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Objectives: Purine-rich element-binding protein alpha (PURA) regulates gene expression and is ubiquitously expressed with an enrichment in neural tissues. Pathogenic variants in PURA cause the neurodevelopmental disorder PURA syndrome that has a variable phenotype but typically comprises moderate-to-severe global developmental delay, intellectual disability, early-onset hypotonia and hypothermia, epilepsy, feeding difficulties, movement disorders, and subtle facial dysmorphism. Speech is reportedly absent in most, but the specific linguistic phenotype is not well described. Methods: We used genome sequencing to identify a pathogenic gene variant as part of a study of children ascertained for severe primary speech disorder in the absence of moderate or severe ID. Results: The novel PURA c.296G>T (p.Arg99Leu) pathogenic missense variant segregated in the female proband and her affected mother. The proband had dysarthria; phonological disorder; and severe receptive and expressive language impairment, borderline intellect, attention difficulties, oropharyngeal dysmotility, and dysmorphic facial features. Her mother had dysarthria, moderate receptive language impairment, and borderline intellect. Both the proband and her mother completed mainstream schooling with classroom support. Discussion: This is the first inherited PURA pathogenic germline variant in over 600 unrelated families documented on ClinVar or reported in the literature. PURA testing should be considered in families with primary speech disorder and borderline intellectual disability, given the specific genetic counseling implications.
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Introduction: Functional magnetic resonance imaging (fMRI) can improve our understanding of neural processes subserving motor speech function. Yet its reproducibility remains unclear. This study aimed to evaluate the reproducibility of fMRI using a word repetition task across two time points. Methods: Imaging data from 14 healthy controls were analysed using a multi-level general linear model. Results: Significant activation was observed during the task in the right hemispheric cerebellar lobules IV-V, right putamen, and bilateral sensorimotor cortices. Activation between timepoints was found to be moderately reproducible across time in the cerebellum but not in other brain regions. Discussion: Preliminary findings highlight the involvement of the cerebellum and connected cerebral regions during a motor speech task. More work is needed to determine the degree of reproducibility of speech fMRI before this could be used as a reliable marker of changes in brain activity.
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This article introduces the Journal of Speech, Language, and Hearing Research Special Issue: Selected Papers From the 2022 Apraxia Kids Research Symposium. The field of childhood apraxia of speech (CAS) has developed significantly in the past 15 years, with key improvements in understanding of basic biology including genetics, neuroscience, and computational modelling; development of diagnostic tools and methods; diversity of evidence-based interventions with increasingly rigorous experimental designs; and understanding of impacts beyond impairment-level measures. Papers in this special issue not only review and synthesize the some of the substantial progress to date but also present novel findings addressing critical research gaps and adding to the overall body of knowledge. A second aim of this prologue is to report the current research needs in CAS, which arose from symposium discussions involving researchers, clinicians, and Apraxia Kids community members (including parents of children with CAS). Four primary areas of need emerged from discussions at the symposium. These were: (a) What questions should we ask? (b) Who should be in the research? (c) How do we conduct the research? and (d) How do we move from research to practice? Across themes, symposium attendees emphasized the need for CAS research to better account for the diversity of people with CAS and improve the timeliness of implementation of high-level evidence-based practice across the lifespan. It is our goal that the articles and prologue discussion in this special issue provide an appreciation of advancements in CAS research and an updated view of the most pressing needs for future research.
