individual's findings regarding:

Cognitive deficits. A clinical psychologist or neuropsychologist may provide strategies to help manage deficits in specific cognitive or social skill domains.

Fine and gross motor deficits. An occupational therapist and physiotherapist can provide strategies to help with these issues.

Surveillance

The following are appropriate:

  • Routine care by a general pediatrician
  • Follow-up evaluations with standardized tests by a speech and language pathologist

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 of the FOXP2 genetic alteration in the family to identify as early as possible those who would benefit from prompt evaluation and initiation of treatment.

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

Therapies Under Investigation

A number of therapies for childhood apraxia of speech (CAS) are under investigation [Morgan & Vogel 2008, Murray et al 2014, Murray et al 2015].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Genetic counseling for a FOXP2-related speech and language disorders depends on the causative genetic alteration:

Risk to Family Members – Large Non-Recurrent Contiguous Gene Deletion including FOXP2

Parents of a proband

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

  • If the deletion found in the proband is not identified in one of the parents, the empiric recurrence risk to sibs is approximately 1% because of the theoretic possibility of parental germline mosaicism.
  • If one of the parents has the deletion identified in the proband, the risk to each sib of inheriting the deletion is 50%; however, it is not possible to reliably predict clinical severity in sibs who inherit the deletion.

Offspring of a proband have a 50% chance of inheriting the deletion; however, it is not possible to reliably predict clinical severity in offspring who inherit the deletion.

Risk to Family Members – Sequence Variant within FOXP2

Parents of a proband

  • 30% of individuals with a sequence variant within FOXP2 have an affected parent.
  • 70% of individuals with a FOXP2 sequence variant have a de novo variant.
  • Molecular genetic testing is recommended for the parents of a proband with a FOXP2 pathogenic variant to determine if the variant was inherited or is de novo in the proband.
  • If the FOXP2 pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo FOXP2 pathogenic variant in the proband or germline mosaicism in a parent.

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, the risk to the sibs of inheriting the variant is 50%.
    • If the FOXP2 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of parental germline mosaicism.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.

Offspring of a proband have a 50% chance of inheriting the FOXP2 sequence variant.

Risk to Family Members – Structural Variant

Parents of a proband

  • Evaluation of the parents by karyotyping that will detect the structural variant present in the proband is recommended.
  • The proportion of parents carrying a structural variant is not known.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the parents.
  • If one of the parents has the structural variant identified in the proband, the risk to sibs is increased and depends on the specific structural variant.

Offspring of a proband. Risk to offspring depends on the specific structural variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the FOXP2 genetic alteration, his or her family members may be at risk.

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.

Considerations when a proband represents an apparently simplex case. When neither parent of a proband with an autosomal dominant disorder has the genetic alteration identified in the proband, the genetic alteration is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal 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 a FOXP2-related speech and language disorder.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the genetic alteration causative of a FOXP2-related speech and language disorder has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis (PGD) are possible.

Note: While prenatal testing and PGD can be used to detect a familial genetic alteration associated with a FOXP2-plus-related disorder or a FOXP2-only-related disorder, severity of the phenotype cannot be predicted on the basis of test results.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

FOXP2-Related Speech and Language Disorders: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
FOXP27q31​.1Forkhead box protein P2FOXP2 databaseFOXP2FOXP2

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for FOXP2-Related Speech and Language Disorders (View All in OMIM)

602081SPEECH-LANGUAGE DISORDER 1; SPCH1
605317FORKHEAD BOX P2; FOXP2

Gene structure. Of the 18 FOXP2 transcripts reported on Ensembl, 13 are protein coding. The canonic transcript according to Ensembl (CCDS43635; NM_148898; NP_683696) is 6443 base pairs long, encodes 740 amino acids, and consists of 18 exons, 17 of which contain coding sequence.

The most commonly referenced isoform in the literature (CCDS5760; NM_014491; NP_055306) is 2638 base pairs long, encodes 715 amino acids, and consists of 17 exons, 16 of which contain coding sequence. Given its high expression in human tissues, this isoform is most frequently used for variant nomenclature.

