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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., (© 2024 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Following cerebellar tumour surgery, children may suffer impairments of spontaneous language. Yet, the language processing deficits underlying these impairments are poorly understood. This study is the first to try to identify these deficits for four levels of language processing in cerebellar tumour survivors. The spontaneous language of twelve patients who underwent cerebellar tumour surgery (age range 3-24 years) was compared against his or her controls using individual case statistics. A distinction was made between patients who experienced postoperative cerebellar mutism syndrome (pCMS) and those who did not. Time since surgery ranged between 11 months and 12;3 years. In order to identify the impaired language processing levels at each processing level (i.e., lexical, semantic, phonological and/or morphosyntactic) nouns and verbs produced in the spontaneous language samples were rated for psycholinguistic variables (e.g., concreteness). Standard spontaneous language measures (e.g., type-token ratio) were calculated as well. First, inter-individual heterogeneity was observed in the spontaneous language outcomes in both groups. Nine out of twelve patients showed language processing deficits three of whom were diagnosed with pCMS. Results implied impairments across all levels of language processing. In the pCMS-group, the impairments observed were predominantly morphosyntactic and semantic, but the variability in nature of the spontaneous language impairments was larger in the non-pCMS-group. Patients treated with cerebellar tumour surgery may show long-term spontaneous language impairments irrespective of a previous pCMS diagnosis. Individualised and comprehensive postoperative language assessments seem necessary, given the inter-individual heterogeneity in the language outcomes., (© 2023. The Author(s).)

People with tumours in specific brain sites might face difficulties in tasks with different linguistic material. Previous lesion-symptom mapping studies (VLSM) demonstrated that people with tumours in posterior temporal regions have more severe linguistic impairments. However, to the best of our knowledge, preoperative performance and lesion location on tasks with different linguistic stimuli have not been examined. In the present study, we performed VLSM on 52 people with left gliomas to examine whether tumour distribution differs depending on the tasks of the Aachen Aphasia Test. The VLSM analysis revealed that single-word production (e.g. object naming) was associated with the inferior parietal lobe and that compound and sentence production were additionally associated with posterior temporal gyri. Word repetition was affected in people with tumours in inferior parietal areas, whereas sentence repetition was the only task to be associated with frontal regions. Subcortically, word and sentence production were found to be affected in people with tumours reaching the arcuate fasciculus, and compound production was primarily associated with tumours affecting the inferior longitudinal and inferior fronto-occipital fasciculus. Our work shows that tasks with linguistic stimuli other than single-word naming (e.g. compound and sentence production) relate to additional cortical and subcortical brain areas. At a clinical level, we show that tasks that target the same processes (e.g. repetition) can have different neural correlates depending on the linguistic stimuli used. Also, we highlight the importance of left temporoparietal areas., (© 2023 The Authors. Journal of Neuropsychology published by John Wiley & Sons Ltd on behalf of The British Psychological Society.)

Language impairment is comorbid in most children with Autism Spectrum Disorder (ASD) but its neural basis is poorly understood. Using structural magnetic resonance imaging (MRI), the present study provides the whole-brain comparison of both volume- and surface-based characteristics between groups of children with and without ASD and investigates the relationships between these characteristics in language-related areas and the language abilities of children with ASD measured with standardized tools. A total of 36 school-aged children participated in the study: 18 children with ASD and 18 age- and sex-matched typically developing controls. The results revealed that multiple regions differed between groups of children in gray matter volume, gray matter thickness, gyrification, and cortical complexity (fractal dimension). White matter volume and sulcus depth did not differ between groups of children in any region. Importantly, gray matter thickness and gyrification of language-related areas were related to language functioning in children with ASD. Thus, the results of the present study shed some light on the structural brain abnormalities associated with language impairment in ASD., (© 2023. The Author(s).)

Background: There is a small, but growing number of reports of pediatric patients with terminal deletions at 3p26.3 involving only the cell adhesion molecule L1-like (CHL1) gene that has been found to have language delays and intellectual disability. Here we report a one month of age patient who developed seizures and tone abnormalities, with persistent and prominent gross and fine motor delays. The patient has microcephaly and deficits in language and cognitive delays, similar to what has been seen in previous case reports., Methods: Chromosome and microarray comparative genomic hybridization (aCGH) analysis was performed to identify clinically significant copy number variants (CNVs). In addition, Fluorescent in-situ hybridization (FISH) was performed to confirm the aCGH findings., Results: Chromosome analysis revealed an apparently normal (46,XX) female karyotype. Microarray CGH analysis revealed a 639 kb loss at 3p26.3 from 62199 to 701052 base pairs encompassing the whole CHL1 gene that was confirmed by FISH. Parental follow-up revealed the deletion as maternal in origin., Conclusion: This case report adds to the limited body of literature that exists on this terminal deletion at 3p26.3 that involves CHL1 gene, and supports prior proposals of an emerging CHL1 microdeletion syndrome that results in language and cognitive delays. Further studies are needed to understand the degree of phenotypic heterogeneity associated with CHL1 gene deletion and whether the size of the deletion or presence of additional copy number variants (CNVs) which were seen in other case reports help predict the expected phenotype for a patient., (© 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Objective , the application of genomic sequencing in clinical practice has allowed us to appreciate the contribution of co-occurring pathogenic variants to complex and unclassified clinical phenotypes. Besides the clinical relevance, these findings have provided evidence of previously unrecognized functional links between genes in the context of developmental processes and physiology. Patients and Methods , a 5-year-old patient showing an unclassified phenotype characterized by developmental delay, speech delay, peculiar behavioral features, facial dysmorphism and severe cardiopathy was analyzed by trio-based whole exome sequencing (WES) analysis to identify the genomic events underlying the condition. Results , two co-occurring heterozygous truncating variants in CNOT3 and SMAD6 were identified. Heterozygous loss-of-function variants in CNOT3 , encoding a subunit of the CCR4-NOT protein complex, have recently been reported to cause a syndromic condition known as intellectual developmental disorder with speech delay, autism and dysmorphic facies (IDDSADF). Enrichment of rare/private variants in the SMAD6 gene, encoding a protein negatively controlling transforming growth factor β/bone morphogenetic protein (TGFB/BMP) signaling, has been described in association with a wide spectrum of congenital heart defects. We dissected the contribution of individual variants to the complex clinical manifestations and profiled a previously unappreciated set of facial features and signs characterizing IDDSADF. Conclusions , two concomitant truncating variants in CNOT3 and SMAD6 are the cause of the combination of features documented in the patient resulting in the unique multisystem neurodevelopmental condition. These findings provide evidence for a functional link between the CCR4-NOT complex and TGFB/BMP signaling in processes controlling cardiac development. Finally, the present revision provides evidence that IDDSADF is characterized by a distinctive facial gestalt.

