Most animals communicate with each other in diverse ways using sounds, gestures, and facial movements to warn about danger, claim territory, and seek attraction from the opposite sex . Compared to non-human species, human communication is mediated by proper sounds and remarkably complex verbal and grammatical pledges in a systematic manner, which helps them to dominate other species on Earth [2,3]. Human-specific communication comprises of speech and language, which are often difficult to distinguish between them. Speech is often defined as mechanical sounds of spoken language and includes articulations, which are the way sounds are generated. In contrast, language is a word and a combined sequence of words that constitute meaningful phrases or sentences based on accepted grammatical rules .
Although disruptions in the function of communication skills are not mostly life-threatening in humans, affected individuals have significant difficulties in leading a normal life. Speech and language disorders include developmental verbal dyspraxia, dyslexia, specific language impairment, and stuttering. Stuttering, also called stammering, is regarded as the most common speech disorder. It is well characterized by repetitions, prolongation of syllables, or by unintended halts in the sequential flow of the speech known as blocks . Clinical diagnosis is performed by measuring the four aspects of speech behaviors including frequency, sustainment time, physical accompanying features, and fluency of the individual’s speech using a stuttering severity instrument-4 . This disorder may be accompanied by eye blinks, lip tremors, facial tics, and clenching fists. Similar to other speech disorders, stuttering occurs in young children with a typical onset age of approximately 3 years, with a male-to-female prevalence rate of 2:1. While it affects approximately 5% of the population, independent of the affected individual’s ethnicity or spoken language, the majority of the stutters (80%) resolve spontaneously or with the help of clinical speech therapy . This recovery is observed more commonly in female than in male stutters, thereby increasing the male-to-female prevalence rate to 4:1 by the age of nine. The overall prevalence rate of persistent stuttering is approximately 1% in the general population.
Several genetic studies have been conducted to identify causative genes and their roles in speech and language disorders, including stuttering. Recently, evidence has accumulated to support genetic contributions that increase the susceptibility to stuttering. Here, we review past significant genetic discoveries and functional studies to reveal the causes of stuttering (Table 1).
Like several other disorders, it was suggested that stuttering is attributed to both non-genetic and genetic factors; thus, the extent to which the risk of this disorder was attributable to these two factors was an initial task that needed to be resolved. There are a few genetic approaches to address this challenge.
First, adoption studies of stuttering are an appropriate method to evaluate the influence of nature and nurture on this disorder. These studies investigated adopted stutters in multiple families, and the results were inconclusive because the sample size was not large enough to indicate statistical significance . Another study group recruited 156 adopted and non-adopted children, and it was determined that the affection risk in adopted children with a genetic background of stuttering was higher than that in adopted children with no known genetic background . In addition, it was reported that stuttering may not be acquired by persistent communication with parents affected by speech disorders. These two adoption studies indicated that genetic factors, rather than family environment, are better predictors of the affection status of the offspring [7,8]. Second, together with the adoption studies aforementioned, twin studies are another useful approach for evaluating genetic contributions to diseases. Several genetic investigations of dizygotic and monozygotic twin pairs with at least one stutter were performed to estimate heritability and mode of inheritance in stuttering [9-13]. It was reported that the concordance rate for this disorder was much higher in identical twins (63%) than in the fraternal twins (19%), suggesting that genetic factors contribute to the etiology of stuttering. However, the possibility that environmental factors have an effect on stuttering could not be completely excluded as several of the monozygotic twins in the study were discordant for stuttering, which implies that both non-genetic and genetic factors contribute to the etiology of stuttering . While these adoption and twin studies varied in sample size, ethnicity, diagnostic criteria, and statistical methods, the results consistently supported the evidence of genetic influences on stuttering. The overall heritability estimates from these studies ranged from 0.42 to 0.85 [13-15]. Third, Cox et al. [16,17] ascertained modestly sized stuttering families with multiple individuals affected by stuttering. With no findings on the involvement of non-genetic factors such as anxiety levels, familial attitudes toward speech, and ratings of parental behavior, the ascertainment of family clustering of stuttering was also strong evidence suggesting a genetic contribution to stuttering.