Pathogenic variants. Pathogenic variants associated with FOXP2-related disorders and the reported phenotypes are summarized in Table 3.

Table 3.

FOXP2 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide Change
NM_014491
(NM_148898)
Protein Change
NP_055306
(NP_683696)
# CasesAgeSexEthnicitySpeechOromotorLanguage & LiteracyCognitionOther
Intragenic FOXP2 variants 1
c.50A>T
(50A>T)
p.Gln17Leu 2
(Gln17Leu)
1NRNRNorthern EuropeanCASNRNRNRNR
c.562_573ins12
(637_648ins12)
p.Gln188_Gln191dup 2
(Gln213_Gln216dup)
1NRNRNorthern EuropeanCASNRNRNRNR
c.982C>T
(1057C>T)
p.Arg328Ter 2
(Arg353Ter)
32y-4yM
2F
Northern EuropeanCAS, nonverbal, poor clarityOropharyngeal dyspraxiaImpaired expressive & receptive, simple grammarComprehension difficultiesMotor dyspraxia
c.982C>T
(1057C>T)
p.Arg328Ter
(Arg353Ter 3)
21: 14y; 2: 35y (Mo)M, FNR1: CAS, "slurred articulation"
2: History of stuttering, CAS, & learning difficulties
NR1: Severe receptive & expressive language deficit; spoke in simple sentences
2: NR
1: NVIQ low normal range at 8y; FSIQ borderline at 14y3m
2: NR
1: Friendly disposition; school for special needs; normal EEG; Morphology: high nasal root; pointed nasal tip, prominent incisors, an overbite, tapering fingers & broad feet
2: NR
c.1168_1169delCA
(1243_1244delCA)
p.Gln390Valfs
(Gln415Valfs 4)
18yMAustralianCASOral-motor apraxiaSeverely impaired expressive & receptiveBorderline IQNR
c.1432C>T
(1507C>T)
p.Arg478Ter
(Arg503Ter 3)
31: 4.5y; 2: 6.5y; 3: 36yF, 2MPhilippines1: NR
2: NR
3: Slurred articulation
NR1: "Mild delay," 3-word sentences at 4.5 y
2: "Severe delay," 5 words at 6.5 y
3: Limited development beyond 1st words at 7 y; speaks simple sentences; can "read & write well"
NR1: Delayed motor development: mildly backwards, rotated, relatively large ears w/uplifted earlobes & horizontal eyebrows;
2: Abnormal hair whorls, backwards rotated relatively large ears w/uplifted earlobes, horizontal eyebrows, wide intermammillary distance & fetal pads (fingers & toes);
3: Horizontal eyebrows & mildly uplifted earlobes; disability pension, lives w/parents.
c.1432C>T
(1507C>T)
p.Arg478Ter
(Arg503Ter 3)
16yFNRPersistent speech impairment 6yNRGood grades in German language class & written testsNRLimited auditory memory capacity; good at maths; ongoing speech & occupational therapies; narrow palpebral fissures, high arched palate, mild finger pads, EEG normal, audiometry normal; strabismus, hyperopia, astigmatism
c.1514C>T
(1589C>T)
p.Pro505Leu
(Pro530Leu 3)
21: 6.5y; 2: 40y2M1: German-Thai;
2: German
1: Mostly unintelligible
2: "Articulation disorder"; speech therapy ongoing
NR1: Impaired expressive & receptive
2: NR
1: Borderline IQ
2: Average IQ at age 29y
1: NR
2: Working as industrial mechanic.
c.1217T>C
(1292T>C)
p.Met406Thr 5
(Met431Thr)
4NR2F
2M
TurkishNRNRImpairedCognitive impairmentPolymicrogyria
c.1658G>A
(1733G>A)
p.Arg553His 6
(Arg578His)
153 genNREnglishCASOrofacial dyspraxiaImpaired expressive & receptiveBorderline IQNR
c.1607G>C
(1682G>C)
p.Arg536Pro
(Arg561Pro 3)
21: 10y10m;2: NR1F
1M
NRNRNR1: Impaired expressive & receptive
2: NR
1: Borderline IQ
2: NR
1: Friendly, some autisitic features (no formal diagnosis), mildly hypotonic.
2: NR
c.1614delT
(1689delT)
p.Phe538Leufs
(Phe563Leufs 3)
119yMNRPoor pronunciation, no fluent speech at 15y; stilted intonation, stuttering and reluctance to speak at 19yNRPoor expressive language at 15y
Better receptive language w/appropriate responses to questions at 15y
Able to read at write
