Audiology and Speech Pathology - Research Publications
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ItemNo Preview AvailableStuttering associated with a pathogenic variant in the chaperone protein cyclophilin 40(OXFORD UNIV PRESS, 2023-12-01)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.
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ItemUsing machine-learning methods to identify early-life predictors of 11-year language outcome(WILEY, 2023-08)BACKGROUND: Language is foundational for neurodevelopment and quality of life, but an estimated 10% of children have a language disorder at age 5. Many children shift between classifications of typical and low language if assessed at multiple times in the early years, making it difficult to identify which children will have persisting difficulties and benefit most from support. This study aims to identify a parsimonious set of preschool indicators that predict language outcomes in late childhood, using data from the population-based Early Language in Victoria Study (n = 839). METHODS: Parents completed surveys about their children at ages 8, 12, 24, and 36 months. At 11 years, children were assessed using the Clinical Evaluation of Language Fundamentals 4th Edition (CELF-4). We used random forests to identify which of the 1990 parent-reported questions best predict children's 11-year language outcome (CELF-4 score ≤81 representing low language) and used SuperLearner to estimate the accuracy of the constrained sets of questions. RESULTS: At 24 months, seven predictors relating to vocabulary, symbolic play, pragmatics and behavior yielded 73% sensitivity (95% CI: 57, 85) and 77% specificity (95% CI: 74, 80) for predicting low language at 11 years. [Corrections made on 5 May 2023, after first online publication: In the preceding sentence 'motor skills' has been corrected to 'behavior' in this version.] At 36 months, 7 predictors relating to morphosyntax, vocabulary, parent-child interactions, and parental stress yielded 75% sensitivity (95% CI: 58, 88) and 85% specificity (95% CI: 81, 87). Measures at 8 and 12 months yielded unsatisfactory accuracy. CONCLUSIONS: We identified two short sets of questions that predict language outcomes at age 11 with fair accuracy. Future research should seek to replicate results in a separate cohort.
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ItemHypothesis-driven genome-wide association studies provide novel insights into genetics of reading disabilities(SPRINGERNATURE, 2022-11-29)Reading Disability (RD) is often characterized by difficulties in the phonology of the language. While the molecular mechanisms underlying it are largely undetermined, loci are being revealed by genome-wide association studies (GWAS). In a previous GWAS for word reading (Price, 2020), we observed that top single-nucleotide polymorphisms (SNPs) were located near to or in genes involved in neuronal migration/axon guidance (NM/AG) or loci implicated in autism spectrum disorder (ASD). A prominent theory of RD etiology posits that it involves disturbed neuronal migration, while potential links between RD-ASD have not been extensively investigated. To improve power to identify associated loci, we up-weighted variants involved in NM/AG or ASD, separately, and performed a new Hypothesis-Driven (HD)-GWAS. The approach was applied to a Toronto RD sample and a meta-analysis of the GenLang Consortium. For the Toronto sample (n = 624), no SNPs reached significance; however, by gene-set analysis, the joint contribution of ASD-related genes passed the threshold (p~1.45 × 10-2, threshold = 2.5 × 10-2). For the GenLang Cohort (n = 26,558), SNPs in DOCK7 and CDH4 showed significant association for the NM/AG hypothesis (sFDR q = 1.02 × 10-2). To make the GenLang dataset more similar to Toronto, we repeated the analysis restricting to samples selected for reading/language deficits (n = 4152). In this GenLang selected subset, we found significant association for a locus intergenic between BTG3-C21orf91 for both hypotheses (sFDR q < 9.00 × 10-4). This study contributes candidate loci to the genetics of word reading. Data also suggest that, although different variants may be involved, alleles implicated in ASD risk may be found in the same genes as those implicated in word reading. This finding is limited to the Toronto sample suggesting that ascertainment influences genetic associations.
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ItemGenome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people(NATL ACAD SCIENCES, 2022-08-18)The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009, P = 1.098 × 10-8) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits.
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ItemAtypical development of Broca's area in a large family with inherited stuttering(OXFORD UNIV PRESS, 2022-04-29)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.
