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Page 22 of 31 Guerra et al. J Transl Genet Genom 2019;3:9. I https://doi.org/10.20517/jtgg.2018.03

MED13L is implicated in neural crest induction and is highly expressed in the cerebellum after birth [175] .
MED13L relates functionally to EP300 and CREBBP products, link proteins between the FOXP2 and ROBO1
[177]
pathway [176] . In a case-report described by Jimenez-Romero et al. a SNP was identified in MED13L (chr12:
116675396A> G, G, GRCh37), which associates with a profound language disturbance in the expressive
domain, cognitive retardation, behavioral disturbances and an autism-like phenotype.

Regarding other genes potentially associated, locus 16p11.2, previously described in DLD, has previously
demonstrated a relationship with ASD [112] . Bartlett et al. [178] identified two loci related to DLD and ASD
(15q25.1 and 16p12.3). The two link signals showed specificity by alterations of oral language for 15q and by
deterioration of written language for 16p. These results show a subset of individuals with reading problems
that do not have a comorbid oral language deficit. Also, high FOXP1 expression may contribute to the
[85]
pathogenesis of ASD . In a study conducted by Chien et al. [179] showed a significant increase in FOXP1
mRNA levels in patients with ASD compared to the control group. Other genes that involve SLD and autism
have yielded conflicting results. The association of CNTNAP2 has been reported. In the Chinese Han
population, susceptibility to autism showed that a common non-coding variant (rs10500171) was related
to increased risk, and T-A (rs7794745- rs10500171) and A-T-A (rs10244837- rs7794745- rs10500171) haplotypes
also showed evidence of association [180] . These variants are involved in several neurological functions; for
instance rs7794745 has a relevant role in audio-visual speech perception, voice-specific brain function and
it is associated with reduced grey matter volume in left superior occipital gyrus [115] . A Spanish case-control
association study did not find those common variants of FOXP2 that contributed to the susceptibility
of autism, which is consistent with previous reports [181,182] . Moreover, the association of two CNTNAP2
SNPs (rs2710102 and rs7794745) with autism was not replicated in futher studies, although their potential
implications in brain connectivity [115,182] . Purkinje-cell Tsc1 mutant mice show behaviors relevant to ASD,
including changes in vocalizations [183] . MET gene is selectively expressed in brain structures involved in
higher levels of not only language skills, but also social, cognitive and executive functions [184,185] . Other
reported genes that involves communication impairments and ASD are CTTNBP2 [186] , EN2 [187] , NBEA [188] ,
HRAS [189] , and PTEN [190] . Other genes involved in language skills contribute to communication traits
in children with ASD. Eicher et al. [191] examined the association of genes previously implicated in SLD
in children with ASD, finding associations with ATP2C2 and MRPL19 genes. Other genes suggestively
associated were CMIP, GCFC2, KIAA0319L, the DYX2 locus and DRD2. It is also possible that somatic
mutations affecting a subset of neurons may cause language deficits in ASD [192,193] .

Other syndromes that associate with speech and language disorders
Patients with Down syndrome (trisomy 21) have a more altered expressive than receptive language [194] .
Children tend to have altered syllable structure, group reduction, and final consonant elimination.
Prevalence of stuttering is also higher [195] . As they grow up, language has shorter and less complex
statements. In senescence, SLD overlap with the increased risk of dementia [194] .

Fragile X syndrome (FXS) is the main inherited cause of intellectual disability, accounting for 40% of all
X-linked mental retardation. The syndrome results from a mutation in the FMR1 gene, which locates on the
X chromosome (Xq27.3). The mutation induces an expansion of CGG triplet repetition within FMR1. FMR1
[196]
encodes fragile X mental retardation protein (FMRP) . In songbirds, FMRP expresses in the HVC, LMAN,
[11]
RA, and area X . FMRP enriches in male RA from the beginning of the sensorimotor learning phase.
Autism is a common comorbid condition in people with FXS, modifying the phenotypic characteristics
of the subject. A characteristic communicative alteration in FXS patients is a repetitive language. Other
alterations implicate delay progress of vocabulary, comprehension, and syntax. FXS patients have significant
weaknesses in pragmatics. Their ability to recognize and provide the necessary informative details in
language discourse affects more than expected their levels of cognitive development [197] .