NRASD diagnosis at 15y; mainstream school w/support; good at math & computers; morphology: small simply folded ears, prominent nose & chin w/large protruding tongue, myopia
c.1690C>T
(1765C>T)
p.Arg564Ter
(Arg589Ter 3)
19y11mMNRNRSeverely impaired expressive & receptiveASD diagnosis at 9y11m, mainstream school w/learning support; fine motor deficits; unusual coughing sounds like choking as young child; normal hearing, left exotropia.
c.1789A>C
(1864A>C)
p.Asn597His 7
(Asn622His)
17-9yNRNRCASOromotor difficultiesImpaired expressive & receptiveNADNR
Deletion exons 12-17 32 (monozygotic twins)11yFNR"Slurred articulation"NRSpeak in short sentences; reading & writing impairedFSIQ 1: 78; 2: 79
Verbal comp: 77; 67
Perceptual reasoning: 86; 88
Working memory: 82; 88
Processing speed: 88; 103
Friendly & shy; normal EEG, morphology: epicanthic folds, mildly upslanting palpebral fissures, prominent incisors, sandal gaps.
FOXP2 disruption by translocation
t(3;7)(q23;q31.2)Translocation 81NRNRNRCASOromotor difficultiesImpaired expressive & receptiveCognitive impairmentNR
t(5;7)(q22;q31.2)Translocation 6, 915yMNRVerbal dyspraxiaSevere orofacial dyspraxiaImpaired expressive & receptiveNormal nonverbal skillsNR
t(7;13)(q31.1;q13.2)Translocation 10, 11218-52y2FAmericanCAS; spastic dysarthriaNo orofacial apraxiaImpaired expressive & receptiveLow averageNR
FOXP2 and additional gene deletions
7q31
(2 Mb)
Upstream deletion 121NRFNRVerbal dyspraxiaNRNRNADDyslexia
7q31.1-q31.31
(8.3 Mb)
Deletion 1323-28y2FEstonianCASOromotor difficultiesPoor vocabularyModerate developmental delayAutistic features, eye disorder
7q31.1-q31.2
(6.5 Mb)
Deletion 1326y/NR2FEstonianCASNADPoor vocabularyModerate IDAggressive
7q31.1-q31.3
(14.8 Mb)
Deletion 14110yFItalianCASNRImpaired expressive & receptiveBorderline IQFine praxis & balance problems
7q31.1-q31.2
(1.57 Mb)
Deletion 1524-24yM/FAmericanCAS, dysarthriaGagging & droolingSeverely impairedLow average / borderline IQFine & gross motor planning difficulty, PDD-NOS
7q31.1-q31.2
(9.1 Mb)
Deletion 1617yMNRCASDrooling, low oral motor toneSeverely impaired expressive & receptiveModerate IDNR
7q31.1-q31.3
(16 Mb)
Deletion 1715yFItalianVerbal dyspraxiaOromotor dyspraxiaSeverely impaired expressive & receptiveBelow averageNR
7q31.1-q31.3
(11 Mb)
Deletion 81NRNRNRCASOromotor difficultiesImpaired expressive & receptiveCognitive impairmentASD
7q31.1-q31.3
(15 Mb)
Deletion 81NRNRNRCASOromotor difficultiesImpaired expressive & receptiveCognitive impairmentNR
7q31.1-q33
(30 Mb)
Deletion 81NRNRNRSevere dyspraxiaNRLanguage delayNRNR
7q31.1-q33
(30 Mb)
Deletion 81NRNRNRSevere dyspraxiaNRLanguage delayNRNR
7q31.2-q32
(13 Mb)
Deletion 81NRNRNRCASOromotor difficultiesImpaired expressive & receptiveCognitive impairmentNR
7q31.2-q32
(14 Mb)
Deletion 81NRNRNRSevere dyspraxiaNRLanguage delayNRNR
7q31.2-q32
(15 Mb)
Deletion 81NRNRNRCASOromotor difficultiesImpaired expressive & receptiveCognitive impairmentNR
7q31.2-q32
(26 Mb)
Deletion 81NRNRNRSevere dyspraxiaNRLanguage delayNRASD
7q22-q31.3
(15 Mb)
Deletion 81NRNRNRCASOromotor difficultiesImpaired expressive & receptiveCognitive impairmentNR
7q22-q31.33
(22 Mb)
Deletion 81NRNRNRSevere dyspraxiaNRLanguage delayNRNR
Other / Complex variants
7q31
(28 kb)
Pericentromeric inversion 18, 191NRFNRSubstitution, omission, mistiming of single articulations in a sequenceNRSpecific language impairmentNormal-low rangeImpulsive behavior, sleep disturbance, obsessive compulsive symptoms, auditory hallucinations (all ceased following medication)
UPD7Uniparental disomy 87NRNRNRCASOromotor dyspraxiaImpaired expressive & receptiveNRRussell-Silver syndrome