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ItemSelf-reported impact of developmental stuttering across the lifespan(WILEY, 2022-10)AIM: To examine the phenomenology of stuttering across the lifespan in the largest prospective cohort to date. METHOD: Participants aged 7 years and older with a history of developmental stuttering were recruited. Self-reported phenotypic data were collected online including stuttering symptomatology, co-occurring phenotypes, genetic predisposition, factors associated with stuttering severity, and impact on anxiety, education, and employment. RESULTS: A total of 987 participants (852 adults: 590 males, 262 females, mean age 49 years [SD = 17 years 10 months; range = 18-93 years] and 135 children: 97 males, 38 females, mean age 11 years 4 months [SD = 3 years; range = 7-17 years]) were recruited. Stuttering onset occurred at age 3 to 6 years in 64.0%. Blocking (73.2%) was the most frequent phenotype; 75.9% had sought stuttering therapy and 15.5% identified as having recovered. Half (49.9%) reported a family history. There was a significant negative correlation with age for both stuttering frequency and severity in adults. Most were anxious due to stuttering (90.4%) and perceived stuttering as a barrier to education and employment outcomes (80.7%). INTERPRETATION: The frequent persistence of stuttering and the high proportion with a family history suggest that stuttering is a complex trait that does not often resolve, even with therapy. These data provide new insights into the phenotype and prognosis of stuttering, information that is critically needed to encourage the development of more effective speech therapies. WHAT THIS PAPER ADDS: Half of the study cohort had a family history of stuttering. While 75.9% of participants had sought stuttering therapy, only 15.5% identified as having recovered. There was a significant negative correlation between age and stuttering frequency and severity in adults.
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ItemSpeech in children with cerebral palsy(WILEY, 2020-12)AIM: To examine the frequency, characteristics, and factors associated with speech delay and disorder in a community sample of children with cerebral palsy (CP). METHOD: Participants were 84 children (37 females, 47 males; aged between 4y 11mo-6y 6mo) with CP identified through a population-based registry. Speech and oromotor function were systematically evaluated to provide a differential diagnosis of articulation, phonological, and motor speech disorders. RESULTS: In total, 82% (69/84) of participants had delayed or disordered speech production, including minimally verbal presentations (n=20). Verbal participants (n=64) presented with dysarthria (78%), articulation delay or disorder (54%), phonological delay or disorder (43%), features of childhood apraxia of speech (CAS) (17%), or mixed presentations across these conditions. Speech intelligibility was poorest in those with dysarthria and features of CAS. Speech delay or disorder in verbal participants was associated with language impairment (p=0.002) and reduced health-related quality of life (p=0.04) (Fisher's exact test). Poorer speech accuracy (i.e. lower percentage consonants correct) correlated with greater impairments in both language (p<0.001) and oromotor function (p<0.001) (Spearman's test). INTERPRETATION: The speech profile of children with CP is characterized by impairment at multiple levels of speech production (phonetic, cognitive-linguistic, neuromuscular execution, and high-level planning/programming), highlighting the importance of a personalized differential diagnosis informing targeted treatment.
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ItemNo Preview AvailableThe neural basis of nonword repetition in children with developmental speech or language disorder: An fMRI study(PERGAMON-ELSEVIER SCIENCE LTD, 2020-02-17)Developmental language disorder (DLD) and developmental speech disorder (DSD) are highly prevalent childhood conditions. An impaired ability to repeat nonsense words ("nonword repetition"), is claimed to be a robust behavioural marker for these conditions. Yet how brain function is altered during this task remains poorly understood. Previous research suggests that DLD or DSD may be associated with reduced brain activation in the inferior frontal and posterior temporal regions when compared to controls. However, this research is limited by within and between group variability in age, speech/language phenotype, and comorbidities. Here, we used functional MRI to examine brain activation during nonword repetition. As anticipated, behavioural findings confirmed that the DLD and DSD groups had poorer nonword repetition performance compared to typical controls. In contrast, fMRI revealed no statistically significant differences in brain activation, despite the groups appearing to engage slightly different regions when compared at identical thresholds. Therefore, whilst nonword repetition is a sensitive clinical marker for DLD and DSD, the findings from this study suggest that this task is not a sensitive brain MRI marker for children with these disorders, unlike for individuals with single gene mutations like FOXP2 mutations.
