Perisylvian and Hippocampal Anomalies in Individuals With Pathogenic GRIN2A Variants.

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.

Clinician Awareness of Stickler Syndromes Among Australian Allied Health Care Professionals.

Purpose: Stickler Syndromes are multisystem collagenopathies affecting 1 in 7500-9000 individuals and are associated with craniofacial, ocular, auditory, and musculoskeletal complications. Prophylactic retinopexy treatment reduces the risk of retinal detachment, emphasising the need for early detection and multidisciplinary referral. This study evaluated knowledge and awareness of Stickler Syndromes among allied health professionals and their perceived needs for targeted education to improve multidisciplinary care. Methods: A cross-sectional survey was undertaken among audiologists, speech pathologists, optometrists, orthoptists, and physiotherapists in Australia. Survey questions included practitioner demographics, awareness and knowledge of Stickler Syndromes, confidence managing Stickler Syndromes, and perception of multidisciplinary care needs for Stickler Syndromes. Results: Of 180 healthcare professions who participated (79% female; 78% aged between 25 and 44 years), 55% indicated that they had heard of Stickler Syndrome, and 14% had directly worked with patients known to have Stickler Syndromes. Practitioners who had were either optometrists, orthoptists, or audiologists. The most recognised clinical sign of Stickler Syndromes was retinal detachment (selected by 66% of optometrists and orthoptists and 16% of other professions), but only 41% of optometrists and orthoptists (27% all respondents) selected cryopexy as a potential management strategy. Vitreous anomaly was recognised as a clinical feature by 20% of all respondents. Overall, 69% of allied health professionals did not feel confident managing Stickler Syndromes, and a similar number of practitioners (69%) indicated that they were willing to attend professional development courses for complex conditions such as Stickler Syndromes. Conclusion: This study provides meaningful insights on awareness and knowledge of Stickler Syndromes among allied healthcare professionals. Targeted clinician education, enhanced communication between healthcare entities, and multidisciplinary care programs can significantly improve the integrated care of Stickler Syndromes leading to better patient outcomes.

The value of genomic testing in severe childhood speech disorders.

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.

Clinical phenotype of FOXP1 syndrome: parent-reported medical signs and symptoms in 40 individuals.

BACKGROUND: The first studies on patients with forkhead-box protein P1 (FOXP1) syndrome reported associated global neurodevelopmental delay, autism symptomatology, dysmorphic features and cardiac and urogenital malformations. The aim of this study was to assess the prevalence of congenital abnormalities in an unbiased cohort of patients with FOXP1 syndrome and to document rare complications. METHODS: Patients with FOXP1 syndrome were included, mostly diagnosed via whole-exome sequencing for neurodevelopmental delay. A parent-report questionnaire was used to assess medical signs and symptoms, including questions about features rated as most burdensome by patients and their family. RESULTS: Forty individuals were included, 20 females and 20 males. The mean age at assessment was 13.2 years (median 8.5 years; range 2-54 years; ≥18 years n = 7). Seven adults were included. All patients had developmental problems, including cognitive, communication, social-emotional and motor delays. The most prevalent medical signs and symptoms include delayed bladder control, sleeping problems, hypermetropia, strabismus, sacral dimple, undescended testes, abnormal muscle tone and airway infections. The most burdensome complaints for patients with FOXP1 syndrome, as perceived by parents, include intellectual disability, impaired communication, behaviour problems, lack of age-appropriate self-reliance, attention problems and anxiety. According to parents, patients have quite similar reported symptoms, although incontinence, obsessions and a complex sensory profile have a higher ranking. CONCLUSION: The results of this study may be used to further guide medical management and identify patient priorities for future research targeted on those features of FOXP1 syndrome that most impair quality of life of patients and their families.

Self-Reported Stuttering Severity Is Accurate: Informing Methods for Large-Scale Data Collection in Stuttering.

