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Guerra et al. J Transl Genet Genom 2019;3:9. I https://doi.org/10.20517/jtgg.2018.03 Page 7 of 31

ROBO1 Roundabout Guidance 3p12.3 SSD, DL, GWAS [100,140,157]
Receptor 1 ASD
ROBO2 Roundabout Guidance 3p12.3 DLD, DL GWAS - Vesicoureteral reflux 2 [127,131]
Receptor 2
SETBP1 SET Binding Protein 1 18q12.3 CAS, DLD WGS - Schinzel-Giedion [89]
midface retraction
syndrome
- Mental retardation,
autosomal dominant 29
SETD1A SET Domain 16p11.2 CAS WGS Newbury et al. [89]
Containing 1A found locus
SETX Sanataxin 9q34.12 CAS, DT WES Additive - Amyotrophic lateral [20,90]
effects sclerosis 4, juvenile
- Spinocerebellar ataxia,
autosomal recessive 1
SMCR8 Smith-Magenis 11p11.2 CAS WES Additive [88]
Syndrome effects
Chromosome Region,
Candidate 8
SRPX2 Sushi Repeat Xq22.1 ASD CG - Rolandic epilepsy, [173,174]
Containing Protein mental retardation, and
X-Linked 2 speech dyspraxia
TDP-43 TAR DNA Binding 1p36.22 AP CG [111]
Protein
TNRC6B Trinucleotide Repeat 22q13.1 CAS WGS [89]
Containing 6B
TTRAP Tyrosyl-DNA 6p22.3 DL GWAS - Spinocerebellar ataxia, [99,155]
Phosphodiesterase 2 autosomal recessive 23
WDR5 WD Repeat Domain 5 9q34.2 CAS WGS [89]
ZFHX4 Zinc Finger Homeobox 8q21.13 CAS WGS - Ptosis congenital [89]
4
ZGRF1 Zinc Finger GRF-Type 15q25.1 CAS WES Additive [88]
Containing 1 effects
ZNF385D Zinc Finger Protein 3p24.3 DLD GWAS [128]
385D

DT: dysarthria; CAS: childhood apraxia of speech; ST: stuttering; SSD: other speech sound disorders; AP: aphasia; DLD: developmental
language disorder; DL: dyslexia; ASD: autism spectrum disorder; CG: candidate gene; TM: targeted mapping; GWAS: genome-wide
association study; GWLA: genome-wide link association; WES: whole exome sequencing; WGS: whole genome sequencing
the main target of the antibodies (Abs). Other Abs may also modify the clinical expression of the disease,
[14]
such as Abs against muscle-specific tyrosine kinase (MusK) . A low percentage of genetic cases relate to
[15]
other immune disorders . Twin studies have shown that the concordance of MG is significantly higher in
monozygotic compared to dizygotic twins. Several HLAs have been identified (HLA-A1,B8,DR3 haplotype
for myasthenia gravis of early-onset and HLA-A3,B7,DR2 and HLA-DR4 for late-onset), as well as other non-
HLA genes, as functional polymorphisms in the promoter of IL-10, haplotypes with TPN22, CTLA-4, TNIP1
[14]
and FOXP3 [14,16] . MuSK Ab-positive patients may associate with HLA-DR14 and DQ5 .

Prominent bulbar symptoms with dysarthria are common in patients with ab-MusK. MusK is necessary
for neuromuscular synapses to organize post-synaptic differentiation, including the clustering of receptors
for the acetylcholine neurotransmitter. Anti-MusK autoantibodies are found in those seronegative
patients. Although losing acetylcholine receptor function produces an autoimmune alteration, phenotypic
particularities differentiate it from the classic MG. Thus, patients have a lower prevalence of ocular
manifestations and greater weakness of neck and oropharynx. It tends to affect women and African-
Americans to a greater degree [14,17] .

Other relevant conditions with flaccid dysarthria: Because amyotrophic lateral sclerosis (ALS) affects
both upper and lower motor neurons, the resulting dysarthria is mixed, (flaccid/spastic type). The initial
symptoms include an alteration in the pattern and rhythm of speech, until it evolves into an unintelligible
voice. As ALS progresses and dysarthria becomes severe, deep weakness resulting in reduced movement of
the speech musculature and a severe reduction in phonation become increasingly common. However, an