Stuttering associated with a pathogenic variant in the chaperone protein cyclophilin 40.

Stuttering is a common speech disorder that interrupts speech fluency and tends to cluster in families. Typically, stuttering is characterized by speech sounds, words or syllables which may be repeated or prolonged and speech that may be further interrupted by hesitations or 'blocks'. Rare variants in a small number of genes encoding lysosomal pathway proteins have been linked to stuttering. We studied a large four-generation family in which persistent stuttering was inherited in an autosomal dominant manner with disruption of the cortico-basal-ganglia-thalamo-cortical network found on imaging. Exome sequencing of three affected family members revealed the PPID c.808C>T (p.Pro270Ser) variant that segregated with stuttering in the family. We generated a Ppid p.Pro270Ser knock-in mouse model and performed ex vivo imaging to assess for brain changes. Diffusion-weighted MRI in the mouse revealed significant microstructural changes in the left corticospinal tract, as previously implicated in stuttering. Quantitative susceptibility mapping also detected changes in cortico-striatal-thalamo-cortical loop tissue composition, consistent with findings in affected family members. This is the first report to implicate a chaperone protein in the pathogenesis of stuttering. The humanized Ppid murine model recapitulates network findings observed in affected family members.

Expanding the speech and language phenotype in Koolen-de Vries syndrome: late onset and periodic stuttering a novel feature.

Speech and language impairment is core in Koolen-de Vries syndrome (KdVS), yet only one study has examined this empirically. Here we define speech, language, and functional/adaptive behaviour in KdVS; while deeply characterising the medical/neurodevelopmental phenotype in the largest cohort to date. Speech, language, literacy, and social skills were assessed using standardised measures, alongside an in-depth health and medical questionnaire. 81 individuals with KdVS were recruited (35 female, mean age 9y 10mo), 56 of whom harboured the typical 500-650 kb 17q21.31 deletion. The core medical phenotype was intellectual disability (largely moderate), eye anomalies/vision disturbances, structural brain anomalies, dental problems, sleep disturbance, musculoskeletal abnormalities, and cardiac defects. Most were verbal (62/81, 76.5%), while minimally-verbal communicators used alternative and augmentative communication (AAC) successfully in spite of speech production delays. Speech was characterised by apraxia (39/61, 63.9%) and dysarthria (28/61, 45.9%) in verbal participants. Stuttering was described in 36/47 (76.6%) verbal participants and followed a unique trajectory of late onset and fluctuating presence. Receptive and expressive language abilities were commensurate with one another, but literacy skills remained a relative weakness. Social competence, successful behavioural/emotional control, and coping skills were areas of relative strength, while communication difficulties impacted daily living skills as an area of comparative difficulty. Notably, KdVS individuals make communication gains beyond childhood and should continue to access targeted therapies throughout development, including early AAC implementation, motor speech therapy, language/literacy intervention, as well as strategies implemented to successfully navigate activities of daily living that rely on effective communication.

The Expansion of the Spectrum in Stuttering Disorders to a Novel ARMC Gene Family (ARMC3).

Stuttering is a common neurodevelopment speech disorder that negatively affects the socio-psychological dimensions of people with disability. It displays many attributes of a complex genetic trait, and a few genetic loci have been identified through linkage studies. Stuttering is highly variable regarding its phenotypes and molecular etiology. However, all stutters have some common features, including blocks in speech, prolongation, and repetition of sounds, syllables, and words. The involuntary actions associated with stuttering often involve increased eye blinking, tremors of the lips or jaws, head jerks, clenched fists, perspiration, and cardiovascular changes. In the present study, we recruited a consanguineous Pakistani family showing an autosomal recessive mode of inheritance. The exome sequencing identified a homozygous splice site variant in ARMC3 (Armadillo Repeat Containing 3) in a consanguineous Pashtun family of Pakistani origin as the underlying genetic cause of non-syndromic stuttering. The homozygous splice site variant (NM_173081.5:c.916 + 1G > A) segregated with the stuttering phenotype in this family. The splice change leading to the skipping of exon-8 is a loss of function (LoF) variant, which is predicted to undergo NMD (Nonsense mediated decay). Here, we report ARMC3 as a novel candidate gene causing the stuttering phenotype. ARMC3 may lead to neurodevelopmental disorders, including stuttering in humans.