ANKRD17 is an ankyrin repeat-containing protein thought to play a role in cell cycle progression, whose ortholog in Drosophila functions in the Hippo pathway as a co-factor of Yorkie. Here, we delineate a neurodevelopmental disorder caused by de novo heterozygous ANKRD17 variants. The mutational spectrum of this cohort of 34 individuals from 32 families is highly suggestive of haploinsufficiency as the underlying mechanism of disease, with 21 truncating or essential splice site variants, 9 missense variants, 1 in-frame insertion-deletion, and 1 microdeletion (1.16 Mb). Consequently, our data indicate that loss of ANKRD17 is likely the main cause of phenotypes previously associated with large multi-gene chromosomal aberrations of the 4q13.3 region. Protein modeling suggests that most of the missense variants disrupt the stability of the ankyrin repeats through alteration of core structural residues. The major phenotypic characteristic of our cohort is a variable degree of developmental delay/intellectual disability, particularly affecting speech, while additional features include growth failure, feeding difficulties, non-specific MRI abnormalities, epilepsy and/or abnormal EEG, predisposition to recurrent infections (mostly bacterial), ophthalmological abnormalities, gait/balance disturbance, and joint hypermobility. Moreover, many individuals shared similar dysmorphic facial features. Analysis of single-cell RNA-seq data from the developing human telencephalon indicated ANKRD17 expression at multiple stages of neurogenesis, adding further evidence to the assertion that damaging ANKRD17 variants cause a neurodevelopmental disorder., (Copyright © 2021 American Society of Human Genetics. All rights reserved.)

Ververi-Brady syndrome (VBS), first reported in 2018, is characterized by intellectual disability, speech delay, and mild dysmorphic facial features. VBS has been linked to de novo loss-of-function variants in the glutamine-rich protein 1 (QRICH1) on chromosome 3p21 and was reported until lately in only five individuals. Four additional cases have just been described substantiating the notion that children with VBS are mildly dysmorphic, mildly to moderately intellectually disabled, have linear growth shortage, are picky eaters, and have notable attention and social behavioral deficits. We describe a new patient and review the clinical and genetic information, on all previously reported VBS cases. The child here reported is noted for maladaptive behavior, sensory hypersensitivity, and slow linear growth. He is mainly hyperactive, distractible, impulsive, and inattentive. His speech, initially delayed, is fair and his verbal comprehension age adequate., (© 2021 Wiley Periodicals LLC.)

Three unrelated patients with similar microdeletions of chromosome 14q32.11 with shared phenotypes including language and developmental delay, and four overlapping genes -CALM1, TTC7B, PSMC1, and RPS6KA5 have been presented. All four genes are expressed in the brain and have haploinsufficiency scores, which reflect low tolerance to loss of function variation. An insight on the genes in the overlapping region, which may influence the resulting phenotype has been provided. Given the three patients' similar phenotypes and lack of normal variation in this region, it was suggested that this microdeletion may be associated with developmental and language delay., (© 2021 Wiley Periodicals LLC.)

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., (© 2021 American Academy of Neurology.)

Background: Rare variants in hundreds of genes have been implicated in developmental delay (DD), intellectual disability (ID) and neurobehavioural phenotypes. TNRC6B encodes a protein important for RNA silencing. Heterozygous truncating variants have been reported in three patients from large cohorts with autism, but no full phenotypic characterisation was described., Methods: Clinical and molecular characterisation was performed on 17 patients with TNRC6B variants. Clinical data were obtained by retrospective chart review, parent interviews, direct patient interaction with providers and formal neuropsychological evaluation., Results: Clinical findings included DD/ID (17/17) (speech delay in 94% (16/17), fine motor delay in 82% (14/17) and gross motor delay in 71% (12/17) of subjects), autism or autistic traits (13/17), attention deficit and hyperactivity disorder (ADHD) (11/17), other behavioural problems (7/17) and musculoskeletal findings (12/17). Other congenital malformations or clinical findings were occasionally documented. The majority of patients exhibited some dysmorphic features but no recognisable gestalt was identified. 17 heterozygous TNRC6B variants were identified in 12 male and five female unrelated subjects by exome sequencing (14), a targeted panel (2) and a chromosomal microarray (1). The variants were nonsense (7), frameshift (5), splice site (2), intragenic deletions (2) and missense (1)., Conclusions: Variants in TNRC6B cause a novel genetic disorder characterised by recurrent neurocognitive and behavioural phenotypes featuring DD/ID, autism, ADHD and other behavioural abnormalities. Our data highly suggest that haploinsufficiency is the most likely pathogenic mechanism. TNRC6B should be added to the growing list of genes of the RNA-induced silencing complex associated with ID/DD, autism and ADHD., Competing Interests: Competing interests: KM, AT and RP are employed by GeneDx, and XW, WB, JAR receive salary support from Baylor Genetics Laboratory. Both laboratories offer extensive genetic laboratory testing, including exome sequencing and derive revenue from this activity., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Sudden Unexplained Death in Childhood (SUDC), the death of a child that remains unexplained after a complete autopsy and investigation, is a rare and poorly understood entity. This case report describes a 3-year-old boy with history of language delay and ptosis, who died suddenly in his sleep without known cause. A pathogenic de novo frameshift mutation in BRPF1, a gene which has been associated with the syndrome of Intellectual Developmental Disorder with Dysmorphic Facies and Ptosis (IDDDFP), was identified during a post-mortem evaluation. The finding of a pathogenic variant in BRPF1, which has not previously been associated with sudden death, in an SUDC case has implications for this child's family and contributes to the broader field of SUDC research. This case demonstrates the utility of post-mortem genetic testing in SUDC., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

We report on a multiply consanguineous Syrian family where two siblings, a boy and a girl, presented with a compilation of symptoms including developmental delay, severe intellectual disability, absent speech, hearing impairment, short stature, subglottic stenosis, increased length of the palpebral fissures, onychodysplasia of index fingers, scoliosis, genu valgum, and malpositioned toes. Two other individuals from the extended family with similar clinical features are also described. Array-CGH did not reveal any pathological copy number variation. Exome sequencing failed to find any causal variants. Differential diagnoses and the possibility that we might be reporting a hitherto unknown syndrome are discussed., (© 2020 Wiley Periodicals LLC.)