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BACKGROUND: Identifying language disorders earlier can help children receive the support needed to improve developmental outcomes and quality of life. Despite the prevalence and impacts of persistent language disorder, there are surprisingly no robust predictor tools available. This makes it difficult for researchers to recruit young children into early intervention trials, which in turn impedes advances in providing effective early interventions to children who need it. AIMS: To validate externally a predictor set of six variables previously identified to be predictive of language at 11 years of age, using data from the Longitudinal Study of Australian Children (LSAC) birth cohort. Also, to examine whether additional LSAC variables arose as predictive of language outcome. METHODS & PROCEDURES: A total of 5107 children were recruited to LSAC with developmental measures collected from 0 to 3 years. At 11-12 years, children completed the Clinical Evaluation of Language Fundamentals, 4th Edition, Recalling Sentences subtest. We used SuperLearner to estimate the accuracy of six previously identified parent-reported variables from ages 2-3 years in predicting low language (sentence recall score ≥ 1.5 SD below the mean) at 11-12 years. Random forests were used to identify any additional variables predictive of language outcome. OUTCOMES & RESULTS: Complete data were available for 523 participants (52.20% girls), 27 (5.16%) of whom had a low language score. The six predictors yielded fair accuracy: 78% sensitivity (95% confidence interval (CI) = [58, 91]) and 71% specificity (95% CI = [67, 75]). These predictors relate to sentence complexity, vocabulary and behaviour. The random forests analysis identified similar predictors. CONCLUSIONS & IMPLICATIONS: We identified an ultra-short set of variables that predicts 11-12-year language outcome with 'fair' accuracy. In one of few replication studies of this scale in the field, these methods have now been conducted across two population-based cohorts, with consistent results. An imminent practical implication of these findings is using these predictors to aid recruitment into early language intervention studies. Future research can continue to refine the accuracy of early predictors to work towards earlier identification in a clinical context. WHAT THIS PAPER ADDS: What is already known on the subject There are no robust predictor sets of child language disorder despite its prevalence and far-reaching impacts. A previous study identified six variables collected at age 2-3 years that predicted 11-12-year language with 75% sensitivity and 81% specificity, which warranted replication in a separate cohort. What this study adds to the existing knowledge We used machine learning methods to identify a set of six questions asked at age 2-3 years with ≥ 71% sensitivity and specificity for predicting low language outcome at 11-12 years, now showing consistent results across two large-scale population-based cohort studies. What are the potential or clinical implications of this work? This predictor set is more accurate than existing feasible methods and can be translated into a low-resource and time-efficient recruitment tool for early language intervention studies, leading to improved clinical service provision for young children likely to have persisting language difficulties.
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The Koolen-de Vries Syndrome Foundation was founded in 2013 with the mission to educate, increase awareness, promote research and develop treatments for individuals living with Koolen-de Vries Syndrome (KdVS) and their families. With this aim, the foundation has focused on: developing scientific resources through patient cell and animal models, providing seed funding to basic and clinical researchers, establishing a natural history study of KdVS and increasing patient engagement. Projects have been prioritized across these areas of focus with an emphasis on expanding international research on KdVS, supporting translational research, establishing an international natural history study and conducting studies to assess patient priorities. With the incredible growth amongst our research and patient community in the last decade, our goal is to have our first clinical trial for KdVS in 2026.
Koolen de-Vries Syndrome: a journey from diagnosis to treatments The Koolen-de Vries Syndrome Foundation ('KdVSF') was founded in 2013 with the mission to develop treatments for all individuals diagnosed with KdVS. With this aim, we have focused on several research priorities for our community: developing cell and animal models for KdVS for our researchers to utilize for experiments, providing research grants to KdVS basic and clinical researchers, establishing a natural history study of KdVS and increasing patient engagement and diversity. The KdVS research and patient community has expanded tremendously over the last decade, and there is growing excitement over the possible treatments currently being investigated amongst KdVS researchers. With our current focus on translational research and research aimed at identifying treatment strategies in KdVS patients, our goal is to have our first clinical trial for KdVS in late 2026.