Stuttering, family history and counselling: A contemporary database.

BACKGROUND: Information about genetic influence is useful to when counselling parents or caregivers who have infants and children at risk for stuttering. Yet, the most comprehensive family aggregate database to inform that counselling is nearly four decades old (Andrews et al., 1983). Consequently, the present study was designed to provide a contemporary exploration of the relationship between stuttering and family history. METHODS: Data were sourced from the Australian Stuttering Research Centre, comprising 739 participants who presented for assessment, treatment, or investigation of stuttering. Reported family history data were acquired from pedigrees collected during assessment. We sought to establish the relation of the following variables to family history of stuttering: incidence, proband sex, parent sex, stuttering severity, age, reported age of stuttering onset, and impact of stuttering. Data were analysed with chi-square tests for independence, logistic and linear regression models. RESULTS: Results were broadly consistent with existing data, but the following findings were novel. Males and females who stutter have the same increased odds of having a father who stutters relative to a mother who stutters. Males had later stuttering onset than females, with genetic involvement in this effect. There was a greater impact of stuttering for females than males with a family history of stuttering. CONCLUSION: These findings have clinical applications. Speech-language pathologists may have infant or child clients known to them who are at risk of beginning to stutter. Information from the present study can be applied to counselling parents or caregivers of such children about stuttering and family history.

The disabling nature of hope in discovering a biological explanation of stuttering.

Discovering developmental stuttering's biological explanation has been an enduring concern. Novel advances in genomics and neuroscience are making it possible to isolate and pinpoint genetic and brain differences implicated in stuttering. This is giving rise to a hope that, in the future, dysfluency could be better managed if stuttering's biological basis could be better understood. Concurrent to this, there is another hope rising: a hope of a future where differing fluencies would not be viewed through a reductive lens of biology and associated pathologies. The central aim of this paper is to edge out ethical implications of novel research into stuttering's biological explanation. In doing so, the paper proposes to look beyond the bifurcation sketched by the medical and social model of disability. The paper demonstrates how the scientific hope of discovering stuttering's biological explanation acts as an accessory of disablement due to the language of 'lack' and 'deficit' employed in reporting scientific findings and proposes participatory research with people who stutter as an antidote to manage this disablement.

Atypical development of Broca's area in a large family with inherited stuttering.

Developmental stuttering is a condition of speech dysfluency, characterized by pauses, blocks, prolongations and sound or syllable repetitions. It affects around 1% of the population, with potential detrimental effects on mental health and long-term employment. Accumulating evidence points to a genetic aetiology, yet gene-brain associations remain poorly understood due to a lack of MRI studies in affected families. Here we report the first neuroimaging study of developmental stuttering in a family with autosomal dominant inheritance of persistent stuttering. We studied a four-generation family, 16 family members were included in genotyping analysis. T1-weighted and diffusion-weighted MRI scans were conducted on seven family members (six male; aged 9-63 years) with two age and sex matched controls without stuttering (n = 14). Using Freesurfer, we analysed cortical morphology (cortical thickness, surface area and local gyrification index) and basal ganglia volumes. White matter integrity in key speech and language tracts (i.e. frontal aslant tract and arcuate fasciculus) was also analysed using MRtrix and probabilistic tractography. We identified a significant age by group interaction effect for cortical thickness in the left hemisphere pars opercularis (Broca's area). In affected family members this region failed to follow the typical trajectory of age-related thinning observed in controls. Surface area analysis revealed the middle frontal gyrus region was reduced bilaterally in the family (all cortical morphometry significance levels set at a vertex-wise threshold of P < 0.01, corrected for multiple comparisons). Both the left and right globus pallidus were larger in the family than in the control group (left P = 0.017; right P = 0.037), and a larger right globus pallidus was associated with more severe stuttering (rho = 0.86, P = 0.01). No white matter differences were identified. Genotyping identified novel loci on chromosomes 1 and 4 that map with the stuttering phenotype. Our findings denote disruption within the cortico-basal ganglia-thalamo-cortical network. The lack of typical development of these structures reflects the anatomical basis of the abnormal inhibitory control network between Broca's area and the striatum underpinning stuttering in these individuals. This is the first evidence of a neural phenotype in a family with an autosomal dominantly inherited stuttering.

