Summary of core features
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. CAS manifests as difficulties 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.
- Reading and spelling impairments.
- More preserved non-verbal IQ compared to verbal IQ.
- Fine motor difficulties.
- “Autistic features” or a diagnosis of autism spectrum disorder (ASD) are reported in some, but not all cases.
- Mild dysmorphology has been reported in a few cases only, including a high arch palate, horizontal eyebrows, simply folded ears and a submucous cleft palate has been reported in one individual.
The type of genetic cause is currently thought to affect whether only speech and language problems are present, i.e., FOXP2-only-related speech and language disorder in cases of FOXP2 only variants, or if more global developmental and behavioral issues are likely to be present as well, i.e., FOXP2-plus speech and language disorder in cases with large CNVs, structural variants, large deletions encompassing genes outside of FOXP2, or maternal uniparental disomy of chromosome 7.
Neuroimaging
Clinical brain MRIs of individuals with a FOXP2-related speech and language disorder reportedly appear normal on visual inspection. In contrast, sophisticated quantitative MRI data acquisition and analysis techniques suggest that bilateral subcortical volume reductions may be markers of FOXP2 disruption in childhood based on findings in:
- members of the KE family with the FOXP2 pathogenic variant p.Arg553His compared to unaffected family members and
- one individual with the FOXP2 pathogenic variant Gln415ValfsTer5. Because data are limited further studies are required to understand the generalizability of this finding.
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.
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.