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Up to half of all people with multiple sclerosis experience communication difficulties due to dysarthria, a disorder that impacts the motor aspects of speech production. Dysarthria in multiple sclerosis is linked to cerebellar dysfunction, disease severity and lesion load, but the neuroanatomical substrates of these symptoms remain unclear. In this study, 52 participants with multiple sclerosis and 14 age- and sex-matched healthy controls underwent structural and diffusion MRI, clinical assessment of disease severity and cerebellar dysfunction and a battery of motor speech tasks. Assessments of regional brain volume and white matter integrity, and their relationships with clinical and speech measures, were undertaken. White matter tracts of interest included the interhemispheric sensorimotor tract, cerebello-thalamo-cortical tract and arcuate fasciculus, based on their roles in motor and speech behaviours. Volumetric analyses were targeted to Broca's area, Wernicke's area, the corpus callosum, thalamus and cerebellum. Our results indicated that multiple sclerosis participants scored worse on all motor speech tasks. Fixel-based diffusion MRI analyses showed significant evidence of white matter tract atrophy in each tract of interest. Correlational analyses further indicated that higher speech naturalness-a perceptual measure of dysarthria-and lower reading rate were associated with axonal damage in the interhemispheric sensorimotor tract and left arcuate fasciculus in people with multiple sclerosis. Axonal damage in all tracts of interest also correlated with clinical scales sensitive to cerebellar dysfunction. Participants with multiple sclerosis had lower volumes of the thalamus and corpus callosum compared with controls, although no brain volumetrics correlated with measures of dysarthria. These findings indicate that axonal damage, particularly when measured using diffusion metrics, underpin dysarthria in multiple sclerosis.
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To examine predictors and growth in language for verbal autistic and non-autistic children with/without low language from 4 to 11 years. Receptive and expressive language trajectories were compared in a community sample of 1026 children at ages 5, 7, and 11 years, across four groups: two autistic groups; one with and one without low language; and two non-autistic groups; one with and one without low language. Groups were delineated on baseline assessment at 4 years. Non-autistic and autistic children with low language had lower mean expressive language scores than the non-autistic typical language group (22.26 and 38.53 units lower, respectively, p < 0.001), yet demonstrated faster language growth across 5 to 11 years (p < 0.001 and p = 0.002, respectively). Both groups without low language had similar mean expressive language scores (p = 0.864) and a comparable rate of growth (p = 0.645). Language at 4 years was the only consistent predictor of language at 11 years for autistic children. Results were similar for receptive language in all analyses except there was no significant difference in rate of progress (slope) for the autistic with low language group compared with the typical language group (p = 0.272). Findings suggest early language ability, rather than a diagnosis of autism, is key to determining language growth and outcomes at 11 years in verbal children. Furthermore, children with low language showed developmental acceleration compared with same age peers.
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Background and Objectives: Pathogenic variants in GRIN2A are associated with a spectrum of epilepsy-aphasia syndromes (EASs). Seizures as well as speech and language disorders occur frequently but vary widely in severity, both between individuals and across the life span. The link between this phenotypic spectrum and brain characteristics is unknown. Specifically, altered brain networks at the root of speech and language deficits remain to be identified. Patients with pathogenic variants in GRIN2A offer an opportunity to interrogate the impact of glutamate receptor dysfunction on brain development. Methods: We characterized brain anomalies in individuals with pathogenic GRIN2A variants and EASs, hypothesizing alterations in perisylvian speech-language regions and the striatum. We compared structural MRI data from 10 individuals (3 children and 7 adults, 3 female) with pathogenic GRIN2A variants with data from age-matched controls (N = 51 and N = 203 in a secondary analysis). We examined cortical thickness and volume in 4 a priori hypothesized speech and language regions (inferior frontal, precentral, supramarginal, and superior temporal) and across the whole brain. Subcortical structures (hippocampus, basal ganglia, thalamus) and the corpus callosum were also compared. Results: Individuals with pathogenic GRIN2A variants showed increased thickness and volume in the posterior part of Broca's area (inferior frontal gyrus, pars opercularis). For thickness, the effects were bilateral but more pronounced in the left (large effect size, η2 = 0.37) than the right (η2 = 0.12) hemisphere. Both volume and thickness were also higher in the bilateral superior temporal region while the supramarginal region showed increased thickness only. Whole-brain analyses confirmed left-sided thickness increases in Broca's area, with additional increases in the occipital and superior frontal cortices bilaterally. Hippocampal volume was reduced in the left hemisphere. There were no age-dependent effects or corpus callosum group differences. Discussion: Anomalies in perisylvian regions, with largest differences in Broca's area, suggest an altered development of classical speech-language networks in GRIN2A-related EAS. Left hippocampal reduction suggests a role for this structure in early speech and language development and is consistent with GRIN2A gene expression in that region. Overall, elucidating the neural correlates of EAS provides insights into the impact of GRIN2A dysfunction, opening avenues for targeted intervention in developmental syndromes with compromised speech-language development.