PURPOSE: To our knowledge, there are no data examining the agreement between self-reported and clinician-rated stuttering severity. In the era of big data, self-reported ratings have great potential utility for large-scale data collection, where cost and time preclude in-depth assessment by a clinician. Equally, there is increasing emphasis on the need to recognize an individual's experience of their own condition. Here, we examined the agreement between self-reported stuttering severity compared to clinician ratings during a speech assessment. As a secondary objective, we determined whether self-reported stuttering severity correlated with an individual's subjective impact of stuttering. METHOD: Speech-language pathologists conducted face-to-face speech assessments with 195 participants (137 males) aged 5-84 years, recruited from a cohort of people with self-reported stuttering. Stuttering severity was rated on a 10-point scale by the participant and by two speech-language pathologists. Participants also completed the Overall Assessment of the Subjective Experience of Stuttering (OASES). Clinician and participant ratings were compared. The association between stuttering severity and the OASES scores was examined. RESULTS: There was a strong positive correlation between speech-language pathologist and participant-reported ratings of stuttering severity. Participant-reported stuttering severity correlated weakly with the four OASES domains and with the OASES overall impact score. CONCLUSIONS: Participants were able to accurately rate their stuttering severity during a speech assessment using a simple one-item question. This finding indicates that self-report stuttering severity is a suitable method for large-scale data collection. Findings also support the collection of self-report subjective experience data using questionnaires, such as the OASES, which add vital information about the participants' experience of stuttering that is not captured by overt speech severity ratings alone.

In-depth characterisation of a cohort of individuals with missense and loss-of-function variants disrupting FOXP2.

BACKGROUND: Heterozygous disruptions of FOXP2 were the first identified molecular cause for severe speech disorder: childhood apraxia of speech (CAS), and yet few cases have been reported, limiting knowledge of the condition. METHODS: Here we phenotyped 28 individuals from 17 families with pathogenic FOXP2-only variants (12 loss-of-function, five missense variants; 14 males; aged 2 to 62 years). Health and development (cognitive, motor, social domains) were examined, including speech and language outcomes with the first cross-linguistic analysis of English and German. RESULTS: Speech disorders were prevalent (23/25, 92%) and CAS was most common (22/25, 88%), with similar speech presentations across English and German. Speech was still impaired in adulthood, and some speech sounds (eg, 'th', 'r', 'ch', 'j') were never acquired. Language impairments (21/25, 84%) ranged from mild to severe. Comorbidities included feeding difficulties in infancy (10/26, 38%), fine (13/26, 50%) and gross (13/26, 50%) motor impairment, anxiety (5/27, 19%), depression (6/27, 22%) and sleep disturbance (10/24, 42%). Physical features were common (22/27, 81%) but with no consistent pattern. Cognition ranged from average to mildly impaired and was incongruent with language ability; for example, seven participants with severe language disorder had average non-verbal cognition. CONCLUSIONS: Although we identify an increased prevalence of conditions like anxiety, depression and sleep disturbance, we confirm that the consequences of FOXP2 dysfunction remain relatively specific to speech disorder, as compared with other recently identified monogenic conditions associated with CAS. Thus, our findings reinforce that FOXP2 provides a valuable entry point for examining the neurobiological bases of speech disorder.

Genetic aetiologies for childhood speech disorder: novel pathways co-expressed during brain development.