Intellectual disability (ID) is a complicated and multifactorial condition often with an unclear cause. Advancements in diagnostic techniques have identified genetic causes in a significant proportion. Pathogenic variants in TRIP12, encoding for an E3 ligand in the ubiquitin-protease pathway, have previously been identified as a cause of ID with autistic behavior and dysmorphic features. We report two unrelated patients with de novo mutations in TRIP12 and diagnoses of global developmental delay, autism spectrum disorder and dysmorphic features, as well as a range of other characteristics. Exome sequencing was utilized as part of an extensive genetic workup for both individuals. The genotypic and phenotypic data for both patients has been collated with previously reported data. Epilepsy was noted in about 20% published cases. One of our patents had epilepsy. These cases highlight the variable phenotypic presentations of TRIP12 variations while emphasizing the core features of ID and speech delay, with or without autistic features and epilepsy., (© 2020 Wiley Periodicals, Inc.)

No data on interstitial microduplications of the 16q24.2q24.3 chromosome region are available in the medical literature and remain extraordinarily rare in public databases. Here, we describe a boy with a de novo 16q24.2q24.3 microduplication at the Single Nucleotide Polymorphism (SNP)-array analysis spanning ~2.2 Mb and encompassing 38 genes. The patient showed mild-to-moderate intellectual disability, speech delay and mild dysmorphic features. In DECIPHER, we found six individuals carrying a "pure" overlapping microduplication. Although available data are very limited, genomic and phenotype comparison of our and previously annotated patients suggested a potential clinical relevance for 16q24.2q24.3 microduplication with a variable and not (yet) recognizable phenotype predominantly affecting cognition. Comparing the cytogenomic data of available individuals allowed us to delineate the smallest region of overlap involving 14 genes. Accordingly, we propose ANKRD11 , CDH15 , and CTU2 as candidate genes for explaining the related neurodevelopmental manifestations shared by these patients. To the best of our knowledge, this is the first time that a clinical and molecular comparison among patients with overlapping 16q24.2q24.3 microduplication has been done. This study broadens our knowledge of the phenotypic consequences of 16q24.2q24.3 microduplication, providing supporting evidence of an emerging syndrome.

Background: Deletions in chromosome 15q13 have been reported both in healthy people and individuals with a wide range of behavioral and neuropsychiatric disturbances. Six main breakpoint (BP) subregions (BP1-BP6) are mapped to the 15q13 region and three further embedded BP regions (BP3-BP5). The deletion at BP4-BP5 is the rearrangement most frequently observed compared to other known deletions in BP3-BP5 and BP3-BP4 regions. Deletions of each of these three regions have previously been implicated in a variable range of clinical phenotypes, including minor dysmorphism, developmental delay/intellectual disability, epilepsy, autism spectrum disorders, behavioral disturbances, and speech disorders. Of note, no overt clinical difference among each group of BP region deletions has been recorded so far., Methods: We report on a four-member family plus an additional unrelated boy affected by a BP3-BP5 deletion that presented with typical clinical signs including speech delay and language impairment. A review of the clinical features associated with the three main groups of BP regions (BP4-BP5, BP3-BP5, and BP3-BP4) deletions is reported., Results: Array-CGH analysis revealed in the mother (case 1) and in her three children (cases 2, 3, and 4), as well as in the unrelated boy (case 5), the following rearrangement: arr (hg19) 15q13.1-q13.3 (29.213.402-32.510.863) x1., Conclusion: This report, along with other recent observations, suggests the hypothesis that the BP region comprised between BP3 and BP5 in chromosome 15q13 is involved in several brain human dysfunctions, including impairment of the language development and, its deletion, may be directly or indirectly responsible for the speech delay and language deficit in the affected individuals., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Background: Noonan Syndrome is a developmental disorder characterized by a distinctive phenotype including facial dysmorphism, webbed neck, short stature, heart defects, and variable cognitive deficits as major features. Over the years, neuropsychological and behavioral studies explored alteration of cognitive functioning and related domains, such as learning, memory, and attention. To our knowledge, however, data concerning the language profile in this disorder is scarce. The aim of the present study was to detect specific language functioning combining nonverbal intelligence quotient and language abilities and to pinpoint strengths and weaknesses in the language domains., Methods: The language profile of 37 Italian participants with molecularly confirmed diagnosis of Noonan Syndrome was evaluated using specific tools to assess vocabulary and grammar comprehension and production, as well as phonological development., Results: We observed that 78% of affected individuals exhibited language impairment. Within language domains, the strong area was lexical production and grammar production was the weak area. Almost half the participants manifested a similar trend of specific language impairment. Nonverbal intelligence quotient only correlated with grammar comprehension., Conclusion: Our study expands present knowledge about the language profile in NS, and provides data that could enable more effective patient management and appropriate intervention., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Purpose: Lamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved., Methods: Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types ofSOX5 alterations. Functional consequences of selected substitutions were investigated., Results: Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype-phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated., Conclusions: This study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features.

In the past decades, neuroscientists and clinicians have collected a considerable amount of data and drastically increased our knowledge about the mapping of language in the brain. The emerging picture from the accumulated knowledge is that there are complex and combinatorial relationships between language functions and anatomical brain regions. Understanding the underlying principles of this complex mapping is of paramount importance for the identification of the brain signature of language and Neuro-Clinical signatures that explain language impairments and predict language recovery after stroke. We review recent attempts to addresses this question of language-brain mapping. We introduce the different concepts of mapping (from diffeomorphic one-to-one mapping to many-to-many mapping). We build those different forms of mapping to derive a theoretical framework where the current principles of brain architectures including redundancy, degeneracy, pluri-potentiality and bow-tie network are described., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objectives: Ischemic stroke affects language production and/or comprehension and leads to devastating long-term consequences for patients and their families. Previous studies have shown that neuroimaging can increase our knowledge of the basic mechanisms of language recovery. Currently, models for predicting patients' outcomes have limited use in the clinic for the evaluation and optimization of rehabilitative strategies mostly because that are often based on high-resolution magnetic resonance imaging (MRI) data, which are not always possible to carry out in the clinical routine. Here, we investigate the use of Voxel-Based Morphometry (VBM), multivariate modelling and native Computed Tomography (nCT) scans routinely acquired in the acute stage of stroke for identifying biological signatures that explicate the relationships between brain anatomy and types of impairments., Methods: 80 stroke patients and 30 controls were included. nCT-scans were acquired in the acute ischemia stage and bedside clinical assessment from board-certified neurologist based on the NIH stroke scale. We use a multivariate Principal Component Analyses (PCA) to identify the brain signatures group the patients according to the presence or absence of impairment and identify the association between local Grey Matter (GM) and White Matter (WM) nCT values with the presence or absence of the impairment., Results: Individual patient's nCT scans were compared to a group of controls' with no radiological signs of stroke to provide an automated delineation of the lesion. Consistently across the whole group the regions that presented significant difference GM and WM values overlap with known areas that support language processing., Conclusion: In summary, the method applied to nCT scans performed in the acute stage of stroke provided robust and accurate information about brain lesions' location and size, as well as quantitative values. We found that nCT and VBQ analyses are effective for identifying neural signatures of concomitant language impairments at the individual level, and neuroanatomical maps of aphasia at the population level. The signatures explicate the neurophysiological mechanisms underlying aetiology of the stroke. Ultimately, similar analyses with larger cohorts could lead to a more integrated multimodal model of behaviour and brain anatomy in the early stage of ischemic stroke., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