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Speech and language disorders are known to have a substantial genetic contribution. Although frequently examined as components of other conditions, research on the genetic basis of linguistic differences as separate phenotypic subgroups has been limited so far. Here, we performed an in-depth characterization of speech and language disorders in 52,143 individuals, reconstructing clinical histories using a large-scale data mining approach of the Electronic Medical Records (EMR) from an entire large paediatric healthcare network. The reported frequency of these disorders was the highest between 2 and 5 years old and spanned a spectrum of twenty-six broad speech and language diagnoses. We used Natural Language Processing to assess to which degree clinical diagnosis in full-text notes were reflected in ICD-10 diagnosis codes. We found that aphasia and speech apraxia could be easily retrieved through ICD-10 diagnosis codes, while stuttering as a speech phenotype was only coded in 12% of individuals through appropriate ICD-10 codes. We found significant comorbidity of speech and language disorders in neurodevelopmental conditions (30.31%) and to a lesser degree with epilepsies (6.07%) and movement disorders (2.05%). The most common genetic disorders retrievable in our EMR analysis were STXBP1 (n=21), PTEN (n=20), and CACNA1A (n=18). When assessing associations of genetic diagnoses with specific linguistic phenotypes, we observed associations of STXBP1 and aphasia (P=8.57 × 10-7, CI=18.62-130.39) and MYO7A with speech and language development delay due to hearing loss (P=1.24 × 10-5, CI=17.46-Inf). Finally, in a sub-cohort of 726 individuals with whole exome sequencing data, we identified an enrichment of rare variants in synaptic protein and neuronal receptor pathways and associations of UQCRC1 with expressive aphasia and WASHC4 with abnormality of speech or vocalization. In summary, our study outlines the landscape of paediatric speech and language disorders, confirming the phenotypic complexity of linguistic traits and novel genotype-phenotype associations. Subgroups of paediatric speech and language disorders differ significantly with respect to the composition of monogenic aetiologies.
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PURPOSE: Stuttering is a speech condition that can have a major impact on a person's quality of life. This descriptive study aimed to identify subgroups of people who stutter (PWS) based on stuttering burden and to investigate differences between these subgroups on psychosocial aspects of life. METHOD: The study included 618 adult participants who stutter. They completed a detailed survey examining stuttering symptomatology, impact of stuttering on anxiety, education and employment, experience of stuttering, and levels of depression, anxiety, and stress. A two-step cluster analytic procedure was performed to identify subgroups of PWS, based on self-report of stuttering frequency, severity, affect, and anxiety, four measures that together inform about stuttering burden. RESULTS: We identified a high- (n = 230) and a low-burden subgroup (n = 372). The high-burden subgroup reported a significantly higher impact of stuttering on education and employment, and higher levels of general depression, anxiety, stress, and overall impact of stuttering. These participants also reported that they trialed more different stuttering therapies than those with lower burden. CONCLUSIONS: Our results emphasize the need to be attentive to the diverse experiences and needs of PWS, rather than treating them as a homogeneous group. Our findings also stress the importance of personalized therapeutic strategies for individuals with stuttering, considering all aspects that could influence their stuttering burden. People with high-burden stuttering might, for example, have a higher need for psychological therapy to reduce stuttering-related anxiety. People with less emotional reactions but severe speech distortions may also have a moderate to high burden, but they may have a higher need for speech techniques to communicate with more ease. Future research should give more insights into the therapeutic needs of people highly burdened by their stuttering. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.25582980.
