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disorders with a wide phenotypic expression [79,81] . FOXP2 acts as a repressor transcription factor that
[81]
can form heterodimers with FOXP1 . Its role in the development of speech and language is not entirely
defined [6,79] . A study identified 27 genes with differential regulation under human FOXP2 control. RT-
qPCR and western blot studies showed the differential regulation of 13 additional target genes in response
[82]
to human over-expression of FOXP2 . The functional deficiency of FOXP2 affects both expressive and
[7]
receptive language with a central characteristic of the abnormal articulation . Its function at central
nervous system has been proven by neuroimaging studies and animal models, participating in cell signaling
and communication, metabolism, migration, differentiation, and expression regulation [82,83] .

Neuroimaging studies in humans have shown that mutations in FOXP2 show alterations in grey matter
in various regions of the cerebral motor cortex associated with speech, such as the superior temporal and
inferior frontal gyrus. FOXP2 is highly expressed in the dorsal striatum during human development. The
mutation of this gene seriously alters this anatomical structure, altering the production and learning of
[1]
speech. In the cerebellum, FOXP2 expression is mainly affected in Purkinje cells . In addition, patients with
intragenic FOXP2 deletions demonstrate a reduction in volume and activation in caudate nucleus, globus
[84]
palidus, thalamus and hippocampus by repeating nonsense words .
Regarding animal models, Foxp2 appears in medium spiny neurons of the mouse dorsal striatum. These
neurons are required for the regulation of the glutamatergic signal in the cortex and the dopaminergic
inputs in the midbrain, in addition to controlling motor behaviors. In Foxp2 heterozygous mice, synaptic
corticostriatal plasticity decreases and extracellular dopamine levels increases in the striatum. They also
[1]
exhibit cerebellar alterations .
Clinically, the risk of developing SLD associated with FOXP2 among siblings depends on the genetic
disorder. Thus, contiguous non-recurring genetic deletions (80% de novo mutations, 20% autosomal
dominant inheritance), FOXP2 sequence variants (70% de novo mutations, 30% autosomal dominant
inheritance) or maternal uniparental disomy 7, with no increased risk for siblings are the acquisition
patterns of FOXP2 mutations. Because large, non-recurring deletions that include FOXP2 and flanking DNA
cause approximately 52% of the SLD related to FOXP2, chromosomal microarray analysis is the first genetic
test recommended. Other tests to consider are whole exome sequencing (WES), whole genome sequencing
[85]
(WGS) and karyotype . Some genetic alterations detected in this case are missense mutations and
[81]
intragenic deletions . In the karyotype screening, a balanced translocation or pericentromeric inversion
[85]
involves 7q31.1 in almost 8% of FOXP2-plus and FOXP2-plus-related disorders alone . Patients usually
[81]
present mild cognitive impairment .
FOXP1
Another relevant gene that participates in brain development with CAS background is FOXP1. The role of
FOXP1 (locus 3p14) in the brain is not clear. However, some reports suggest that it may play a role in the
diversification of motor neurons, through their interactions with Hox proteins, in neuronal migration, by
[81]
activating Reelin signaling pathways, and in neuronal differentiation, through regulating Pitx3 protein .
FOXP1 mutations relate to mental retardation with apraxia of speech and language alterations [86,87] . The
phenotypic expression is variable. FOXP1, unlike FOXP2, contributes more significantly to global cognitive
[7]
impairments that include the most severely affected expressive language .

Foxp1 is one of several genes expressed in the mouse striatum. Deletions encompassing FOXP1 have been
found in autistic patients with severe phenotype. Haploinsufficiency of FOXP1 may be directly implicated
in the disorder by deregulation of FOXP2. Relevant Foxp1 haploinsufficiency produces altered vocal
communication, deregulation of the Foxp2 target genes in the striatum and changes in excitability of the
[1]
medium spiny neurons .