Page 154 - Read Online

Guerra et al. J Transl Genet Genom 2019;3:9. I https://doi.org/10.20517/jtgg.2018.03 Page 21 of 31

is unknown. In one study, transcripts of one allele from MRLP19 and C2ORF3 decreased in individuals
carrying risk haplotypes in the adjacent region suggesting that a mutation unknown in the SNP association
region might affect the expression of both genes [158] . TTRAP (6p22.3), required in magnesium ion binding
[99]
and DNA binding and repair , and ROBO2 (3p12.3) are other genes potentially involved in DL. ROBO2 is
[160]
implicated in the guidance of axon and tumor molecular signaling and necrosis factor [98,159] . Landi et al.
found a COMT Val/Met polymorphism (rs4680) associated with reading skills. Other relevant genes are
CMIP, MC5R, DYM, NEDD4L and DGK1 [161,154] .

Other suggested associations reported by Eicher et al. [162] were dopaminergic genes related to ANKK1 and
DRD2, and nicotinic genes related to CHRNA3 and BDNF with case-control status and articulation. DRD2
has demonstrated its role in vocabulary alterations and a direct association with dyslexia [163,164] . ASPM is
another gene whose alterations involve dysfunctions in vocabulary and reading, and AVPR1A with them
and phonological memory [163] . These results support previous reports involving dopaminergic and nicotinic
neural signaling in human communication and cognitive development.

Several CNV studies identified genes involved in dyslexia. Thus, the interruption of a gene involved in
learning, cognition, and memory through dendritic spinal synaptic plasticity, the PCDH11X protocadherin
gene (by duplication or elimination of the gene) located in Xp21.3, could be caused by unequal recombination
between the X transposed region (XTR) of Yp11.2 and the X chromosome [165] . The same authors in a
subsequent report with similar methods identified rearrangements at 17q21.31, with KIAA1267, LRRC37A,
ARL17A/B, NSFP1, and NSF as candidate genes. Some of these genes seem to play a role in membrane fusion
and synaptic transmission [166] . A further study searching for another large group of genes including, among
others, CHRNA7, Corf22, IMMP2L and CNTNAP2 found no substantial proportion of variance in DL [167] .

OTHER COMPLEX GENETIC DISORDERS WITH SPEECH AND LANGUAGE IMPAIRMENTS
As observed in dysarthria, there are multiple disorders that can be associated with speech and language
impairments. Several genetic syndromes such as Worster-Drought or Flotaing-Harbor are characterized
[85]
by alterations in verbal communication . In this section of the review we will focus on some of the most
prevalent genetic syndromes.

Autism-spectrum disorders
The great clinical heterogeneity of ASD implies variability in the phenotypic characteristics of language and
speech. ASD has comorbid phenogenotypes, such as ADHD [168,169] . Therefore, there may be alterations in
the comprehension, dyspraxia or motor alterations [170] . The inversion of the pronoun, echolalia and a delay
in understanding the reduced or even inverted production are the most frequent language alterations [171] .
Because of this complexity, this review will focus on the major known genes directly associated with oral
comunication disorders.

The sushi domain protein SRPX2 is a FOXP2 target [172] . Historically, it has been primarily studied as a
complement cascade regulator in the innate immune system. SRPX2 is involved in neural development
and migration. It encodes a protein that regulates synapse formation and ultrasonic vocalization in mice.
SRPX2 mutations in humans have been linked to SLD, such as apraxia of speech in cases with rolandic
seizures. The Sprx2 knockout mouse shows a decrease in VGlut2 synapse density in the IV layer of the
somatosensory cortex, and a reduction of VGlut1, VGlut2 and VGAT synapse densities in the CA2 region
of the hippocampus. Srpx2 KO mice show an abnormal ultrasonic vocalization ontogenetic profile [173] .
Interestingly, Srpx2 KO mice show a reduced preference for social novelty, which may prove a relationship
between SRPX2 and autism-related behaviors [174] .