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Ansiedad , Costo de Enfermedad , Depresión , Calidad de Vida , Tartamudeo , Humanos , Tartamudeo/psicología , Femenino , Masculino , Adulto , Calidad de Vida/psicología , Persona de Mediana Edad , Ansiedad/psicología , Depresión/psicología , Depresión/etiología , Adulto Joven , Estrés Psicológico/psicología , Adolescente , Anciano , Empleo/psicología , Encuestas y Cuestionarios , AutoinformeAsunto(s)
Ecocardiografía , Ventrículos Cardíacos , Humanos , Ecocardiografía/métodos , Ventrículos Cardíacos/diagnóstico por imagen , Masculino , Femenino , Reproducibilidad de los Resultados , Valores de Referencia , Adulto , Sensibilidad y Especificidad , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Hipertrofia Ventricular Izquierda/diagnóstico , Hipertrofia Ventricular Izquierda/fisiopatología , Tamaño de los ÓrganosRESUMEN
Most patients with GNB1 encephalopathy have developmental delay and/or intellectual disability, brain anomalies and seizures. Recently, two cases with GNB1 encephalopathy caused by haploinsufficiency have been reported that also show a Prader-Willi-like phenotype of childhood hypotonia and severe obesity. Here we present three new cases from our expert centre for genetic obesity in which GNB1 truncating and splice variants, probably leading to haploinsufficiency, were identified. They all have obesity, hyperphagia and intellectual deficit. The clinical cases and their weight courses are presented, together with a review of all 68 published cases with GNB1 encephalopathy. Information on weight was not mentioned in most of these articles, so we contacted authors for additional clinical information on weight status and hyperphagia. Of the 42 patients whose weight status we could determine, obesity was present in 8 patients (19%). Obesity is significantly over-represented in the group with truncating and splicing variants. In this group, we see an obesity prevalence of 75%. Since GNB1 has been linked to several key genes in the hypothalamic leptin-melanocortin pathway, which regulates satiety and energy expenditure, our data support the potential association between GNB1 haploinsufficiency and genetic obesity. We also suggest GNB1 is a candidate gene for the known obesity phenotype of the 1p36 microdeletion syndrome given this chromosomal region includes the GNB1 gene. Knowledge of an additional obesity phenotype is important for prognosis, early interventions against obesity and awareness when prescribing weight-inducing medication.
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Subunidades beta de la Proteína de Unión al GTP , Haploinsuficiencia , Obesidad , Humanos , Masculino , Femenino , Subunidades beta de la Proteína de Unión al GTP/genética , Obesidad/genética , Niño , Discapacidad Intelectual/genética , Preescolar , Fenotipo , Adolescente , Hiperfagia/genética , AdultoRESUMEN
With increasing gene discoveries for severe speech disorders, genomic testing can alter the diagnostic and clinical paradigms, enabling better life outcomes for children and their families. However, evidence on the value of the outcomes generated is lacking, impeding optimal translation into health care. This study aims to estimate the value and uptake of genomic testing for severe childhood speech disorders. A discrete choice experiment was undertaken to elicit preferences for genomic testing from the perspective of the Australian public (n = 951) and parents of children experiencing severe speech disorder (n = 56). Choice attributes associated with genomic testing were identified through focus groups. A Bayesian D-efficient design was used to develop choice scenarios and choice data were analyzed using a panel error component mixed logit model and a latent class model. Statistically significant preferences were identified across all seven attributes. The mean monetary value of the benefits of genomic testing relative to standard diagnostic care in Australia was estimated at AU$7489 (US$5021) and AU$4452 (US$2985) from the perspectives of the Australian public and families with lived experience of severe speech disorders, with a corresponding test uptake of 94.2% and 99.6%. To ensure fair prioritization of genomics, decision-makers need to consider the wide range of risks and benefits associated with genomic information.