Phenome risk classification enables phenotypic imputation and gene discovery in developmental stuttering.

Developmental stuttering is a speech disorder characterized by disruption in the forward movement of speech. This disruption includes part-word and single-syllable repetitions, prolongations, and involuntary tension that blocks syllables and words, and the disorder has a life-time prevalence of 6-12%. Within Vanderbilt's electronic health record (EHR)-linked biorepository (BioVU), only 142 individuals out of 92,762 participants (0.15%) are identified with diagnostic ICD9/10 codes, suggesting a large portion of people who stutter do not have a record of diagnosis within the EHR. To identify individuals affected by stuttering within our EHR, we built a PheCode-driven Gini impurity-based classification and regression tree model, PheML, by using comorbidities enriched in individuals affected by stuttering as predicting features and imputing stuttering status as the outcome variable. Applying PheML in BioVU identified 9,239 genotyped affected individuals (a clinical prevalence of ∼10%) for downstream genetic analysis. Ancestry-stratified GWAS of PheML-imputed affected individuals and matched control individuals identified rs12613255, a variant near CYRIA on chromosome 2 (B = 0.323; p value = 1.31 × 10-8) in European-ancestry analysis and rs7837758 (B = 0.518; p value = 5.07 × 10-8), an intronic variant found within the ZMAT4 gene on chromosome 8, in African-ancestry analysis. Polygenic-risk prediction and concordance analysis in an independent clinically ascertained sample of developmental stuttering cases validate our GWAS findings in PheML-imputed affected and control individuals and demonstrate the clinical relevance of our population-based analysis for stuttering risk.

IFNAR1 gene mutation may contribute to developmental stuttering in the Chinese population.

BACKGROUND: Developmental stuttering is the most common form of stuttering without apparent neurogenic or psychogenic impairment. Recently, whole-exome sequencing (WES) has been suggested to be a promising approach to study Mendelian disorders. METHODS: Here, we describe an application of WES to identify a gene potentially responsible for persistent developmental stuttering (PDS) by sequencing DNA samples from 10 independent PDS families and 11 sporadic cases. Sanger sequencing was performed for verification with samples obtained from 73 additional patients with sporadic cases. RESULTS: We first searched for cosegregating variants/candidate genes in a Chinese family (Family 0) by sequencing DNA obtained from 3 affected members and 3 controls. Next, we sequenced DNA samples obtained from 9 additional Chinese families (Families 1-9) with stuttering to verify the identified candidate genes. Intriguingly, we found that two missense variants (Leu552Pro and Lys428Gln) of interferon-alpha/beta receptor 1 (IFNAR1) cosegregated with stuttering in three independent families (Families 0, 5 and 9). Moreover, we found two additional mutations (Gly301Glu and Pro335del) in the IFNAR1 gene in 4 patients with sporadic cases by using WES or Sanger sequencing. Further receptor mutagenesis and cell signaling studies revealed that these IFNAR1 variants may impair the activity of type I IFN signaling. CONCLUSION: Our data indicate that IFNAR1 might be a potential pathogenic gene of PDS in the Chinese population.

A influência da hereditariedade na ocorrência de variáveis preditoras na gagueira crônica do desenvolvimento / The influence of heredity on the predictor variables of chronic developmental stuttering