White-Sutton syndrome (WHSUS) is a recently-identified genetic disorder resulting from de novo heterozygous pathogenic variants in POGZ. Thus far, over 50 individuals have been reported worldwide, however phenotypic characterization and data regarding the natural history are still incomplete. Here we report the clinical features of 22 individuals with 21 unique loss of function POGZ variants. We observed a broad spectrum of intellectual disability and/or developmental delay with or without autism, and speech delay in all individuals. Other common problems included ocular abnormalities, hearing loss and gait abnormalities. A validated sleep disordered breathing questionnaire identified symptoms of obstructive sleep apnea in 4/12 (33%) individuals. A higher-than-expected proportion of cases also had gastrointestinal phenotypes, both functional and anatomical, as well as genitourinary anomalies. In line with previous publications, we observed an increased body mass index (BMI) z-score compared to the general population (mean 0.59, median 0.9; p 0.0253). Common facial features included microcephaly, broad forehead, midface hypoplasia, triangular mouth, broad nasal root and flat nasal bridge. Analysis of the Baylor Genetics clinical laboratory database revealed that POGZ variants were implicated in approximately 0.14% of cases who underwent clinical exome sequencing for neurological indications with or without involvement of other body systems. This study describes a greater allelic series and expands the phenotypic spectrum of this new syndromic form of intellectual disability and autism., (© 2019 Wiley Periodicals, Inc.)

Background: During the first 3-years of life, as the brain undergoes dramatic growth, children begin to develop speech and language. Hallmarks of this progression are seen when children reach developmental milestones, forming the foundation of language. Expressive language milestones, such as the production of a child's first word, are delayed in 5-8% of children. While for some children delays in reaching these milestones are harbingers of developmental disorders, for others expressive language delays appear to resolve. Regardless of whether or not early language skills appear resolved, difficulty with later comprehension is a likely outcome. Whether this heightened risk for poor comprehension differs based on text features, individual characteristics, or receipt of intervention remains unknown. Moreover, this relationship between expressive language development and comprehension is not yet linked to neurobiology, though the inferior longitudinal fasciculus (ILF) is a potential neurobiological correlate. Therefore, we investigated the impact of, and interactions between, expressive language development, early intervention, and the ILF on comprehension., Methods: Longitudinal recurrent survival analyses predicted the risk of answering a comprehension question incorrectly. Predictors of comprehension included expressive language development, passage features, participant characteristics, fractional anisotropy, receipt of early intervention, and later diagnosis of speech or language disorders., Results: Children with later expressive language milestones had poorer comprehension. When comprehension text features were examined, children with later milestones had poorer listening and reading comprehension, and poorer narrative and expository comprehension. The left ILF acted as a neurodevelopmental correlate, one that moderated the relationship between expressive language milestones and comprehension. Specifically, the left ILF exacerbated the relationship for those who did not receive early intervention and buffered the relationship for those who received intervention services. Early intervention decreased the risk of poor comprehension by 39% for children later diagnosed with a speech or language disorder., Conclusions: Early intervention should be provided for children with delayed expressive language milestones, particularly those who are at risk for speech or language disorders. The ILF plays a critical role in the relationship between expressive language development and comprehension, which may be that of a protective factor for children with the most severe early issues with speech and language.

Developmental language disorder (DLD) and developmental speech disorder (DSD) are common, yet their etiologies are not well understood. Atypical volume of the inferior and posterior language regions and striatum have been reported in DLD; however, variability in both methodology and study findings limits interpretations. Imaging research within DSD, on the other hand, is scarce. The present study compared grey matter volume in children with DLD, DSD, and typically developing speech and language. Compared to typically developing controls, children with DLD had larger volume in the right cerebellum, possibly associated with the procedural learning deficits that have been proposed in DLD. Children with DSD showed larger volume in the left inferior occipital lobe compared to controls, which may indicate a compensatory role of the visual processing regions due to sub-optimal auditory-perceptual processes. Overall, these findings suggest that different neural systems may be involved in the specific deficits related to DLD and DSD.

Background: Since the establishment of chromosomal microarrays in clinical practice, many new microdeletion/microduplication syndromes have been identified, including 18q11.2 microdeletion. Chromosome 18q deletion syndrome is commonly classified into distal deletion and a much rarer proximal interstitial deletion spanning the 18q11.2-q21.1 region., Methods: We report two new patients and review 27 additional cases in DECIPHER/ClinGen databases and four cases from the literature, with more proximal 18q deletions involving 18q11-q12 (band 1 only; 17.2-43.5 Mb position) deletion., Results: Common presentations of 18q11-q12 deletions include developmental delay/intellectual disability (DD/ID) (82%); speech delay/autism/attention deficit and hyperactivity/other behavioral problems (30%); conotruncal heart defects (15%); and subtle/non-specific facial dysmorphism. The deletion in four out of five cases with cardiac defect was distal to GATA6, suggesting an alternative mechanism other than haploinsufficiency of GATA6 as an underlying cause of cardiac malformations. Precocious puberty with advanced skeletal age was first observed in one patient, suggesting a unique and expanded phenotype of proximal 18q deletion. When comparing genotype-phenotype correlations from the present study with previous reports, the critical regions for selected phenotypes of 18q11-q12 deletion syndrome could be narrowed down as follows: 38.8-43.5 Mb for moderate to severe DD/ID, 19.6-24.4 Mb and 26.9-28.6 Mb for conotruncal heart defect., Conclusion: The detailed clinical delineation of the proximal 18q deletions identified in this study should contribute to better understanding of the genotype-phenotype correlations and better long-term care of patients with this rare syndrome., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Purpose: To investigate the effect of different DEAF1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and on DEAF1 activity in vitro., Methods: We assembled a cohort of 23 patients with de novo and biallelic DEAF1 variants, described the genotype-phenotype correlation, and investigated the differential effect of de novo and recessive variants on transcription assays using DEAF1 and Eif4g3 promoter luciferase constructs., Results: The proportion of the most prevalent phenotypic features, including intellectual disability, speech delay, motor delay, autism, sleep disturbances, and a high pain threshold, were not significantly different in patients with biallelic and pathogenic de novo DEAF1 variants. However, microcephaly was exclusively observed in patients with recessive variants (p < 0.0001)., Conclusion: We propose that different variants in the DEAF1 gene result in a phenotypic spectrum centered around neurodevelopmental delay. While a pathogenic de novo dominant variant would also incapacitate the product of the wild-type allele and result in a dominant-negative effect, a combination of two recessive variants would result in a partial loss of function. Because the clinical picture can be nonspecific, detailed phenotype information, segregation, and functional analysis are fundamental to determine the pathogenicity of novel variants and to improve the care of these patients.