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

NR = not reported

Mo = mother

MZ = monozygotic

Gen = generation, mutation across three generations of the family

PDD-NOS = pervasive developmental disorder, not otherwise specified

1.

Reference sequences for two alternative isoforms: NM_014491​.3, NP_055306​.1 (Isoform I) & NM​_148898, NP​_683696 (Isoform II)

2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.

Normal gene product. The full-length FOXP2 protein assayed at the cellular level consists of 715 amino acid residues. The protein, Forkhead box protein P2, is a transcription factor with zinc finger (residues 346 to 371) and DNA binding (residues 504 to 594) functional domains (UniProt). 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.

Abnormal gene product. 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.

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

Partial reduction in FOXP2 protein due to large copy number and complex variants (including deletions, translocations, and inversions) affecting one allele also leads to the clinical features of FOXP2-related disorders (Table 3).

References

Literature Cited

  • Adegbola AA, Cox GF, Bradshaw EM, Hafler DA, Gimelbrant A, Chess A. Monoallelic expression of the human FOXP2 speech gene. Proc Natl Acad Sci U S A. 2015;112:6848–54. [PMC free article: PMC4460484] [PubMed: 25422445]
  • Alcock KJ, Passingham RE, Watkins KE, Vargha-Khadem F. Oral dyspraxia in inherited speech and language impairment and acquired dysphasia. Brain Lang. 2000;75:17–33. [PubMed: 11023636]
  • American Speech-Language-Hearing Association. Childhood apraxia of speech [Position Statement]. Available online. 2007. Accessed 3-22-17.
  • Becker M, Devanna P, Fisher SE, Vernes SC. A chromosomal rearrangement in a child with severe speech and language disorder separates FOXP2 from a functional enhancer. Mol Cytogenet. 2015;8:69. [PMC free article: PMC4546047] [PubMed: 26300977]
  • Clark M, Carr L, Reilly S, Neville BG. Worster-Drought syndrome, a mild tetraplegic perisylvian cerebral palsy. Review of 47 cases. Brain. 2000;123:2160–70. [PubMed: 11004132]
  • Dodd B, Holm A, Hua Z, Crosbie S. Phonological development: a normative study of British English-speaking children. Clin Linguist Phon. 2003;17:617–43. [PubMed: 14977026]
  • Fedorenko E, Morgan A, Murray E, Cardinaux A, Mei C, Tager-Flusberg H, Fisher SE, Kanwisher N. A highly penetrant form of childhood apraxia of speech due to deletion of 16p11.2. Eur J Hum Genet. 2016;24:310. [PMC free article: PMC4717201] [PubMed: 26763793]
  • Fee EJ. The phonological system of a specifically language-impaired population. Clin Linguist Phon. 1995;9:189–209. [PubMed: 21749311]
  • Feuk L, Kalervo A, Lipsanen-Nyman M, Skaug J, Nakabayashi K, Finucane B, Hartung D, Innes M, Kerem B, Nowaczyk MJ, Rivlin J, Roberts W, Senman L, Summers A, Szatmari P, Wong V, Vincent JB, Zeesman S, Osborne LR, Cardy JO, Kere J, Scherer SW, Hannula-Jouppi K. Absence of a paternally inherited FOXP2 gene in developmental verbal dyspraxia. Am J Hum Genet. 2006;79:965–72. [PMC free article: PMC1698557] [PubMed: 17033973]