Genetic studies in the twins and adoptees, coupled with the finding of family clustering of stutters, implied the contribution of genetics contributions to the susceptibility to stuttering. These results developed a few study groups to perform parametric or non-parametric genome-wide linkage analyses to identify genetic loci and further mutated genes in the families of European descent ascertained in North America [18,19]. These two studies showed only suggestive linkage to chromosomes 2q, 9p, 15q, 18p, and 18q, while another study ascertained an isolated population, called Hutterrite, but the results from neither multipoint linkage analysis nor meta-analysis met the genome-wide statistical criteria .
In addition to genome-wide linkage analysis in families, association studies in the unrelated case-control groups might be an alternative approach in the genetic studies of stuttering. A few association studies were performed in the Kurdish and Han Chinese populations, and it was reported that two single-nucleotide polymorphisms (SNPs) in each of the
These failures in family-based genome-wide linkage and case-control replication studies may be ascribed to the two reasons. First, the transmission of stuttering in the populations does not follow the typical Mendelian mode of inheritance; therefore, the highly complex segregation pattern made it difficult to perform appropriate statistical analyses. Second, stuttering resolves spontaneously in most of the affected family members (>70%), especially females; therefore, there is a chance that unaffected individuals might have recovered from their former stuttering status. This raises the question of whether the clinical diagnosis regards recovered stutters as affected or not. Thus, these puzzling features of stuttering have hindered successful genetic studies of stuttering for several decades.
In genetic studies, the employment of consanguineous families is often advantageous and may increase the success of identifying causative genes owing to the homogeneous genomic structure in the family. Consanguineous marriages in the families usually create a pedigree structure with a significantly increased incidence of recessive genetic disorders than in outbreeding families. In addition, when their genome is sequenced, the number of candidate variants found is dramatically decreased because of the high homogeneity of the genomic variants in these families, allowing researchers to readily pinpoint causative mutations readily . Thus, the same is likely true for complex disorders such as stuttering. From this perspective, genetic studies in the Pakistani stuttering familiy by Riaz et al.  could be promising because 60% to 70% of all matings were between cousins in the family. The authors ascertained 46 highly inbred families from the city of Lahore, Pakistan, and significant genetic linkage (nonparametric logarithm of odds ratio [LOD] score=4.6) was detected in microsatellite variants dispersed on the chromosome 12q. These strong linkage results were attributed to the enrichment of consanguineous marriages in the recruited families.
The first causative gene for stuttering was discovered by a research group led by Dr. Drayna at the National Institute on Deafness and Other Communication Disorders, National Institutes of Health, USA. They focused on the largest family, designated PKST72, out of 46 families that had previously undergone genome-wide linkage scans . Upon further bioinformatic investigation of the University of California, Santa Cruz (UCSC) genome database (https://genome.ucsc.edu), they identified that there were 87 genes within the 10 Mb linkage region on the chromosome 12q23.3 bounded by D12S101 and D12S1597 microsatellite markers were identified. Sequencing exons, exon/intron junctions and promoter regions in these 87 genes revealed that a mutation (c.3598G>A, p.Glu1200Lys, rs137853825) in the
Subsequent haplotype analysis of the 650 kb region surrounding the
Considering that both GlcNAc-1-phosphotransferase and NAGPA enzymes are involved in the two-step process of attaching the M6P tagging signal onto the lysosomal hydrolases as described above, it could be rationally hypothesized that genetic mutations in the
Data on the molecular mechanisms underlying how genetic mutations in the
Although genetic mutations in the
Other remarkable genetic studies of stuttering have investigated a large Cameroonian family harboring 33 individuals affected by developmental persistent stuttering. Raza et al.  performed genome-wide linkage scans by combining genotyping 332 microsatellites (Marshifield Weber 10 panel) and 6,090 SNPs (Human Linkage 12 Panel). Initial analyses of the entire family found no genetic markers associated with stuttering. The authors then divided the large family into five subfamilies, and finally discovered significant linkage in the sub-family named 1E to the markers on chromosomes 2p and 15q with LOD scores ranging from 4.7 to 6.6. Further whole-exome sequencing of these linkage regions and subsequent bioinformatic analyses in the Cameroonian subfamily members discovered two heterozygous mutations (p.Val517Ile [rs7600211635] and p.Glu801Lys [rs556450190]) in the