Objective: Evidence suggests relationships between abnormalities in various cortical and subcortical brain structures and language dysfunction in individuals with schizophrenia, and to some extent in those with increased genetic risk for this diagnosis. The topological features of the structural brain network at the systems-level and their impact on language function in schizophrenia and in those at high genetic risk has been less well studied., Method: Single-subject morphological brain network was constructed in a total of 71 subjects (20 patients with schizophrenia, 19 individuals at high genetic risk for schizophrenia, and 32 controls). Among these 71 subjects, 56 were involved in our previous neuroimaging studies. Graphic Theoretical Techniques was applied to calculate the global and nodal topological characteristics of the morphological brain network of each participant. Index scores for five language-related cognitive tests were also attained from each participant., Results: Significantly smaller nodal degree in bilateral superior occipital gyri (SOG) were observed in individuals with schizophrenia, as compared to the controls and those at high risk; while significantly reduced nodal betweenness centrality (quantifying the level of a node in connecting other nodes in the network) in right middle frontal gyrus (MFG) was found in the high-risk group, relative to controls. The right MFG nodal efficiency and hub capacity (represented by both nodal degree and betweenness centrality) of the morphological brain network were negatively associated with the wide range achievement test (WRAT) standard performance score; while the right SOG nodal degree was positively associated with the WRAT standard performance score, in the entire study sample., Conclusions: These findings enhance the understanding of structural brain abnormalities at the systems-level in individuals with schizophrenia and those at high genetic risk, which may serve as critical neural substrates for the origin of the language-related impairments and symptom manifestations of schizophrenia., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The present study investigated whether children with a typical dyslexia profile and children with isolated spelling deficits show a distinct pattern of white matter alteration compared with typically developing peers. Relevant studies on the topic are scarce, rely on small samples, and often suffer from the limitations of conventional tensor-based methods. The present Constrained Spherical Deconvolution study includes 27 children with typical reading and spelling skills, 21 children with dyslexia and 21 children with isolated spelling deficits. Group differences along major white matter tracts were quantified utilizing the Automated Fiber Quantification software and a lateralization index was calculated in order to investigate the structural asymmetry of the tracts. The two deficit groups mostly displayed different patterns of white matter alterations, located in the bilateral inferior longitudinal fasciculi, right superior longitudinal fasciculus, and cingulum for the group with dyslexia and in the left arcuate fasciculus for the group with isolated spelling deficits. The two deficit groups differed also with respect to structural asymmetry. Children with dyslexia did not show the typical leftward asymmetry of the arcuate fasciculus, whereas the group with isolated spelling deficits showed absent rightward asymmetry of the inferior fronto-occipital fasciculus. This study adds evidence to the notion that different profiles of combined or isolated reading and spelling deficits are associated with different neural signatures., (© 2018 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

Developmental language disorder (DLD) and speech sound disorder (SSD) are common, and although scientific evidence for structural and functional alterations in DLD/SSD is accumulating, current neuroimaging studies provide an incongruent picture. Here, we hypothesized that children affected by DLD and SSD present with gray matter (or gray matter asymmetry) aberrations in brain areas associated with language processing compared to typically developing (TD) children. To assess this hypothesis, we enhanced MRI-based information with microscopically defined cytoarchitectonic probabilities of Broca's area (BA 45, BA 44) as well as an auditory area (TE 3.0). We detected a larger rightward gray matter asymmetry in BA 45 in children with DLD (n = 13) and with SSD (n = 18) compared to TD children (n = 18), albeit only on a trend level. Interestingly though, we observed significantly larger gray matter volumes in right BA 45 in DLD compared to SSD children (and also compared to TD children)., (© 2018 Wiley Periodicals, Inc.)

Primordial dwarfism (PD) is mainly characterized by growth deficiency with heterogeneous phenotypes. A group of genes are known to be associated with PD or PD-related syndrome. WD repeat domain 4 (WDR4) is recently reported to be responsible for PD. Here we report a 6-year-old boy from a non-consanguineous couple with motor and speech delay as well as intellectual disability. Whole exome sequencing (WES) identified a missense mutation (NM&#95;033661.4:c.491A > C; p.(Asp164Ala)) and a small insertion (NM&#95;033661.4:c.940dupC; p.(Leu314Profs*16)) of WDR4 in this patient. Two novel mutations confirmed by Sanger sequencing are from father and mother respectively according to a recessive inheritance pattern. Asp164Ala located in functional region is predicted to be deleterious by two kinds of algorithm. The small insertion causing a frameshift mutation leads to truncated protein. In this study, we present two novel WDR4 mutations responsible for PD in a 6-year-old patient, expanding the molecular and phenotype spectrum of WDR4-related PD., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Preterm children often have language problems. This atypical language development is probably due to atypical brain development. We conducted a systematic review to provide an overview of the extensive and diverse scientific literature on the relations between language outcome and underlying brain structures in school-aged preterm-born children. Embase, Medline Ovid, Web of Science, Cochrane central and Google scholar were searched for relevant studies. Inclusion criteria were: cases are school-aged preterm children; structural MRI (T1- and T2-weighted sequences) or DTI used in combination with a neurocognitive language test; publication in an English-language peer-reviewed journal. Correlational measures between language scores and brain volume or fractional anisotropy of a brain structure were extracted. 23 studies were included. The relations between oral language, verbal fluency and/or written language and MRI/DTI measurements of white matter, gray matter, cerebellum, corpus callosum and/or the fasciculi are presented. Oral language skills and verbal fluency appear to be related to the corpus callosum. Oral language skills are also related to the uncinate fasciculus. There seems to be no clear relation between cerebellar development and verbal fluency skills. Not one single brain area is responsible for atypical language development, but several brain areas and their connections are essential. For future research it is recommended to relate brain areas to oral language skills on a microstructural level in preterm children. We also recommend to use language tests in which it is possible to distinguish between several language domains, such as perceptive and expressive language., Competing Interests: The authors have declared that no competing interests exist.

