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Page 14 of 31 Guerra et al. J Transl Genet Genom 2019;3:9. I https://doi.org/10.20517/jtgg.2018.03

Stuttering
Stuttering is a speech disorder in which the flow of speech is interrupted by involuntary repetitions and
prolongations of sounds, syllables, words or phrases, as well as pauses or blockages in which the patient is
not able to make sounds. Numerous mechanisms explain the genesis of stuttering, with a strong genetic
correlation. In this review we will only cite those genes that are present in non-syndromic stuttering.
Around 9% of patients with a familiar background associates with the GNPTAB, GNPTG, and NAGPA
[68]
genes . The importance of these genes is based on replication in subsequent studies, confirming a key role
[69]
in stuttering . These genes may also be affected in mucolipidosis. Unlike mucolipidosis, the characteristics
of the mutations found in stuttering lie in their typically heterozygous character, with nonsense mutations, a
[68]
modest reduction of enzyme function and different mutation sites .
GNPTAB catalyzes the addition of mannose 6-phosphate label to hydrolytic enzymes, allowing lysosomal
configuration. The gene is located at locus 12q23.3 and encodes the enzyme N-acetylglucosamine-1-
phosphotransferase. It was the first gene implicated in stuttering, with non-sense mutations in several
[70]
families regarding inbreeding .

Through a systemic sequence of candidate genes, the GNPTG and NAGPA genes at 16p13 were identified in
isolated stuttering cases. Variants of two genes were almost exclusively non-sense amino acid substitutions.
GNPTG catalyzes the initial step in the synthesis of the mannose 6-phosphate (M6P) required for efficient
intracellular targeting of newly synthesized lysosomal hydrolases. It encodes a protein subunit that combines
with the product of the GNPTAB gene to form the functional phosphotransferase enzyme. NAGPA
catalyzes the second step in hydrolytic enzyme labeling for lysosomal orientation. It encodes the N-acetyl
glucosamine-1-phosphodiester alpha-N-acetylglucosaminidase enzyme. These two enzymes comprise a
simple two-step biochemical pathway, which serves to bind a remainder of mannose 6-phosphate that acts as
[68]
a signal to a diverse group of hydrolytic enzymes in lysosomes .
Another interesting gene is AP4E1, which encodes the adaptive protein complex 4, subunit epsilon 1. A
study in one Cameroonian family identified two cis mutations in the same haplotype [p.Val517Ile (c.G1549A)
and p.Glu801Lys (c.G2401A)]. The stuttering cases had many predicted loss of function variants in AP4E1,
including deletions, frame changes, nonsense, and splice site variants, while only nonsense substitutions
[68]
were observed in the controls. All the mutations in cases and controls were present in a single copy .

Other authors described association in additional chromosomal regions [71-73] . Using high density genotyping,
[74]
SLC6A3 and DRD2 were identified as other candidate genes in the Chinese Han population . FOXP2 and
[75]
CNTNAP2 variants do not seem to be involved in the genetics of familial persistent ST , although the
reports of some authors question this categorical assertion [7,76] .

Childhood apraxia of speech
Childhood apraxia of speech (CAS) is a neurological speech disorder that affects the accuracy and
consistency of the movements underlying speech. It may occur as a result of a known neurological
impairment, in association with complex neurobehavioral disorders of known or unknown origin, or as
[77]
an idiopathic neurogenic speech disorder . Although in most cases its etiology is unknown, a genetic
[5]
association has proven to be related to this disorder . Authors define a synonymical for adults, verbal
[78]
apraxia, albeit with particularities that differentiate it from CAS .
FOXP2
The FOXP2 gene (locus 7q31), part of the forkhead box family, was first described in the KE family (medical
name designated for a British family), which showed speech articulation disorders, cognitive deficit and
[79]
[80]
language delay . It is the first and one of the most studied genes involved in speech and language