RESUMO Objetivo Testar a variável da hereditariedade familiar para a gagueira crônica do desenvolvimento (GCD) como preditora de efeito direto no desfecho da fluência da fala em crianças. Métodos Participaram do estudo 200 crianças, de 2 a 12 anos, de ambos os gêneros, sem distinção de raça e nível sócio-econômico-cultural, que apresentaram queixa de GCD, sem outras intercorrências de linguagem e/ou audição, no período de cinco anos. Os 200 participantes deste estudo foram divididos em três grupos (baixo risco para GCD, médio risco para GCD e alto risco para GCD) conforme os indicadores de risco aferidos pelo Protocolo de risco para a gagueira do desenvolvimento. Para determinação da variável de controle (hereditariedade positiva para a gagueira) foi considerado afetado o participante que apresentava familiar de primeiro grau (pai, mãe, irmãos) que se auto identificava como pessoa com gagueira. Todos os participantes foram avaliados segundo o Protocolo de risco para a gagueira do desenvolvimento e pela Avaliação do Perfil da Fluência de Fala. Resultados Os grupos de baixo, médio e alto risco para GCD com hereditariedade positiva não se diferenciaram estatisticamente dos grupos de baixo, médio e alto risco para GCD com hereditariedade negativa para nenhuma das variáveis demográficas e resultado da análise do Perfil de Fluência da Fala. Conclusão A variável hereditariedade não indicou o grau de risco na manifestação da fala nem identificou, decisivamente, as crianças em risco de persistência para a GCD.

ABSTRACT Purpose To test if the variable family heredity for chronic developmental stuttering (CDS) is a direct predictor of the speech fluency outcome in children. Methods Participants of the study were 200 children, between 2 and 12 years of age, of both genders, with no racial and socioeconomic distinction, diagnosed with a complaint of CDS, and with no language and/or hearing comorbidity, over a period of 5 years. Participants were divided in three study groups (low risk for CDS, moderate risk for CDS, and high risk for CDS) according to the risk indicators determined by the Risk Protocol for Developmental Stuttering. In order to determine the control variable (positive heredity for stuttering), we considered the participant as being affected if he/she presented a first-degree family member (father, mother, siblings) who self-declared themselves as a person who stuttered. All of the participants were assessed according to Risk Protocol for Developmental Stuttering and to The Speech Fluency Profile Assessment. Results No significant difference was observed for the demographic variables and for the results on The Fluency Profile Assessment among the groups with mild, moderate and high risk of stuttering when comparing the groups with positive and negative family heredity. Conclusion The variable family heredity did not indicate the risk level for the manifestation of stuttering and also did not identify those at risk of presenting CDS.

Loci of stuttering of English- and Korean-speaking children who stutter: Preliminary findings.

PURPOSE: The purpose of the study was to determine whether differences exist between young English- and Korean-speaking children who stutter (CWS) in the loci of stuttering. METHOD: Participants were 10 Korean-speaking and 11 English-speaking CWS between the ages of 3 and 7 years. Participants produced narratives while viewing various picture scenes and a wordless picture book. RESULTS: Findings indicated that Korean-speaking CWS stuttered more on content than function words whereas English-speaking CWS stuttered more on function than content words. Furthermore, both Korean- and English-speaking CWS tended to stutter more on utterance-initial words. These findings appear to be related to the differences in linguistic/syntactic structures between Korean and English. Specifically, in the Korean-speaking CWS's narratives, most utterance-initial words (73.60 %) were content words whereas in the English-speaking CWS's narratives, most utterance-initial words (83.57 %) were function words. CONCLUSION: These preliminary findings, although in need of replication with a larger sample size, seem to suggest that the word class (i.e., content/function words) contributions to stuttering loci are more language-specific whereas the word position (i.e., utterance-initial position) contributions to stuttering loci are more language-nonspecific. Given that the true characteristics of stuttering may be rather language-nonspecific than language-specific, further research may need to focus more on stuttering loci related to word position than word class.

Neurofilament-lysosomal genetic intersections in the cortical network of stuttering.