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Conducta de Elección , Pruebas Genéticas , Niño , Humanos , Australia , Teorema de Bayes , Trastornos del Habla/diagnóstico , Trastornos del Habla/genética , Encuestas y Cuestionarios , Prioridad del PacienteRESUMEN
Pathogenic variants in BRPF1 cause intellectual disability, ptosis and facial dysmorphism. Speech and language deficits have been identified as a manifestation of BRPF1-related disorder but have not been systematically characterized. We provide a comprehensive delineation of speech and language abilities in BRPF1-related disorder and expand the phenotype. Speech and language, and health and medical history were assessed in 15 participants (male = 10, median age = 7 years 4 months) with 14 BRPF1 variants. Language disorders were common (11/12), and most had mild to moderate deficits across receptive, expressive, written, and social-pragmatic domains. Speech disorders were frequent (7/9), including phonological delay (6/9) and disorder (3/9), and childhood apraxia of speech (3/9). All those tested for cognitive abilities had a FSIQ ≥70 (4/4). Participants had vision impairment (13/15), fine (8/15) and gross motor delay (10/15) which often resolved in later childhood, infant feeding impairment (8/15), and infant hypotonia (9/15). We have implicated BRPF1-related disorder as causative for speech and language disorder, including childhood apraxia of speech. Adaptive behavior and cognition were strengths when compared to other monogenic neurodevelopmental chromatin-related disorders. The universal involvement of speech and language impairment is noteable, relative to the high degree of phenotypic variability in BRPF1-related disorder.
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Apraxias , Discapacidad Intelectual , Trastornos del Desarrollo del Lenguaje , Niño , Humanos , Masculino , Proteínas Adaptadoras Transductoras de Señales/genética , Apraxias/genética , Proteínas que Contienen Bromodominio , Proteínas de Unión al ADN/genética , Discapacidad Intelectual/genética , Trastornos del Desarrollo del Lenguaje/genética , Fenotipo , Habla , Trastornos del Habla , FemeninoAsunto(s)
Equilibrio Ácido-Base , Diferenciación Celular , Factores de Transcripción Forkhead , Animales , Factores de Transcripción Forkhead/metabolismo , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/fisiología , Ratones , Equilibrio Ácido-Base/fisiología , Proteínas Represoras/metabolismo , Proteínas Represoras/genética , Riñón/citología , Riñón/metabolismoRESUMEN
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.
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Trastornos del Habla , Humanos , Trastornos del Habla/genética , Niño , Predisposición Genética a la Enfermedad/genética , Apraxias/genética , Factores de Transcripción Forkhead/genética , Masculino , FemeninoRESUMEN
Pathogenic variants in DDX3X are associated with neurodevelopmental disorders. Communication impairments are commonly reported, yet specific speech and language diagnoses have not been delineated, preventing prognostic counseling and targeted therapies. Here, we characterized speech and language in 38 female individuals, aged 1.69-24.34 years, with pathogenic and likely pathogenic DDX3X variants (missense, n = 13; nonsense, n = 12; frameshift, n = 7; splice site, n = 3; synonymous, n = 2; deletion, n = 1). Standardized speech, language, motor, social, and adaptive behavior assessments were administered. All participants had gross motor deficits in infancy (34/34), and fine motor deficits were common throughout childhood (94%; 32/34). Intellectual disability was reported in 86% (24/28) of participants over 4 years of age. Expressive, receptive, and social communication skills were, on average, severely impaired. However, receptive language was significantly stronger than expressive language ability. Over half of the assessed participants were minimally verbal (66%; 22/33; range = 2 years 2 months-24 years 4 months; mean = 8 years; SD = 6 years) and augmented speech with sign language, gestures, or digital devices. A quarter of the cohort had childhood apraxia of speech (25%; 9/36). Despite speech and language impairments, social motivation was a relevant strength. Many participants used augmentative and alternative communication (AAC), underscoring the need for early, tailored, and comprehensive AAC intervention.