  • Fisher SE, Vargha-Khadem F, Watkins KE, Monaco AP, Pembrey ME. Localisation of a gene implicated in a severe speech and language disorder. Nat Genet. 1998;18:168–70. [PubMed: 9462748]
  • Flipsen P. Measuring the intelligibility of conversational speech in children. Clin Linguist Phon. 2006;20:303–12. [PubMed: 16644588]
  • Gauthier J, Joober R, Mottron L, Laurent S, Fuchs M, De Kimpe V, Rouleau GA. Mutation screening of FOXP2 in individuals diagnosed with autistic disorder. Am J Med Genet A. 2003;118A:172–5. [PubMed: 12655497]
  • Han TU, Park J, Domingues CF, Moretti-Ferreira D, Paris E, Sainz E, Gutierrez J, Drayna D. A study of the role of the FOXP2 and CNTNAP2 genes in persistent developmental stuttering. Neurobiol Dis. 2014;69:23–31. [PMC free article: PMC4099264] [PubMed: 24807205]
  • Laffin JJ, Raca G, Jackson CA, Strand EA, Jakielski KJ, Shriberg LD. Novel candidate genes and regions for childhood apraxia of speech identified by array comparative genomic hybridization. Genet Med. 2012;14:928–36. [PMC free article: PMC3563158] [PubMed: 22766611]
  • Lai CS, Fisher SE, Hurst JA, Levy ER, Hodgson S, Fox M, Jeremiah S, Povey S, Jamison DC, Green ED, Vargha-Khadem F, Monaco AP. The SPCH1 region on human 7q31: genomic characterization of the critical interval and localization of translocations associated with speech and language disorder. Am J Hum Genet. 2000;67:357–68. [PMC free article: PMC1287211] [PubMed: 10880297]
  • Lai CS, Fisher SE, Hurst JA, Vargha-Khadem F, Monaco AP. A forkhead-domain gene is mutated in a severe speech and language disorder. Nature. 2001;413:519–23. [PubMed: 11586359]
  • Law J, Garrett Z, Nye C. Speech and language therapy interventions for children with primary speech and language delay or disorder. Cochrane Database Syst Rev. 2003;(3):CD004110. [PubMed: 12918003]
  • Lennon PA, Cooper ML, Peiffer DA, Gunderson KL, Patel A, Peters S, Cheung SW, Bacino CA. Deletion of 7q31.1 supports involvement of FOXP2 in language impairment: clinical report and review. Am J Med Genet A. 2007;143A:791–8. [PubMed: 17330859]
  • Liégeois FJ, Hildebrand MS, Bonthrone A, Turner SJ, Scheffer IE, Bahlo M, Connelly A, Morgan AT. Early neuroimaging markers of FOXP2 intragenic deletion. Sci Rep. 2016;6:35192. [PMC free article: PMC5062117] [PubMed: 27734906]
  • MacDermot KD, Bonora E, Sykes N, Coupe AM, Lai CS, Vernes SC, Vargha-Khadem F, McKenzie F, Smith RL, Monaco AP, Fisher SE. Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits. Am J Hum Genet. 2005;76:1074–80. [PMC free article: PMC1196445] [PubMed: 15877281]
  • Moralli D, Nudel R, Chan MT, Green CM, Volpi EV, Benítez-Burraco A, Newbury DF, García-Bellido P. Language impairment in a case of a complex chromosomal rearrangement with a breakpoint downstream of FOXP2. Mol Cytogenet. 2015;8:36. [PMC free article: PMC4460787] [PubMed: 26060509]
  • Morgan AT, Liégeois F, Vargha-Khadem F. Motor speech outcome as a function of the site of brain pathology: A developmental perspective. Chap 6. In: Maassen B, van Lieshout P, eds. Speech Motor Control: New Developments in Basic and Applied Research. Oxford, UK: Oxford University Press; 2010:95-115.
  • Morgan AT, Vogel AP. Intervention for childhood apraxia of speech. Cochrane Database Syst Rev. 2008;(3):CD006278. [PubMed: 18646142]