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ItemNo Preview AvailableSevere childhood speech disorder: Gene discovery highlights transcriptional dysregulation(LIPPINCOTT WILLIAMS & WILKINS, 2020-05-19)OBJECTIVE: Determining the genetic basis of speech disorders provides insight into the neurobiology of human communication. Despite intensive investigation over the past 2 decades, the etiology of most speech disorders in children remains unexplained. To test the hypothesis that speech disorders have a genetic etiology, we performed genetic analysis of children with severe speech disorder, specifically childhood apraxia of speech (CAS). METHODS: Precise phenotyping together with research genome or exome analysis were performed on children referred with a primary diagnosis of CAS. Gene coexpression and gene set enrichment analyses were conducted on high-confidence gene candidates. RESULTS: Thirty-four probands ascertained for CAS were studied. In 11/34 (32%) probands, we identified highly plausible pathogenic single nucleotide (n = 10; CDK13, EBF3, GNAO1, GNB1, DDX3X, MEIS2, POGZ, SETBP1, UPF2, ZNF142) or copy number (n = 1; 5q14.3q21.1 locus) variants in novel genes or loci for CAS. Testing of parental DNA was available for 9 probands and confirmed that the variants had arisen de novo. Eight genes encode proteins critical for regulation of gene transcription, and analyses of transcriptomic data found CAS-implicated genes were highly coexpressed in the developing human brain. CONCLUSION: We identify the likely genetic etiology in 11 patients with CAS and implicate 9 genes for the first time. We find that CAS is often a sporadic monogenic disorder, and highly genetically heterogeneous. Highly penetrant variants implicate shared pathways in broad transcriptional regulation, highlighting the key role of transcriptional regulation in normal speech development. CAS is a distinctive, socially debilitating clinical disorder, and understanding its molecular basis is the first step towards identifying precision medicine approaches.
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ItemPredicting speech-sound disorder outcomes in school-age children with hearing loss: The VicCHILD experience(WILEY, 2020-07)BACKGROUND: Congenital hearing loss is the most common birth anomaly, typically influencing speech and language development, with potential for later academic, social and employment impacts. Yet, surprisingly, the nuances of how speech is affected have not been well examined with regards to the subtypes of speech-sound disorder (SSD). Nor have the predictors of speech outcome been investigated within a sizeable population cohort. AIMS: (1) To describe the subtypes and prevalence of SSD in children with hearing loss. (2) To determine which characteristics of hearing loss predict the presence of SSD. METHODS & PROCEDURES: A total of 90 children (5-12 years of age) with permanent hearing loss were recruited from an Australian population cohort. Children completed a standardized speech assessment to determine the presence and subtype of SSD. Logistic regression was used to determine the predictors of speech outcome. Demographic, developmental and hearing-related predictors were examined. OUTCOMES & RESULTS: The prevalence of speech disorder overall was 58%, with the most common subtype being phonological delay in 49% of the sample. Factors most predictive of speech disorder were being male, younger and a bimodal user (i.e., using both a hearing aid and a cochlear implant). CONCLUSIONS & IMPLICATIONS: This is the first study, in a sizeable cohort, to describe the prevalence and predictive factors for SSD associated with hearing loss. Clinically, it could be beneficial to implement earlier targeted phonological interventions for children with hearing loss. What this paper adds What is already known on this subject Speech issues are common in children with hearing loss; however, the breakdown of subtypes of SSD (e.g., articulation versus phonological disorder) have not been previously described in a population cohort. This distinction is relevant, as each subtype calls for specific targeted intervention. Studies examining factors predictive of speech outcomes, across a range of hearing levels, are also lacking in a population cohort. What this paper adds to existing knowledge Data suggest the most common type of SSD in children with hearing loss is phonological delay. Males, younger children, and bimodal users were at greater risk of having a subtype of SSD. What are the potential or actual clinical implications of this work? The results are clinically pertinent as the speech diagnosis determines the targeted treatment. Phonological delay is responsive to treatment, and early targeted intervention may improve prognosis for speech outcomes for children with hearing loss.