Childhood apraxia of speech (CAS), the prototypic severe childhood speech disorder, is characterized by motor programming and planning deficits. Genetic factors make substantive contributions to CAS aetiology, with a monogenic pathogenic variant identified in a third of cases, implicating around 20 single genes to date. Here we aimed to identify molecular causation in 70 unrelated probands ascertained with CAS. We performed trio genome sequencing. Our bioinformatic analysis examined single nucleotide, indel, copy number, structural and short tandem repeat variants. We prioritised appropriate variants arising de novo or inherited that were expected to be damaging based on in silico predictions. We identified high confidence variants in 18/70 (26%) probands, almost doubling the current number of candidate genes for CAS. Three of the 18 variants affected SETBP1, SETD1A and DDX3X, thus confirming their roles in CAS, while the remaining 15 occurred in genes not previously associated with this disorder. Fifteen variants arose de novo and three were inherited. We provide further novel insights into the biology of child speech disorder, highlighting the roles of chromatin organization and gene regulation in CAS, and confirm that genes involved in CAS are co-expressed during brain development. Our findings confirm a diagnostic yield comparable to, or even higher, than other neurodevelopmental disorders with substantial de novo variant burden. Data also support the increasingly recognised overlaps between genes conferring risk for a range of neurodevelopmental disorders. Understanding the aetiological basis of CAS is critical to end the diagnostic odyssey and ensure affected individuals are poised for precision medicine trials.

The Genetic and Molecular Basis of Developmental Language Disorder: A Review.

Language disorders are highly heritable and are influenced by complex interactions between genetic and environmental factors. Despite more than twenty years of research, we still lack critical understanding of the biological underpinnings of language. This review provides an overview of the genetic landscape of developmental language disorders (DLD), with an emphasis on the importance of defining the specific features (the phenotype) of DLD to inform gene discovery. We review the specific phenotype of DLD in the genetic literature, and the influence of historic variation in diagnostic inclusion criteria on researchers' ability to compare and replicate genotype-phenotype studies. This review provides an overview of the recently identified gene pathways in populations with DLD and explores current state-of-the-art approaches to genetic analysis based on the hypothesised architecture of DLD. We will show how recent global efforts to unify diagnostic criteria have vastly increased sample size and allow for large multi-cohort metanalyses, leading the identification of a growing number of contributory loci. We emphasise the important role of estimating the genetic architecture of DLD to decipher underlying genetic associations. Finally, we explore the potential for epigenetics and environmental interactions to further unravel the biological basis of language disorders.

Social motivation a relative strength in DYRK1A syndrome on a background of significant speech and language impairments.

Speech and language impairments are commonly reported in DYRK1A syndrome. Yet, speech and language abilities have not been systematically examined in a prospective cohort study. Speech, language, social behaviour, feeding, and non-verbal communication skills were assessed using standardised tools. The broader health and medical phenotype was documented using caregiver questionnaires, interviews and confirmation with medical records. 38 individuals with DYRK1A syndrome (23 male, median age 8 years 3 months, range 1 year 7 months to 25 years) were recruited. Moderate to severe intellectual disability (ID), autism spectrum disorder (ASD), vision, motor and feeding impairments were common, alongside epilepsy in a third of cases. Speech and language was disordered in all participants. Many acquired some degree of verbal communication, yet few (8/38) developed sufficient oral language skills to rely solely on verbal communication. Speech was characterised by severe apraxia and dysarthria in verbal participants, resulting in markedly poor intelligibility. Those with limited verbal language (30/38) used a combination of sign and graphic augmentative and alternative communication (AAC) systems. Language skills were low across expressive, receptive, and written domains. Most had impaired social behaviours (25/29). Restricted and repetitive interests were most impaired, whilst social motivation was a relative strength. Few individuals with DYRK1A syndrome use verbal speech as their sole means of communication, and hence, all individuals need early access to tailored, graphic AAC systems to support their communication. For those who develop verbal speech, targeted therapy for apraxia and dysarthria should be considered to improve intelligibility and, consequently, communication autonomy.

Severe speech impairment is a distinguishing feature of FOXP1-related disorder.

