Genetic architecture of childhood speech disorder: a review.

Severe speech disorders lead to poor literacy, reduced academic attainment and negative psychosocial outcomes. As early as the 1950s, the familial nature of speech disorders was recognized, implying a genetic basis; but the molecular genetic basis remained unknown. In 2001, investigation of a large three generational family with severe speech disorder, known as childhood apraxia of speech (CAS), revealed the first causative gene; FOXP2. A long hiatus then followed for CAS candidate genes, but in the past three years, genetic analysis of cohorts ascertained for CAS have revealed over 30 causative genes. A total of 36 pathogenic variants have been identified from 122 cases across 3 cohorts in this nascent field. All genes identified have been in coding regions to date, with no apparent benefit at this stage for WGS over WES in identifying monogenic conditions associated with CAS. Hence current findings suggest a remarkable one in three children have a genetic variant that explains their CAS, with significant genetic heterogeneity emerging. Around half of the candidate genes identified are currently supported by medium (6 genes) to strong (9 genes) evidence supporting the association between the gene and CAS. Despite genetic heterogeneity; many implicated proteins functionally converge on pathways involved in chromatin modification or transcriptional regulation, opening the door to precision diagnosis and therapies. Most of the new candidate genes for CAS are associated with previously described neurodevelopmental conditions that include intellectual disability, autism and epilepsy; broadening the phenotypic spectrum to a distinctly milder presentation defined by primary speech disorder in the setting of normal intellect. Insights into the genetic bases of CAS, a severe, rare speech disorder, are yet to translate to understanding the heritability of more common, typically milder forms of speech or language impairment such as stuttering or phonological disorder. These disorders likely follow complex inheritance with polygenic contributions in many cases, rather than the monogenic patterns that underly one-third of patients with CAS. Clinical genetic testing for should now be implemented for individuals with CAS, given its high diagnostic rate, which parallels many other neurodevelopmental disorders where this testing is already standard of care. The shared mechanisms implicated by gene discovery for CAS highlight potential new targets for future precision therapies.

To speak may draw on epigenetic writing and reading: Unravelling the complexity of speech and language outcomes across chromatin-related neurodevelopmental disorders.

Speech and language development are complex neurodevelopmental processes that are incompletely understood, yet current evidence suggests that speech and language disorders are prominent in those with disorders of chromatin regulation. This review aimed to unravel what is known about speech and language outcomes for individuals with chromatin-related neurodevelopmental disorders. A systematic literature search following PRISMA guidelines was conducted on 70 chromatin genes, to identify reports of speech/language outcomes across studies, including clinical reports, formal subjective measures, and standardised/objective measures. 3932 studies were identified and screened and 112 were systematically reviewed. Communication impairment was core across chromatin disorders, and specifically, chromatin writers and readers appear to play an important role in motor speech development. Identification of these relationships is important because chromatin disorders show promise as therapeutic targets due to the capacity for epigenetic modification. Further research is required using standardised and formal assessments to understand the nuanced speech/language profiles associated with variants in each gene, and the influence of chromatin dysregulation on the neurobiology of speech and language development.

A Cross-sectional Study of Perceptual and Acoustic Voice Characteristics in Healthy Aging.

