Foxp2-Related Speech And Language Disorders

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:

• A large non-recurrent contiguous gene deletion that includes FOXP2 (52% of affected individuals)
• A sequence variant within FOXP2 (~29%)
• Maternal uniparental disomy of chromosome 7 (UPD7) that reduces FOXP2 expression (~11%)
• A structural variant (e.g., chromosome translocation, inversion) that disrupts FOXP2 (~8%)

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

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):

• A large non-recurrent contiguous gene deletion that includes FOXP2 (52% of affected individuals)
• A sequence variant within FOXP2 (~29%)
• Maternal uniparental disomy of chromosome 7 (UPD7) that reduces FOXP2 expression (~11%)
• A structural variant (e.g., translocation, inversion) that disrupts FOXP2 (~8%).

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 are likely to change 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 is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) 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 Silver-Russell 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.

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

• Oral motor deficits commonly reported [Lennon et al 2007, Zilina et al 2012, Laffin et al 2012]
• "Global" developmental delay (presumably involving speech, cognitive, gross, and fine motor abilities) [Feuk et al 2006]
• Autism spectrum disorder (ASD) [Feuk et al 2006, Zilina et al 2012] or presence of features of ASD such as repetitive behaviors and unusual interests [Zeesman et al 2006]. Of note, many individuals with FOXP2-only-related disorders are explicitly stated not to meet diagnostic criteria for ASD [Feuk et al 2006, Lennon et al 2007, Rice et al 2012], suggesting that these features may relate to disruption of neighboring genes on chromosome 7.
• Facial dysmorphology [Zeesman et al 2006, Lennon et al 2007, Zilina et al 2012, Reuter et al 2017]. Oral structures are typically intact in the absence of a cleft lip or palate, but a high arched palate has been reported in one individual [Palka et al 2012].

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).