AIM: To delineate the speech and language phenotype of a cohort of individuals with FOXP1-related disorder. METHOD: We administered a standardized test battery to examine speech and oral motor function, receptive and expressive language, non-verbal cognition, and adaptive behaviour. Clinical history and cognitive assessments were analysed together with speech and language findings. RESULTS: Twenty-nine patients (17 females, 12 males; mean age 9y 6mo; median age 8y [range 2y 7mo-33y]; SD 6y 5mo) with pathogenic FOXP1 variants (14 truncating, three missense, three splice site, one in-frame deletion, eight cytogenic deletions; 28 out of 29 were de novo variants) were studied. All had atypical speech, with 21 being verbal and eight minimally verbal. All verbal patients had dysarthric and apraxic features, with phonological deficits in most (14 out of 16). Language scores were low overall. In the 21 individuals who carried truncating or splice site variants and small deletions, expressive abilities were relatively preserved compared with comprehension. INTERPRETATION: FOXP1-related disorder is characterized by a complex speech and language phenotype with prominent dysarthria, broader motor planning and programming deficits, and linguistic-based phonological errors. Diagnosis of the speech phenotype associated with FOXP1-related dysfunction will inform early targeted therapy. What this paper adds Individuals with FOXP1-related disorder have a complex speech and language phenotype. Dysarthria, which impairs intelligibility, is the dominant feature of the speech profile. No participants were receiving speech therapy for dysarthria, but were good candidates for therapy Features of speech apraxia occur alongside persistent phonological errors. Language abilities are low overall; however, expressive language is a relative strength.

Clinical delineation of SETBP1 haploinsufficiency disorder.

SETBP1 haploinsufficiency disorder (MIM#616078) is caused by haploinsufficiency of SETBP1 on chromosome 18q12.3, but there has not yet been any systematic evaluation of the major features of this monogenic syndrome, assessing penetrance and expressivity. We describe the first comprehensive study to delineate the associated clinical phenotype, with findings from 34 individuals, including 24 novel cases, all of whom have a SETBP1 loss-of-function variant or single (coding) gene deletion, confirmed by molecular diagnostics. The most commonly reported clinical features included mild motor developmental delay, speech impairment, intellectual disability, hypotonia, vision impairment, attention/concentration deficits, and hyperactivity. Although there is a mild overlap in certain facial features, the disorder does not lead to a distinctive recognizable facial gestalt. As well as providing insight into the clinical spectrum of SETBP1 haploinsufficiency disorder, this reports puts forward care recommendations for patient management.

Speech and language deficits are central to SETBP1 haploinsufficiency disorder.

Expressive communication impairment is associated with haploinsufficiency of SETBP1, as reported in small case series. Heterozygous pathogenic loss-of-function (LoF) variants in SETBP1 have also been identified in independent cohorts ascertained for childhood apraxia of speech (CAS), warranting further investigation of the roles of this gene in speech development. Thirty-one participants (12 males, aged 0; 8-23; 2 years, 28 with pathogenic SETBP1 LoF variants, 3 with 18q12.3 deletions) were assessed for speech, language and literacy abilities. Broader development was examined with standardised motor, social and daily life skills assessments. Gross and fine motor deficits (94%) and intellectual impairments (68%) were common. Protracted and aberrant speech development was consistently seen, regardless of motor or intellectual ability. We expand the linguistic phenotype associated with SETBP1 LoF syndrome (SETBP1 haploinsufficiency disorder), revealing a striking speech presentation that implicates both motor (CAS, dysarthria) and language (phonological errors) systems, with CAS (80%) being the most common diagnosis. In contrast to past reports, the understanding of language was rarely better preserved than language expression (29%). Language was typically low, to moderately impaired, with commensurate expression and comprehension ability. Children were sociable with a strong desire to communicate. Minimally verbal children (32%) augmented speech with sign language, gestures or digital devices. Overall, relative to general development, spoken language and literacy were poorer than social, daily living, motor and adaptive behaviour skills. Our findings show that poor communication is a central feature of SETBP1 haploinsufficiency disorder, confirming this gene as a strong candidate for speech and language disorders.

Speech, Language, and Oromotor Skills in Patients With Polymicrogyria.