PURPOSE: The human voice qualitatively changes across the lifespan. Although some of these vocal changes may be pathologic, other changes likely reflect natural physiological aging. Normative data for voice characteristics in healthy aging is limited and disparate studies have used a range of different acoustic features, some of which are implicated in pathologic voice changes. We examined the perceptual and acoustic features that predict healthy aging. METHOD: Participants (N = 150) aged between 50 and 92 years performed a sustained vowel task. Acoustic features were measured using the Multi-Dimensional Voice Program and the Analysis of Dysphonia in Speech and Voice. We used forward and backward variable elimination techniques based on the Bayesian information criterion and linear regression to assess which of these acoustic features predict age and perceptual features. Hearing thresholds were determined using pure-tone audiometry tests at frequencies 250 Hz, 500 Hz, 1000 Hz, 2000 Hz, and 4000 Hz. We further explored potential relationships between these acoustic features and clinical assessments of voice quality using the Consensus Auditory-Perceptual Evaluation of Voice. RESULTS: Chronological age was significantly predicted by greater voice turbulence, variability of cepstral fundamental frequency, low relative to high spectral energy, and cepstral intensity. When controlling for hearing loss, age was significantly predicted by amplitude perturbations and cepstral intensity. Clinical assessments of voice indicated perceptual characteristics of speech were predicted by different acoustic features. For example, breathiness was predicted by the soft phonation index, mean cepstral peak prominence, mean low-high spectral ratio, and mean cepstral intensity. CONCLUSIONS: Findings suggest that acoustic features that predict healthy aging are different than those previously reported for the pathologic voice. We propose a model of healthy and pathologic voice development in which voice characteristics are mediated by the inability to monitor vocal productions associated with age-related hearing loss. This normative data of healthy vocal aging may assist in separating voice pathologies from healthy aging.

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.

Speech and language development and genotype-phenotype correlation in 49 individuals with KAT6A syndrome.

Pathogenic KAT6A variants cause syndromic neurodevelopmental disability. "Speech delay" is reported, yet none have examined specific speech and language features of KAT6A syndrome. Here we phenotype the communication profile of individuals with pathogenic KAT6A variants. Medical and communication data were acquired via standardized surveys and telehealth-assessment. Forty-nine individuals (25 females; aged 1;5-31;10) were recruited, most with truncating variants (44/49). Intellectual disability/developmental delay (42/45) was common, mostly moderate/severe, alongside concerns about vision (37/48), gastrointestinal function (33/48), and sleep (31/48). One-third (10/31) had a diagnosis of autism. Seventy-three percent (36/49) were minimally-verbal, relying on nonverbal behaviors to communicate. Verbal participants (13/49) displayed complex and co-occurring speech diagnoses regarding the perception/production of speech sounds, including phonological impairment (i.e., linguistic deficits) and speech apraxia (i.e., motor planning/programming deficits), which significantly impacted intelligibility. Receptive/expressive language and adaptive functioning were also severely impaired. Truncating variants in the last two exons of KAT6A were associated with poorer communication, daily-living skills, and socialization outcomes. In conclusion, severe communication difficulties are present in KAT6A syndrome, typically on a background of significant intellectual disability, vision, feeding and motor deficits, and autism in some. Most are minimally-verbal, with apparent contributions from underlying motor deficits and cognitive-linguistic impairment. Alternative/augmentative communication (AAC) approaches are required for many into adult life. Tailored AAC options should be fostered early, to accommodate the best communication outcomes.

Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders.

Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we describe 19 novel episignature disorders and compare the findings alongside 38 previously established episignatures for a total of 57 episignatures associated with 65 genetic syndromes. We demonstrate increasing resolution and specificity ranging from protein complex, gene, sub-gene, protein domain, and even single nucleotide-level Mendelian episignatures. We show the power of multiclass modeling to develop highly accurate and disease-specific diagnostic classifiers. This study significantly expands the number and spectrum of disorders with detectable DNA methylation episignatures, improves the clinical diagnostic capabilities through the resolution of unsolved cases and the reclassification of variants of unknown clinical significance, and provides further insight into the molecular etiology of Mendelian conditions.

Predicting speech-sound disorder outcomes in school-age children with hearing loss: The VicCHILD experience.

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.

Communication in children born very preterm: a prospective cohort study.