  • Murray E, McCabe P, Ballard KJ. A randomized controlled trial for children with childhood apraxia of speech comparing Rapid Syllable Transition treatment and the Nuffield Dyspraxia Programme -Third edition. J Speech Lang Hear Res. 2015; 58:669-86. [PubMed: 25807891]
  • Murray E, McCabe P, Ballard KJ. A systematic review of treatment outcomes for children with childhood apraxia of speech. Am J Speech Lang Pathol. 2014;23:486–504. [PubMed: 24686844]
  • Newbury DF, Bonora E, Lamb JA, Fisher SE, Lai CS, Baird G, Jannoun L, Slonims V, Stott CM, Merricks MJ, Bolton PF, Bailey AJ, Monaco AP, et al. FOXP2 is not a major susceptibility gene for autism or specific language impairment. Am J Hum Genet. 2002;70:1318–27. [PMC free article: PMC447606] [PubMed: 11894222]
  • Palka C, Alfonsi M, Mohn A, Cerbo R, Guanciali Franchi P, Fantasia D, Morizio E, Stuppia L, Calabrese G, Zori R, Chiarelli F, Palka G. Mosaic 7q31 deletion involving FOXP2 gene associated with language impairment. Pediatrics. 2012;129:e183–8. [PubMed: 22144704]
  • Pennington L, Miller N, Robson S. Speech therapy for children with dysarthria acquired before three years of age. Cochrane Database Syst Rev. 2009;(4):CD006937. [PubMed: 19821391]
  • Potter NL, Nievergelt Y, Shriberg LD. Motor and speech disorders in classic galactosemia. JIMD Rep. 2013;11:31–41. [PMC free article: PMC3755563] [PubMed: 23546812]
  • Rice GM, Raca G, Jakielski KJ, Laffin JJ, Iyama-Kurtycz CM, Hartley SL, Sprague RE, Heintzelman AT, Shriberg LD. Phenotype of FOXP2 haploinsufficiency in a mother and son. Am J Med Genet A. 2012;158A:174–81. [PMC free article: PMC3319495] [PubMed: 22106036]
  • Reuter MS, Riess A, Moog U, Briggs TA, Chandler KE, Rauch A, Stampfer M, Steindl K, Glaser D, Joset P, Study DDD, Krumbiegel M, Rabe H, Schulte-Mattler U, Bauer P, Beck-Wödl S, Kohlhase J, Reis A, Zweier C. FOXP2 variants in 14 individuals with developmental speech and language disorders broaden the mutational and clinical spectrum. J Med Genet. 2017;54:64–72. [PubMed: 27572252]
  • Roll P, Vernes SC, Bruneau N, Cillario J, Ponsole-Lenfant M, Massacrier A, Rudolf G, Khalife M, Hirsch E, Fisher SE, Szepetowski P. Molecular networks implicated in speech-related disorders: FOXP2 regulates the SRPX2/uPAR complex. Hum Mol Genet. 2010;19:4848–60. [PMC free article: PMC2989892] [PubMed: 20858596]
  • Royal College of Speech and Language Therapists. Policy statement on developmental verbal dyspraxia. Available online. 2011. Accessed 3-22-17.
  • Shriberg LD, Aram DM, Kwiatkowski J. Developmental apraxia of speech: I. Descriptive and theoretical perspectives. J Speech Lang Hear Res. 1997;40:273–85. [PubMed: 9130199]
  • Shriberg LD, Ballard KJ, Tomblin JB, Duffy JR, Odell KH, Williams CA. Speech, prosody, and voice characteristics of a mother and daughter with a 7;13 translocation affecting FOXP2. J Speech Lang Hear Res. 2006;49:500–25. [PubMed: 16787893]
  • Shriberg LD, Potter NL, Strand EA. Prevalence and phenotype of childhood apraxia of speech in youth with galactosemia. J Speech Lang Hear Res. 2011;54:487–519. [PMC free article: PMC3070858] [PubMed: 20966389]