The neurobiological underpinnings of stuttering, a speech disorder characterized by disrupted speech fluency, remain unclear. While recent developments in the field have afforded researchers the ability to pinpoint several genetic profiles associated with stuttering, how these specific genetic backgrounds impact neuronal circuits and how they generate or facilitate the emergence of stuttered speech remains unknown. In this study, we identified the large-scale cortical network that characterizes stuttering using functional connectivity MRI and graph theory. We performed a spatial similarity analysis that examines whether the topology of the stuttering cortical network intersects with genetic expression levels of previously reported genes for stuttering from the protein-coding transcriptome data of the Allen Human Brain Atlas. We found that GNPTG - a gene involved in the mannose-6-phosphate lysosomal targeting pathways - was significantly co-localized with the stuttering cortical network. An enrichment analysis demonstrated that the genes identified with the stuttering cortical network shared a significantly overrepresented biological functionality of Neurofilament Cytoskeleton Organization (NEFH, NEFL and INA). The relationship between lysosomal pathways, cytoskeleton organization, and stuttering, was investigated by comparing the genetic interactome between GNPTG and the neurofilament genes implicated in the current study. We found that genes of the interactome network, including CDK5, SNCA, and ACTB, act as functional links between lysosomal and neurofilament genes. These findings support the notion that stuttering is due to a lysosomal dysfunction, which has deleterious effects on the neurofilament organization of the speech neuronal circuits. They help to elucidate the intriguing, unsolved link between lysosomal mutations and the presence of stuttering.

Human GNPTAB stuttering mutations engineered into mice cause vocalization deficits and astrocyte pathology in the corpus callosum.

Stuttering is a common neurodevelopmental disorder that has been associated with mutations in genes involved in intracellular trafficking. However, the cellular mechanisms leading to stuttering remain unknown. Engineering a mutation in N-acetylglucosamine-1-phosphate transferase subunits α and ß (GNPTAB) found in humans who stutter into the mouse Gnptab gene resulted in deficits in the flow of ultrasonic vocalizations similar to speech deficits of humans who stutter. Here we show that other human stuttering mutations introduced into this mouse gene, Gnptab Ser321Gly and Ala455Ser, produce the same vocalization deficit in 8-day-old pup isolation calls and do not affect other nonvocal behaviors. Immunohistochemistry showed a marked decrease in staining of astrocytes, particularly in the corpus callosum of the Gnptab Ser321Gly homozygote mice compared to wild-type littermates, while the staining of cerebellar Purkinje cells, oligodendrocytes, microglial cells, and dopaminergic neurons was not significantly different. Diffusion tensor imaging also detected deficits in the corpus callosum of the Gnptab Ser321Gly mice. Using a range of cell type-specific Cre-drivers and a Gnptab conditional knockout line, we found that only astrocyte-specific Gnptab-deficient mice displayed a similar vocalization deficit. These data suggest that vocalization defects in mice carrying human stuttering mutations in Gnptab derive from abnormalities in astrocytes, particularly in the corpus callosum, and provide support for hypotheses that focus on deficits in interhemispheric communication in stuttering.

Genetic factors and therapy outcomes in persistent developmental stuttering.

PURPOSE: We investigated whether outcomes of therapy for persistent developmental stuttering differ in individuals who carry a mutation in one of the known genes associated with stuttering compared to individuals without such mutations. METHOD: We studied outcomes of an intensive fluency shaping-based therapy program in individuals with persistent developmental stuttering. We evaluated a cohort of 51 stuttering individuals with who carried a mutation in either the GNPTAB, GNPTG, NAGPA, or AP4E1 gene. We compared therapy outcomes in these individuals with outcomes in 51 individuals matched for age, gender, and ethnicity, who stutter and underwent the same therapy program, and did not carry a mutation in any of these genes. Fluency pre- and post-therapy was evaluated using blinded observer-based quantitative stuttering dysfluency measures (Dysfluent Words Score, DWS), and by subjects' self-reported measures of struggle, avoidance and expectancy behavior associated with speaking (Perceptions of Stuttering Inventory, PSI). The difference between pre- and post-therapy fluency scores was taken as the measure of near-term therapy efficacy. RESULTS: Comparison of fluency measures showed a strong effect of therapy overall. Mutation carriers achieved significantly less resolution in PSI following therapy, with PSI scores showing significantly less improvement in individuals who carry a mutation (p = 0.0157, RR = 1.75, OR = 2.92) while the group difference in DWS between carriers and non-carriers was statistically not significant in the present study, the trend observed in the results warrants further research focused on this important issue. CONCLUSIONS: These results suggest stuttering is more resistant to therapy in individuals who carry a mutation in one of the genes known to be associated with stuttering.