Animal models are useful tools for the genetic studies of human diseases. In this point of view, generating a mouse model of speech and language disorders is a major challenge because speech and language are human-specific functions. Interestingly, it was discovered that mice communicate with each other by generating ultrasonic vocalizations at a frequency of 30 to 110 kHz . Based on this finding, a knock-in mouse model of stuttering was engineered to determine whether the mutations found in the genes of lysosomal enzyme-trafficking pathway genes lead to the same or similar phenotypes found in from human stutters. This study found out that mice carrying mutations in the
While the mouse model of stuttering displayed abnormal features similar to human stutters, the location and role of the speech center, which is assumed to be in the brain, are entirely unknown. Han et al.  cleverly introduced
For several decades, many studies have been performed to identify the genetic causes of stuttering, and to date a few genes, particularly those associated with intracellular protein trafficking pathways, are known to cause this human-specific disorder. Although links between these genes, namely the
Mutations in the
For several decades, many studies have been performed to pinpoint speech centers in the human brain, and it has been suggested that the Broca’s and the Wernicke’s areas are the brain regions responsible for speech and language functions [38,39]. In addition, the corpus callosum, which is involved in interhemispheric processing by interconnecting the left and right hemispheres of the brain may be another potential brain region for human speech, because it was reported that the overall area of the corpus callosum was significantly larger in the stutters than in normal individuals . However, the detailed association between corpus callosum size and stuttering at the cellular level is currently unknown.
For the last several decades, tremendous effort has been devoted to discovering the genetic causes associated with speech and language disorders, including stuttering. Although, the enigmatic characteristics of the stuttering, such as a high spontaneous recovery rate, have hindered the success of these studies, employment of consanguineous Pakistani, and large Cameroonian stuttering families have enabled researchers to identify genetic mutations in the
I declare that I do not have any conflicts of interest.
This work was supported by the National Research Foundation of Korea funded by the Korean Government (Ministry of Science and ICT) (Grant no. 2021R1F1A1058330).
Notable studies contributed to understand genetic causes of stuttering
|Study group [reference]||Year||Method||Major finding|
|Shugart et al. ||2004||Genome-wide linkage scans in 68 North American stuttering families||Found non-parametric linkage score of 5.35 at the marker on chromosome 18p|
|Riaz et al. ||2005||Genome-wide linkage analysis in Pakistani consanguineous families||Found significant genetic linkage to markers on the chromosome 12q|
|Wittke-Thompson et al. ||2007||Genome-wide linkage and association analyses in a large founder population named Hutterites||Identified suggestive linkage to the microsatellite markers on chromosomes 2 and 5|
|Kang et al. ||2010||Sanger Sequencing of linkage region of chromosome 12q||Found association of stuttering with mutations in the
|Lee et al. ||2011||Enzyme assay for the mutations found in the
||Demonstrated that the mutations in the GNPTAB and
|Fedyna et al. ||2011||Haplotype analysis with the SNP markers surrounding
||Revealed that the variant of
|Raza et al. ||2013||Whole-genome linkage analysis using SNP chips and microsatellite markers in the large west African stuttering family||Detected significant LOD scores ranging from 4.7-6.6 on the chromoses 2p and 15q|
|Raza et al. ||2015||Whole-exome sequencing of Cameroonian stuttering family||Suggested association of the mutations in
|Barnes et al. ||2016||Analysis of ultrasonic vocalizations in mouse model of stuttering||Found altered vocalization patterns in the knock-in mouse carrying
|Han et al. ||2019||Characterized mouse model of stuttering with mutations in the
||Detected altered ultrasonic vocalization in the knock-in mouse and found astrocyte deficits in the corpus callosum|
|Choo et al. ||2011||Analyzed gene expression data at Allen Brain Institute and voxel-based morphometry||Association of lysosomal enzyme trafficking genes with area size of gray matter in stutters and normal subjects|
SNP, single-nucleotide polymorphism; LOD, logarithm of odds ratio.