  • Snowling MJ, Hulme C. Interventions for children's language and literacy difficulties. Int J Lang Commun Disord. 2012;47:27–34. [PMC free article: PMC3429860] [PubMed: 22268899]
  • Tomblin JB, O'Brien M, Shriberg LD, Williams C, Murray J, Patil S, Bjork J, Anderson S, Ballard K. Language features in a mother and daughter of a chromosome 7;13 translocation involving FOXP2. J Speech Lang Hear Res. 2009;52:1157–74. [PMC free article: PMC2760059] [PubMed: 19797137]
  • Turner SJ, Hildebrand MS, Block S, Damiano J, Fahey M, Reilly S, Bahlo M, Scheffer IE, Morgan AT. Small intragenic deletion in FOXP2 associated with childhood apraxia of speech and dysarthria. Am J Med Genet A. 2013;161A:2321–6. [PubMed: 23918746]
  • Vargha-Khadem F, Gadian DG, Copp A, Mishkin M. FOXP2 and the neuroanatomy of speech and language. Nat Rev Neurosci. 2005;6:131–8. [PubMed: 15685218]
  • Vargha-Khadem F, Watkins K, Alcock K, Fletcher P, Passingham R. Praxic and nonverbal cognitive deficits in a large family with a genetically transmitted speech and language disorder. Proc Natl Acad Sci U S A. 1995;92:930–3. [PMC free article: PMC42734] [PubMed: 7846081]
  • Vargha-Khadem F, Watkins KE, Price CJ, Ashburner J, Alcock KJ, Connelly A, Frackowiak RS, Friston KJ, Pembrey ME, Mishkin M, Gadian DG, Passingham RE. Neural basis of an inherited speech and language disorder. Proc Natl Acad Sci U S A. 1998;95:12695–700. [PMC free article: PMC22893] [PubMed: 9770548]
  • Velleman SL, Mervis CB. Children with 7q11.23 Duplication Syndrome: Speech, Language, Cognitive, and Behavioral Characteristics and their Implications for Intervention. Perspect Lang Learn Educ. 2011;18:108–116. [PMC free article: PMC3383616] [PubMed: 22754604]
  • Vernes SC, Nicod J, Elahi FM, Coventry JA, Kenny N, Coupe AM, Bird LE, Davies KE, Fisher SE. Functional genetic analysis of mutations implicated in a human speech and language disorder. Hum Mol Genet. 2006;15:3154–67. [PubMed: 16984964]
  • Watkins KE, Dronkers NF, Vargha-Khadem F. Behavioural analysis of an inherited speech and language disorder: comparison with acquired aphasia. Brain. 2002;125:452–64. [PubMed: 11872604]
  • White SM, Morgan A, Da Costa A, Lacombe D, Knight SJ, Houlston R, Whiteford ML, Newbury-Ecob RA, Hurst JA. The phenotype of Floating-Harbor syndrome in 10 patients. Am J Med Genet A. 2010;152A:821–9. [PubMed: 20358590]
  • Zeesman S, Nowaczyk MJ, Teshima I, Roberts W, Cardy JO, Brian J, Senman L, Feuk L, Osborne LR, Scherer SW. Speech and language impairment and oromotor dyspraxia due to deletion of 7q31 that involves FOXP2. Am J Med Genet A. 2006;140:509–14. [PubMed: 16470794]
  • Zilina O, Reimand T, Zjablovskaja P, Männik K, Männamaa M, Traat A, Puusepp-Benazzouz H, Kurg A, Ounap K. Maternally and paternally inherited deletion of 7q31 involving the FOXP2 gene in two families. Am J Med Genet A. 2012;158A:254–6. [PubMed: 22105961]

Chapter Notes

Revision History

  • 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
Copyright © 1993-2019, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2019 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK368474PMID: 27336128

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Gene

Related information

  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...