Speech sound disorder (SSD) is common, yet its neurobiology is poorly understood. Recent studies indicate atypical structural and functional anomalies either in one hemisphere or both hemispheres, which might be accompanied by alterations in inter-hemispheric connectivity. Indeed, abnormalities of the corpus callosum - the main fiber tract connecting the two hemispheres - have been linked to speech and language deficits in associated disorders, such as stuttering, dyslexia, aphasia, etc. However, there is a dearth of studies examining the corpus callosum in SSD. Here, we investigated whether a sample of 18 children with SSD differed in callosal morphology from 18 typically developing children carefully matched for age. Significantly reduced dimensions of the corpus callosum, particularly in the callosal anterior third, were observed in children with SSD. These findings indicating pronounced callosal aberrations in SSD make an important contribution to an understudied field of research and may suggest that SSD is accompanied by atypical lateralization of speech and language function., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)

Purpose: Relative lengths of the index (2D) and ring (4D) fingers in humans represent a retrospective biomarker of prenatal hormonal exposures. For this reason, the 2D:4D digit ratio can be used to investigate potential hormonal contributions to the etiology of neurodevelopmental disorders. This study tested potential group differences in 2D:4D digit ratios in a sample of boys with and without developmental language disorder (DLD) and examined the strength of associations between 2D:4D digit ratio and a battery of verbal and nonverbal measures., Method: A group of 29 boys affected by DLD and a group of 76 boys with typical language abilities participated (age range = 5;6-11;0 years). Scanned images were used to measure finger lengths. Language measures included the core language subtests from the Clinical Evaluation of Language Fundamentals-Fourth Edition (Semel, Wiig, & Secord, 2003), a nonword repetition task, a sentence recall task, and the Test of Early Grammatical Impairment (Rice & Wexler, 2001)., Results: Significant group differences indicated lower 2D:4D digit ratios in the group with DLD. Modest associations were found between 2D:4D digit ratios and some Clinical Evaluation of Language Fundamentals-Fourth Edition subtests., Conclusions: Prenatal hormone exposures may play a role in the etiology of some language symptoms.

Background: Younger siblings of children with autism spectrum disorder (ASD) are themselves at increased risk for ASD and other developmental concerns. It is unclear if infants who display developmental concerns, but are unaffected by ASD, share similar or dissimilar behavioral and brain phenotypes to infants with ASD. Most individuals with ASD exhibit heterogeneous difficulties with language, and their receptive-expressive language profiles are often atypical. Yet, little is known about the neurobiology that contributes to these language difficulties., Methods: In this study, we used behavioral assessments and structural magnetic resonance imaging to investigate early brain structures and associations with later language skills. High-risk infants who were later diagnosed with ASD (n = 86) were compared with high-risk infants who showed signs of early language delay (n = 41) as well as with high- and low-risk infants who did not have ASD or language delay (n = 255 and 143, respectively)., Results: Results indicated that diminished language skills were evident at 12 months in infants with ASD and infants with early language delay. At 24 months of age, only the infants with ASD displayed atypical receptive-expressive language profiles. Associations between 12-month subcortical volumes and 24-month language skills were moderated by group status, indicating disordinal brain-behavior associations among infants with ASD and infants with language delay., Conclusions: These results suggest that there are different brain mechanisms influencing language development in infants with ASD and infants with language delay, and that the two groups likely experience unique sets of genetic and environmental risk factors., (Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Bromodomain PHD finger transcription factor (BPTF) is the largest subunit of nucleosome remodeling factor (NURF), a member of the ISWI chromatin-remodeling complex. However, the clinical consequences of disruption of this complex remain largely uncharacterized. BPTF is required for anterior-posterior axis formation of the mouse embryo and was shown to promote posterior neuroectodermal fate by enhancing Smad2-activated wnt8 expression in zebrafish. Here, we report eight loss-of-function and two missense variants (eight de novo and two of unknown origin) in BPTF on 17q24.2. The BPTF variants were found in unrelated individuals aged between 2.1 and 13 years, who manifest variable degrees of developmental delay/intellectual disability (10/10), speech delay (10/10), postnatal microcephaly (7/9), and dysmorphic features (9/10). Using CRISPR-Cas9 genome editing of bptf in zebrafish to induce a loss of gene function, we observed a significant reduction in head size of F0 mutants compared to control larvae. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and phospho-histone H3 (PH3) staining to assess apoptosis and cell proliferation, respectively, showed a significant increase in cell death in F0 mutants compared to controls. Additionally, we observed a substantial increase of the ceratohyal angle of the craniofacial skeleton in bptf F0 mutants, indicating abnormal craniofacial patterning. Taken together, our data demonstrate the pathogenic role of BPTF haploinsufficiency in syndromic neurodevelopmental anomalies and extend the clinical spectrum of human disorders caused by ablation of chromatin remodeling complexes., (Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: DYRK1A is a gene recurrently disrupted in 0.1-0.5% of the ASD population. A growing number of case reports with DYRK1A haploinsufficiency exhibit common phenotypic features including microcephaly, intellectual disability, speech delay, and facial dysmorphisms., Methods: Phenotypic information from previously published DYRK1A cases ( n  = 51) and participants in an ongoing study at the University of Washington (UW, n  = 10) were compiled. Frequencies of recurrent phenotypic features in this population were compared to features observed in a large sample with idiopathic ASD from the Simons Simplex Collection ( n  = 1981). UW DYRK1A cases were further characterized quantitatively and compared to a randomly subsampled set of idiopathic ASD cases matched on age and gender ( n  = 10) and to cases with an ASD-associated disruptive mutation to CHD8 ( n  = 12). Contribution of familial genetic background to clinical heterogeneity was assessed by comparing head circumference, IQ, and ASD-related symptoms of UW DYRK1A cases to their unaffected parents., Results: DYRK1A haploinsufficiency results in a common phenotypic profile including intellectual disability, speech and motor difficulties, microcephaly, feeding difficulties, and vision abnormalities. Eighty-nine percent of DYRK1A cases ascertained for ASD presented with a constellation of five or more of these symptoms. When compared quantitatively, DYRK1A cases presented with significantly lower IQ and adaptive functioning compared to idiopathic cases and significantly smaller head size compared to both idiopathic and CHD8 cases. Phenotypic variability in parental head circumference, IQ, and ASD-related symptoms corresponded to observed variability in affected child phenotype., Conclusions: Results confirm a core clinical phenotype for DYRK1A disruptions, with a combination of features that is distinct from idiopathic ASD. Cases with DYRK1A mutations are also distinguishable from disruptive mutations to CHD8 by head size. Measurable, quantitative characterization of DYRK1A haploinsufficiency illuminates clinical variability, which may be, in part, due to familial genetic background.