Genetic epidemiology of stuttering among school children in the state of Tamil Nadu, India.

PURPOSE: Stuttering is a fluency disorder with a worldwide prevalence of 1%. Reports on the epidemiology of stuttering in India are limited. Our primary goal was to examine the prevalence of the disorder among school children. The study also aimed to examine risk factors associated with severity and the impact of parental consanguinity in stuttering. METHOD: Children from 97 schools in the State of Tamil Nadu, India were screened. Extensive speech characterization, epidemiological details and three-generational pedigrees were collected for 180 probands. The genetic basis of stuttering was examined using the analysis of genealogical index of families (GIF), kinship group and sibling recurrence risk (SRR) measures. Regression analysis and chi-square tests were performed to test the association of risk factors with severity of the disorder. RESULTS: Among the 74,544 school children screened, the prevalence of stuttering was found to be 0.46%. Pedigree analysis revealed a positive family history in 101 (56%) probands; overall familial incidence was 11%. We observed an overall male-favored sex ratio (4:1). Familial aggregation (GIF = 442.60, p-value <0.001) and sibling recurrence risk ratio (Ks = 0.197, SD = 0.041) was high among consanguineous families. Severity of stuttering was strongly associated with gender and moderately associated with age at onset. CONCLUSION: The prevalence of stuttering in Tamil Nadu is estimated for the first time in this study. High familial incidence, familial aggregation and sibling recurrence risk ratio point to the presence of a genetic basis. Familial aggregation was high among consanguineous families although consanguinity did not seem to play a role in severity.

Relationship between serum homovanillic acid, DRD2 C957T (rs6277), and hDAT A559V (rs28364997) polymorphisms and developmental stuttering.

The involvement of the brain dopamine system in the pathophysiology of developmental stuttering has been previously suggested. In the present study, we aimed to investigate the relationship between developmental stuttering in children and the levels of serum homovanillic acid (HVA), dopamine D2 receptor (DRD2) C957T (rs6277), and solute carrier family 6 member 3 (SLC6A3) human dopamine transporter (hDAT) A559V (rs28364997) single-nucleotide polymorphisms. In a case-control study, serum level of HVA, DRD2 C957T, and DAT A559V were compared between 85 children who stuttered (CWS) and 85 age- and sex-matched children who did not stutter (CWNS). Although serum level of HVA was higher among the CWS (median = 25.50 ng/mL) than that in the CWNS (median = 17.40 ng/mL), the difference between the two groups was not significant (p = 0.43). No significant correlation was observed between age and the level of HVA among all the participants (r = -0.15, p = 0.06), nor was there any correlation among the CWS (r = -0.19, p = 0.14) or among the CWNS (r = -0.13, p = 0.27) according to the Spearman correlation coefficient. On the other hand, there was a significant negative correlation between age from stuttering onset and the serum level of HVA among the CWS group (r = -0.32, p = 0.01). The Spearman correlation coefficient did not indicate any significant correlation between stuttering severity and HVA in CWS (r = -0.06, p = 0.59). The mutant allele of hDAT A559V was observed neither in the CWS nor in the controls. The allele frequencies of DRD2 C957T were not significantly different between the CWS and the CWNS; however, the frequency of the TT genotype was significantly higher among the CWS (p = 0.02), which was associated with 2.25-fold susceptibility to stuttering (OR = 2.25, 95% CI = 1.03 to 4.90, p = 0.04). Our findings suggest that the serum level of HVA might be a biomarker for dopaminergic involvement in the pathogenesis of stuttering. Moreover, the present study indicates that the DRD2 C957T polymorphism might be a risk factor for the development of stuttering among Iranian Kurdish population.

Variants in GNPTAB, GNPTG and NAGPA genes are associated with stutterers.