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ARN Helicasas DEAD-box , Trastornos del Neurodesarrollo , Habla , Humanos , Femenino , Preescolar , Niño , Adolescente , Trastornos del Neurodesarrollo/genética , Lactante , Adulto Joven , ARN Helicasas DEAD-box/genética , Habla/fisiología , Discapacidad Intelectual/genética , Adulto , Masculino , Lenguaje , Trastornos del Habla , Comunicación , Trastornos del Desarrollo del Lenguaje/genéticaRESUMEN
The disconnected (disco)-interacting protein 2 (DIP2) gene was first identified in D. melanogaster and contains a DNA methyltransferase-associated protein 1 (DMAP1) binding domain, Acyl-CoA synthetase domain and AMP-binding sites. DIP2 regulates axonal bifurcation of the mushroom body neurons in D. melanogaster and is required for axonal regeneration in the neurons of C. elegans. The DIP2 homologues in vertebrates, Disco-interacting protein 2 homolog A (DIP2A), Disco-interacting protein 2 homolog B (DIP2B), and Disco-interacting protein 2 homolog C (DIP2C), are highly conserved and expressed widely in the central nervous system. Although there is evidence that DIP2C plays a role in cognition, reports of pathogenic variants in these genes are rare and their significance is uncertain. We present 23 individuals with heterozygous DIP2C variants, all manifesting developmental delays that primarily affect expressive language and speech articulation. Eight patients had de novo variants predicting loss-of-function in the DIP2C gene, two patients had de novo missense variants, three had paternally inherited loss of function variants and six had maternally inherited loss-of-function variants, while inheritance was unknown for four variants. Four patients had cardiac defects (hypertrophic cardiomyopathy, atrial septal defects, and bicuspid aortic valve). Minor facial anomalies were inconsistent but included a high anterior hairline with a long forehead, broad nasal tip, and ear anomalies. Brainspan analysis showed elevated DIP2C expression in the human neocortex at 10-24 weeks after conception. With the cases presented herein, we provide phenotypic and genotypic data supporting the association between loss-of-function variants in DIP2C with a neurocognitive phenotype.
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Haploinsuficiencia , Trastornos del Desarrollo del Lenguaje , Humanos , Masculino , Femenino , Haploinsuficiencia/genética , Trastornos del Desarrollo del Lenguaje/genética , Trastornos del Desarrollo del Lenguaje/patología , Trastornos del Desarrollo del Lenguaje/fisiopatología , Preescolar , Niño , Lactante , Fenotipo , Predisposición Genética a la EnfermedadRESUMEN
OBJECTIVES: Speech and language impairments are core features of the neurodevelopmental genetic condition Kleefstra syndrome. Communication has not been systematically examined to guide intervention recommendations. We define the speech, language and cognitive phenotypic spectrum in a large cohort of individuals with Kleefstra syndrome. METHOD: 103 individuals with Kleefstra syndrome (40 males, median age 9.5 years, range 1-43 years) with pathogenic variants (52 9q34.3 deletions, 50 intragenic variants, 1 balanced translocation) were included. Speech, language and non-verbal communication were assessed. Cognitive, health and neurodevelopmental data were obtained. RESULTS: The cognitive spectrum ranged from average intelligence (12/79, 15%) to severe intellectual disability (12/79, 15%). Language ability also ranged from average intelligence (10/90, 11%) to severe intellectual disability (53/90, 59%). Speech disorders occurred in 48/49 (98%) verbal individuals and even occurred alongside average language and cognition. Developmental regression occurred in 11/80 (14%) individuals across motor, language and psychosocial domains. Communication aids, such as sign and speech-generating devices, were crucial for 61/103 (59%) individuals including those who were minimally verbal, had a speech disorder or following regression. CONCLUSIONS: The speech, language and cognitive profile of Kleefstra syndrome is broad, ranging from severe impairment to average ability. Genotype and age do not explain the phenotypic variability. Early access to communication aids may improve communication and quality of life.