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Page 2 of 31 Guerra et al. J Transl Genet Genom 2019;3:9. I https://doi.org/10.20517/jtgg.2018.03

language. The arcuate fasciculus connects Wernicke’s to Broca’s area, in the inferior-posterior frontal lobe.
This area generates language and starts the muscular activity involved in speech. The second language
pathway drives through the angular and supramarginal gyrus, region located in the posterior parietal lobe,
[2]
and connects with Broca’s and Wernicke’s areas . Syntax-related networks are located in the opercular/
triangular parts of the left inferior frontal gyrus and lateral premotor cortex. The basal ganglia are involved
[3]
in prosodic modulation and language acquisition, and are responsible for language learning in adults .
Finally, the cerebellum is also required in the processing of expressive and receptive language, and writing
[4]
skills .

Sometimes, the causes of speech and language disorders (SLD) are acquired (due to stroke or trauma). The
characteristics will depend on the damaged nerve structures and the degree of involvement. However,
[5,6]
genetic factors involve various pathologies that may associate SLD [Table 1]. Genetic factors associated
with language contribute to various molecular, cellular and regulatory processes that shape neuronal
architecture through neuronal migration, axon guidance, brain network development including connectivity
[7]
and determine neurodevelopmental characteristics . The same gene may be linked to different disorders,
[6]
showing the great complexity of the speech and language process . Also, language disabilities in children
may appear along with other developmental diagnoses, such as intellectual impairments, hearing loss, and
syndromes such as autism spectrum disorders (ASD), Down’s and Fragile X syndromes. The construction
of a knowledge base for genetic etiology makes it possible to identify patients with genetic risk and motivate
[8]
early intervention programmes . In addition, it is mandatory to identify those epigenetic factors that
characterize language and speech [9,10] .

Because genomic knowledge of these disorders is limited, the aim of this review is to allow a rational
classification of the main causes of both early and late-onset speech and language disorders and characterize
their genomic and epigenetic background. Based on the definitions of each case, the genes involved in each
language and speech phenotype will be described. We will observe the complex network of genetic pathways
involving different disorders, and note how these disorders have important limitations due to lack of
replication or information. Finally, we will attempt to demonstrate briefly the importance of these disorders
as part of other more complex pathologies and how the knowledge of these genes may be useful as markers
of early diagnosis and prognosis.

GENOMICS OF SPEECH DISORDERS
Dysarthria
Dysarthria is a motor speech disorder that causes poor coordination of the articulation with pharyngeal,
laryngeal, lingual or facial muscle involvement. This condition is due to alterations that affect the cranial
nerves, neuromuscular, cerebellar, basal ganglia or cortical-bulbar tract diseases, while it preserves the
[11]
cortical function of speech . Dysarthria is divided into six groups: flaccid, ataxia, spastic, hypokinetic,
[12]
hyperkinetic and mixed [Table 2]. Little is known about the role of dysarthria in different neurological
pathologies, so we will focus on some of the genes that have been identified so far, their phenotypic
characteristics and their potential applications.

Flaccid dysarthria
Flaccid dysarthria relates to disorders of the lower motor neuron system and/or muscle. It generates
[12]
continuous expiratory speech, diplophonia, and hypernasality . Myasthenia gravis, amyotrophic lateral
[13]
sclerosis, or Prader-Willi syndrome are examples of flaccid dysarthria .
Myasthenia gravis: Myasthenia gravis (MG) is an autoimmune disorder, caused by antibody formation
at the neuromuscular junction. CHRNA1 gene encodes the alpha subunit of the acetylcholine receptor,