Non-syndromic stuttering is a neurodevelopmental disorder characterized by disruptions in normal flow of speech in the form of repetition, prolongation and involuntary halts. Previously, mutations with more severe effects on GNPTAB and GNPTG have been reported to cause Mucolipidosisll (ML-ll) and Mucolipidosislll (ML-lll), two lysosomal storage disorders with multiple pathologies. We used homozygosity mapping and Sanger sequencing to investigate variants of the three genes in 25 Iranian families with at least two first degree related non-syndromic stutterers. Bioinformatic evaluation and Segregation analysis of the found variants helped us define probable consequences. We also compared our findings with those related to Mucolipidosis. 14 variations were found in the three genes 3 of which, including a novel variant within intronic region of GNPTG and a heterozygous 2-bp deletion in coding region of GNPTAB, co-segregated with stuttering in the families they were found. Bioinformatics analysis predicted all three variants causing deleterious effects on gene functioning. Our findings support the role of these three variants in non-syndromic stuttering. This finding may challenge the current belief that variations causing stuttering are at different sites and have less severe consequences than genetic changes that cause ML-ll and ML-lll.

Young children's family history of stuttering and their articulation, language and attentional abilities: An exploratory study.

PURPOSE: The purpose of this study was to determine whether young children who do (CWS) and do not stutter (CWNS) with a positive versus negative family history of stuttering differ in articulation, language and attentional abilities and family histories of articulation, language and attention related disorders. METHOD: Participants were 25 young CWS and 50 young CWNS. All 75 participants' caregivers consistently reported a positive or negative family history of stuttering across three consecutive time points that were about 8 months apart for a total of approximately 16 months. Each participant's family history focused on the same, relatively limited number of generations (i.e., participants' parents & siblings). Children's family history of stuttering as well as articulation, language, and attention related disorders was obtained from one or two caregivers during an extensive interview. Children's speech and language abilities were measured using four standardized articulation and language tests and their attentional abilities were measured using caregiver reports of temperament. RESULTS: Findings indicated that (1) most caregivers (81.5% or 75 out 92) were consistent in their reporting of positive or negative history of stuttering; (2) CWNS with a positive family history of stuttering, compared to those with a negative family history of stuttering, were more likely to have reported a positive family history of attention deficit/hyperactivity disorder (ADHD), and (3) CWNS with a positive family history of stuttering had lower language scores than those with a negative family history of stuttering. However, there were no such significant differences in family histories of ADHD and language scores for CWS with a positive versus negative family history of stuttering. In addition, although 24% of CWS versus 12% of CWNS's caregivers reported a positive family history of stuttering, inferential analyses indicated no significant differences between CWS and CWNS in relative proportions of family histories of stuttering. CONCLUSION: Finding that a relatively high proportion (i.e., 81.5%) of caregivers consistently reported a positive or negative family history of stuttering across three consecutive time points should provide some degree of assurance to those who collect such caregiver reports. Based on such consistent caregiver reports, linguistic as well as attentional vulnerabilities appear associated with a positive family history of stuttering, a finding that must await further empirical study for confirmation or refutation.

Sex steroid hormones and sex hormone binding globulin levels, CYP17 MSP AI (-34T:C) and CYP19 codon 39 (Trp:Arg) variants in children with developmental stuttering.

Developmental stuttering is known to be a sexually dimorphic and male-biased speech motor control disorder. In the present case-control study, we investigated the relationship between developmental stuttering and steroid hormones. Serum levels of testosterone, dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA), oestradiol, progesterone, cortisol, and sex hormone binding globulin (SHBG), as well as the 2nd/4th digit ratio (2D:4D), an indicator of prenatal testosterone level, were compared between children who stutter (CWS) and children who do not stutter (CWNS). Moreover, two SNPs (CYP17 -34 T:C (MSP AI) and CYP19 T:C (Trp:Arg)) of cytochrome P450, which is involved in steroid metabolism pathways, were analysed between the groups. Our results showed significantly higher levels of testosterone, DHT, and oestradiol in CWS in comparison with CWNS. The severity of stuttering was positively correlated with the serum levels of testosterone, DHEA, and cortisol, whereas no association was seen between the stuttering and digit ratio, progesterone, or SHBG. The CYP17CC genotype was significantly associated with the disorder.