KIF1A is a brain-specific anterograde motor protein that transports cargoes towards the plus-ends of microtubules. Many variants of the KIF1A gene have been associated with neurodegenerative diseases and developmental delay. Homozygous mutations of KIF1A have been identified in a recessive subtype of hereditary spastic paraplegia (HSP), SPG30. In addition, KIF1A mutations have been found in pure HSP with autosomal dominant inheritance. Here we report the first case of familial complicated HSP with a KIF1A mutation transmitted in autosomal dominant inheritance. A heterozygous p.T258M mutation in KIF1A was found in a Korean family through targeted exome sequencing. They displayed phenotypes of mild intellectual disability with language delay, epilepsy, optic nerve atrophy, thinning of corpus callosum, periventricular white matter lesion, and microcephaly. A structural modeling revealed that the p.T258M mutation disrupted the binding of KIF1A motor domain to microtubules and its movement along microtubules. Assays of peripheral accumulation and proximal distribution of KIF1A motor indicated that the KIF1A motor domain with p.T258M mutation has reduced motor activity and exerts a dominant negative effect on wild-type KIF1A. These results suggest that the p.T258M mutation suppresses KIF1A motor activity and induces complicated HSP accompanying intellectual disability transmitted in autosomal dominant inheritance.

Childhood speech and language deficits are highly prevalent and are a common feature of neurodevelopmental disorders. However, it is difficult to investigate the underlying causal pathways because many diagnostic groups have a heterogeneous aetiology. Studying disorders with a shared genetic cause and shared cognitive deficits can provide crucial insight into the cellular mechanisms and neural systems that give rise to those impairments. The current study investigated structural brain differences of individuals with mutations in ZDHHC9 , which is associated with a specific neurodevelopmental phenotype including prominent speech and language impairments and intellectual disability. We used multiple structural neuroimaging methods to characterise neuroanatomy in this group, and observed bilateral reductions in cortical thickness in areas surrounding the temporo-parietal junction, parietal lobule, and inferior frontal lobe, and decreased microstructural integrity of cortical, subcortical-cortical, and interhemispheric white matter projections. These findings are compared to reports for other genetic groups and genetically heterogeneous disorders with a similar presentation. Overlap in the neuroanatomical phenotype suggests a common pathway that particularly affects the development of temporo-parietal and inferior frontal areas, and their connections.

While it has long been thought that most of cerebral creatine is of peripheral origin, the last 20 years has provided evidence that the creatine synthetic pathway (AGAT and GAMT enzymes) is expressed in the brain together with the creatine transporter (SLC6A8). It has also been shown that SLC6A8 is expressed by microcapillary endothelial cells at the blood-brain barrier, but is absent from surrounding astrocytes, raising the concept that the blood-brain barrier has a limited permeability for peripheral creatine. The first creatine deficiency syndrome in humans was also discovered 20 years ago (GAMT deficiency), followed later by AGAT and SLC6A8 deficiencies, all three diseases being characterized by creatine deficiency in the CNS and essentially affecting the brain. By reviewing the numerous and latest experimental studies addressing creatine transport and synthesis in the CNS, as well as the clinical and biochemical characteristics of creatine-deficient patients, our aim was to delineate a clearer view of the roles of the blood-brain and blood-cerebrospinal fluid barriers in the transport of creatine and guanidinoacetate between periphery and CNS, and on the intracerebral synthesis and transport of creatine. This review also addresses the question of guanidinoacetate toxicity for brain cells, as probably found under GAMT deficiency.

Deficiency of guanidinoacetate methyltransferase (GAMT) causes creatine depletion and guanidinoacetate accumulation in brain with the latter deemed to be responsible for the severe seizure disorder seen in affected patients. We studied electrical brain activity and GABAA mediated mechanisms of B6J.Cg-Gamt(tm1Isb) mice. Electrocorticographic (ECoG) monitoring of pharmacological treatments with ornithine (5 % in drinking water for 5-18 days) and/or Picrotoxin (PTX) (a GABAA receptor antagonist) (1.5 mg/kg, I.P.) in Gamt(MUT) and Gamt(WT) groups [n = 3, mean age (SEM) = 6.9 (0.2) weeks]. Mice were fitted with two frontal and two parietal epidural electrodes under ketamine/xylazine anesthesia. Baseline and test recordings were performed for determination of seizure activity over a 2 h period. The ECoG baseline of Gamt(MUT) exhibited an abnormal monotonous cortical rhythm (7-8 Hz) with little variability during awake and sleep states compared to wild type recordings. Ornithine treatment and also PTX administration led to a relative normalization of the Gamt(MUT) ECoG phenotype. Gamt(WT) on PTX exhibited electro-behavioral seizures, whereas the Gamt(MUT) did not have PTX induced seizures at the same PTX dose. Gamt(MUT) treated with both ornithine and PTX did not show electro-behavioral seizures while ornithine elevated the PTX seizure threshold of Gamt(MUT) mice even further. These data demonstrate: (1) that there is expression of electrical seizure activity in this Gamt-deficient transgenic mouse strain, and (2) that the systemic availability of guanidinoacetate affects GABAA receptor function and seizure thresholds. These findings are directly and clinically relevant for patients with a creatine-deficiency syndrome due to genetic defects in GAMT and provide a rational basis for a combined ornithine/picrotoxin therapeutic intervention.

Cyclin-dependent kinase 5 (CDK5) and cyclin-dependent kinase 5, regulatory subunit 1 (CDK5R1), encoding CDK5 activator p35, have a fundamental role in central nervous system (CNS) development and function, and are involved in the pathogenesis of several neurodegenerative disorders, thus constituting strong candidate genes for the onset of intellectual disability (ID). We carried out a mutation screening of CDK5 and CDK5R1 coding regions and CDK5R1 3'-UTR on a cohort of 360 patients with non-syndromic ID (NS-ID) using denaturing high performance liquid chromatography (DHPLC) and direct sequencing. We found one novel silent mutation in CDK5 and one novel silent mutation in CDK5R1 coding regions, three novel intronic variations in CDK5, not causing any splicing defect, and four novel heterozygous variations in CDK5R1 3'-UTR. None of these variations was present in 450 healthy controls and single-nucleotide polymorphism (SNP) databases. The functional study of CDK5R1 p.A108V mutation evidenced an impaired p35 cleavage by the calcium-dependent protease calpain. Moreover, luciferase constructs containing the CDK5R1 3'-UTR mutations showed altered gene expression levels. Eight known polymorphisms were also identified displaying different frequencies in NS-ID patients compared with the controls. In particular, the minor allele of CDK5R1 3'-UTR rs735555 polymorphism was associated with increased risk for NS-ID. In conclusion, our data suggest that mutations and polymorphisms in CDK5 and CDK5R1 genes may contribute to the onset of the NS-ID phenotype.