AIM: To compare language, speech, and voice of children born preterm and at term, and determine relevant predictors of outcome. METHOD: Three hundred infants (150 males, 150 females; 149 born at <30wks' gestation, 151 term-born) were prospectively recruited at birth from the Royal Women's Hospital. We administered the Preschool Language Scales, Fifth Edition, Diagnostic Evaluation of Articulation and Phonology, Grade Roughness Breathiness Asthenia Strain Scale, and Pediatric Voice Handicap Index at 3 years, and compared groups. We examined hypothesized predictors in children born preterm: gestational age at birth, birthweight, sex, chronic lung disease, high social risk, multilingualism, neurodevelopmental diagnosis, and oromotor feeding. RESULTS: Children born preterm had poorer language than children born at term (coefficient -5.43). Speech and voice were similar between groups (coefficients -0.70 to 1.63). Chronic lung disease predicted voice (coefficient 6.05); male sex (coefficients 4.54-6.18), high social risk (coefficient -6.02 to -9.30), and neurodevelopmental diagnosis (coefficients -16.42 to -20.61) predicted language. INTERPRETATION: Children born before 30 weeks' gestation had poorer language than children born at term. Children born preterm with neurodevelopmental disabilities or high social risk experience poorer language outcomes, and would benefit from enrichment of their language environment. WHAT THIS PAPER ADDS: Speech and voice outcomes were similar between children born preterm and at term. Male sex, high social risk, and neurodevelopmental diagnosis predicted language outcomes.

Speech and language in children with Klinefelter syndrome.

BACKGROUND: Speech and language deficits are frequent in males with Klinefelter syndrome (KS), yet the research base is slim and specific strengths and deficits in communication have not been well characterised. Nor have studies examined communication abilities across a wide age-range from infancy to adolescence. OBJECTIVE: To characterise communication in children and adolescents with KS. METHOD: Twenty-six males, aged 1;1-17;4 years, took part in the study. Oromotor, speech, language, literacy and pragmatic abilities were assessed. RESULTS: Communication impairment was seen in 92% of cases (24/26), with salient findings being impairments in social-pragmatic language (15/18; 83%), language-memory (12/15; 80%) and literacy (13/17; 76%). Mild to severe receptive and expressive language deficits were common (16/23; 70%), although performance was varied across linguistic domains of semantics, syntax, and morphology. Oromotor impairment (21/21; 100%) and speech impairments were evident from preschool through to adolescence. Whilst speech was highly intelligible (22/26; 85%), articulation errors (12/26; 46%), phonological delay (12/26; 46%), phonological disorder (5/26; 19%) and dysarthria (2/23 8.7%) were observed. Other atypical, yet mild, speech features were noted such as hyponasality (16/23; 70%). CONCLUSIONS: Language, literacy and social-pragmatic deficits are common in KS. Data suggested a trend for more notable deficits with age and increasing academic and social demands. We added novel data on the nature of speech production deficits, including persistent phonological errors in a number of cases. Earlier detection and intervention of phonological errors may reduce the risk for later language and literacy challenges and optimise academic, and ultimately social and behavioural difficulties later in life.

Characterization of speech and language phenotype in children with NRXN1 deletions.

Neurexin 1 gene (NRXN1) deletions are associated with several neurodevelopmental disorders. Communication difficulties have been reported, yet no study has examined specific speech and language features of individuals with NRXN1 deletions. Here, we characterized speech and language phenotypes in 21 children (14 families), aged 1.8-17 years, with NRXN1 deletions. Deletions ranged from 74 to 702 kb and consisted mostly of either exons 1-3 or 1-5. Speech sound disorders were frequent (69%), although few were severe. The majority (57%) of children had difficulty with receptive and/or expressive language, although no homogeneous profiles of deficit were seen across semantic, morphological, or grammatical systems. Social language difficulties were seen in over half the sample (53%). All but two individuals with language difficulties also had intellectual disability/developmental delay. Overall, while speech and language difficulties were common, there was substantial heterogeneity in the severity and type of difficulties observed and no striking communication phenotype was seen. Rather, the speech and language deficits are likely part of broader concomitant neurodevelopmental profiles (e.g., intellectual disability, social skill deficits). Nevertheless, given the high rate of affectedness, it is important speech/language development is assessed so interventions can be applied during childhood in a targeted and timely manner.