OBJECTIVE: To determine whether specific speech, language, and oromotor profiles are associated with different patterns of polymicrogyria, we assessed 52 patients with polymicrogyria using a battery of standardized tests and correlated findings with topography and severity of polymicrogyria. METHODS: Patients were identified via clinical research databases and invited to participate, irrespective of cognitive and verbal language abilities. We conducted standardized assessments of speech, oromotor structure and function, language, and nonverbal IQ. Data were analyzed according to normative assessment data and descriptive statistics. We conducted a correlation analysis between topographic pattern and speech and language findings. RESULTS: Fifty-two patients (33 male, 63%) were studied at an average age of 12.7 years (range 2.5-36 years). All patients had dysarthria, which ranged from mild impairment to anarthria. Developmental speech errors (articulation and phonology), oral motor structure and function deficits, and language disorder were frequent. A total of 23/29 (79%) had cognitive abilities in the low average to extremely low range. In the perisylvian polymicrogyria group (36/52), speech, everyday language, and oral motor impairments were more severe, compared to generalized (1 patient), frontal (3), polymicrogyria with periventricular nodular heterotopia (3), parasagittal parieto-occipital (1), mesial occipital (1), and other (7) patterns. CONCLUSIONS: Dysarthria is a core feature of polymicrogyria, often accompanied by receptive and expressive language impairments. These features are associated with all polymicrogyria distribution patterns and more severe in individuals with bilateral polymicrogyria, particularly in the perisylvian region.

Severe childhood speech disorder: Gene discovery highlights transcriptional dysregulation.

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.

Inhibition of Upf2-Dependent Nonsense-Mediated Decay Leads to Behavioral and Neurophysiological Abnormalities by Activating the Immune Response.

In humans, disruption of nonsense-mediated decay (NMD) has been associated with neurodevelopmental disorders (NDDs) such as autism spectrum disorder and intellectual disability. However, the mechanism by which deficient NMD leads to neurodevelopmental dysfunction remains unknown, preventing development of targeted therapies. Here we identified novel protein-coding UPF2 (UP-Frameshift 2) variants in humans with NDD, including speech and language deficits. In parallel, we found that mice lacking Upf2 in the forebrain (Upf2 fb-KO mice) show impaired NMD, memory deficits, abnormal long-term potentiation (LTP), and social and communication deficits. Surprisingly, Upf2 fb-KO mice exhibit elevated expression of immune genes and brain inflammation. More importantly, treatment with two FDA-approved anti-inflammatory drugs reduced brain inflammation, restored LTP and long-term memory, and reversed social and communication deficits. Collectively, our findings indicate that impaired UPF2-dependent NMD leads to neurodevelopmental dysfunction and suggest that anti-inflammatory agents may prove effective for treatment of disorders with impaired NMD.

Speech and language in bilateral perisylvian polymicrogyria: a systematic review.

AIM: We aimed to systematically review the speech production, language, and oral function phenotype of bilateral perisylvian polymicrogyria (BPP), and examine the correlation between the topography of polymicrogyria and the severity of speech, language, and oral functional impairment. METHOD: A systematic search of MEDLINE, Embase, and PubMed databases was completed on 26th October 2017 using Medical Subject Heading terms synonymous with BPP and speech, language, or oral motor impairment. In total, 2411 papers were identified and 48 met inclusion criteria. RESULTS: Expressive and receptive language impairment and oral structural and functional deficits are frequent in BPP. Expressive deficits are frequently more severe than receptive. Only one study used formal assessments to demonstrate the presence of speech disorder, namely dysarthria. Seven studies reported an association between diffuse BPP and more severe language impairment. INTERPRETATION: Findings confirmed that language deficits are common in BPP, though assessment of the specific speech phenotype is limited. The paucity of high quality studies detailing the specific communication phenotype of BPP highlights the need for further investigation. Improving understanding of this phenotype will inform the development of targeted therapies and lead to better long-term outcomes. WHAT THIS PAPER ADDS: Speech, language, and oral functional impairments are common in individuals with bilateral perisylvian polymicrogyria. Posterior polymicrogyria is associated with a less severe language impairment than anterior polymicrogyria. Deeper investigation of speech is needed to understand implicated networks in this malformation.