Page 149 - Read Online

Page 16 of 31 Guerra et al. J Transl Genet Genom 2019;3:9. I https://doi.org/10.20517/jtgg.2018.03

Other genes potentially associated with childhood apraxia of speech
There are multiple reports of diverse genes that in isolated form have been associated with CAS. We
[88]
highlight, by the variety of genes described and their technique, some of them. Peter et al. identified two
chromosome regions of interest (5p15.1-p14.1 and 17p13.1-q11.1) through copy number of variants (CNV)
and complete exome sequencing in two multigenerational families. The primary gene of interest was
CDH18, expressed primarily in the cerebellum. They described other genes with possible additive effects,
such as MYO10, which has high levels of gene expression in the basal ganglia and thalamus; NIPBL, which
is present in basal ganglia, the cerebellum and the corpus callosum; GLP2R, expressed in cortex and also
implicated in other language disorders, such as autism; NCOR1, present in basal ganglia and cerebellar
cortex; FLCN, present in dentate rotation and the cerebellar cortex and other genes with more dispersed
expression, especially in the cerebellum, such as SMCR8, NEK8 and ANKRD12. ANKRD12 is located in a
dyslexia candidate region, DYX6, at 18p11.22. Another gene of interest is C4orf21 (ZGRF1) at 4q25-q28.2.
ZGFR1 encodes a protein with similar functions related to motor praxis, highly expressed in the cerebellum.
A set of co-expressed regulatory genes in the human embryonic brain also relates to CAS. By analyzing
whole genome sequences of nineteen subjects, de novo mutations in CHD3, SETD1A and WDR5 and loss of
[89]
function mutations in SETBP1, KAT6A, TNRC6B, and ZFHX4 were characterized as pathogenic . Other
genes described were CNTNAP2 alone or associated with overlapping CAS phenotype disorders (ATP13A4,
[90]
CNTNAP1, KIAA0319, and SETX) . Rare mutations in ELKS/ERC1 suppressions, a member of the RIM-
[91]
binding protein family, have been reported . Surprisingly, in this case the ANKRD12 gene, among others,
[91]
were considered variants of uncertain significance . Through array comparative genomic hybridization
other candidate genes were identified in a multigenerational London pedigree, at locus 2p16, 5q22, 6p21,
[93]
[92]
13q21, 15q4, 16p13, 16q23.2, and 19 . Newbury et al. described dual copy number variants involving
16p11 (a region of genes involved in speech disorders already described such as SETD1A and FUS) and 6q22
in a CAS case-report with developmental disorder.

Other speech sound disorders
This section includes other speech disorders in which the patient has difficulties in the formation of
phonemes that interfere with verbal communication. It can cause articulation, phonemic or mixed
[94]
alterations . These conditions can also alter the literacy process by concurring with other language
disorders, such as dyslexia and developmental language disorder, to determine patients’ literacy skills, and
[95]
share genetic determinants .

In other speech sound disorders (SSD), several chromosomal alterations have been identified (chromosomes
[7]
1, 3, 6, 7, 8 and 15) . DCDC2 and KIAA0319 strongly correlate with phonological awareness, influencing
[97]
language and cognitive traits [82,96] . Nopola-Hemmi et al. analyzed a large Finnish family and found a link
with DYX5 (3p12-q13). Others reported involvement of DYX8 (1p36-34), whose role is unknown. CYP19A1
(15q21.2), implicated in the synthesis of lipids and hormones, has been associated with SSD and dyslexia [98,99] .
Some reports correlate DYX1C1 with SSD phenotypes. A ROBO1 linkage has been found to other SSD.
Additional candidate genes include ELP4, PAX6 and FOXP2 [100] .

GENOMICS OF LANGUAGE DISORDERS
Aphasia
Aphasia is an alteration in the understanding and/or production of language because of damage to specific
brain regions. Stroke is the most common cause of aphasia with alterations normally limited to the injured
area, although neurodegenerative diseases such as Alzheimer’s disease (AD) or primary progressive
aphasia (PPA) may also associate with more diffuse lesions. In these conditions, the genes involved in the
development of aphasia have been studied in a more in-depth perspective. In AD, cognitive impairment
extends beyond language and typically involves episodic memory, while in PPA affects gradually language
skills with acceptable retention of nonverbal skills and activities of daily living. The type of aphasia seen