Dyslexia and language impairment (LI) are complex traits with substantial genetic components. We recently completed an association scan of the DYX2 locus, where we observed associations of markers in DCDC2, KIAA0319, ACOT13, and FAM65B with reading-, language-, and IQ-related traits. Additionally, the effects of reading-associated DYX3 markers were recently characterized using structural neuroimaging techniques. Here, we assessed the neuroimaging implications of associated DYX2 and DYX3 markers, using cortical volume, cortical thickness, and fractional anisotropy. To accomplish this, we examined eight DYX2 and three DYX3 markers in 332 subjects in the Pediatrics Imaging Neurocognition Genetics study. Imaging-genetic associations were examined by multiple linear regression, testing for influence of genotype on neuroimaging. Markers in DYX2 genes KIAA0319 and FAM65B were associated with cortical thickness in the left orbitofrontal region and global fractional anisotropy, respectively. KIAA0319 and ACOT13 were suggestively associated with overall fractional anisotropy and left pars opercularis cortical thickness, respectively. DYX3 markers showed suggestive associations with cortical thickness and volume measures in temporal regions. Notably, we did not replicate association of DYX3 markers with hippocampal measures. In summary, we performed a neuroimaging follow-up of reading-, language-, and IQ-associated DYX2 and DYX3 markers. DYX2 associations with cortical thickness may reflect variations in their role in neuronal migration. Furthermore, our findings complement gene expression and imaging studies implicating DYX3 markers in temporal regions. These studies offer insight into where and how DYX2 and DYX3 risk variants may influence neuroimaging traits. Future studies should further connect the pathways to risk variants associated with neuroimaging/neurocognitive outcomes.

De novo truncating mutations in Additional sex combs-like 3 (ASXL3) have been identified in individuals with Bainbridge-Ropers syndrome (BRS), characterized by failure to thrive, global developmental delay, feeding problems, hypotonia, dysmorphic features, profound speech delays and intellectual disability. We identified three novel de novo heterozygous truncating variants distributed across ASXL3, outside the original cluster of ASXL3 mutations previously described for BRS. Primary skin fibroblasts established from a BRS patient were used to investigate the functional impact of pathogenic variants. ASXL3 mRNA transcripts from the mutated allele are prone to nonsense-mediated decay, and expression of ASXL3 is reduced. We found that ASXL3 interacts with BAP1, a hydrolase that removes mono-ubiquitin from histone H2A lysine 119 (H2AK119Ub1) as a component of the Polycomb repressive deubiquitination (PR-DUB) complex. A significant increase in H2AK119Ub1 was observed in ASXL3 patient fibroblasts, highlighting an important functional role for ASXL3 in PR-DUB mediated deubiquitination. Transcriptomes of ASXL3 patient and control fibroblasts were compared to investigate the impact of chromatin changes on transcriptional regulation. Out of 564 significantly differentially expressed genes (DEGs) in ASXL3 patient fibroblasts, 52% were upregulated and 48% downregulated. DEGs were enriched in molecular processes impacting transcriptional regulation, development and proliferation, consistent with the features of BRS. This is the first single gene disorder linked to defects in deubiquitination of H2AK119Ub1 and suggests an important role for dynamic regulation of H2A mono-ubiquitination in transcriptional regulation and the pathophysiology of BRS., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

De novo disruptions of the neural transcription factor FOXP1 are a recently discovered, rare cause of sporadic intellectual disability (ID). We report three new cases of FOXP1-related disorder identified through clinical whole-exome sequencing. Detailed phenotypic assessment confirmed that global developmental delay, autistic features, speech/language deficits, hypotonia and mild dysmorphic features are core features of the disorder. We expand the phenotypic spectrum to include sensory integration disorder and hypertelorism. Notably, the etiological variants in these cases include two missense variants within the DNA-binding domain of FOXP1. Only one such variant has been reported previously. The third patient carries a stop-gain variant. We performed functional characterization of the three missense variants alongside our stop-gain and two previously described truncating/frameshift variants. All variants severely disrupted multiple aspects of protein function. Strikingly, the missense variants had similarly severe effects on protein function as the truncating/frameshift variants. Our findings indicate that a loss of transcriptional repression activity of FOXP1 underlies the neurodevelopmental phenotype in FOXP1-related disorder. Interestingly, the three novel variants retained the ability to interact with wild-type FOXP1, suggesting these variants could exert a dominant-negative effect by interfering with the normal FOXP1 protein. These variants also retained the ability to interact with FOXP2, a paralogous transcription factor disrupted in rare cases of speech and language disorder. Thus, speech/language deficits in these individuals might be worsened through deleterious effects on FOXP2 function. Our findings highlight that de novo FOXP1 variants are a cause of sporadic ID and emphasize the importance of this transcription factor in neurodevelopment., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background and Purpose: Patients with epilepsy and malformations of cortical development have a high prevalence of language deficits. The purpose of this study was to investigate whether the status of the arcuate fasciculus at diffusion tractography could provide a clinically meaningful marker of language function in patients with cortical malformations., Materials and Methods: Thirty-seven patients 3-18 years of age who had DTI performed at 3T and language evaluation by a pediatric neurologist were retrospectively identified. Twenty-two age-matched children without any neurologic, language, or MR imaging abnormalities who had identical DTI performed for an indication of headache were selected as a control cohort. The arcuate fasciculi were constructed and segmented by deterministic tractography for all subjects., Results: Twenty-one patients had intact language; 11 had mild-to-moderate and 5, profound language impairment. All patients with normal language and all control subjects had an identifiable left arcuate. The left arcuate was absent in 11 patients; all 11 were language-impaired. Failure to identify the left arcuate was strongly associated with some degree of language impairment (P < .001). Sensitivity, specificity, and positive predictive value for language dysfunction were 65%, 100%, and 100%, respectively. The absence of the arcuate bilaterally was associated with complete failure to develop oral language (P < .015)., Conclusions: Failure to identify the left arcuate fasciculus at diffusion tractography was a highly specific marker of language dysfunction in a cohort of pediatric patients with malformations of cortical development. Failure to identify the arcuate fasciculus on either side was associated with failure to develop oral language., (© 2016 by American Journal of Neuroradiology.)

One potential source of heterogeneity within autism spectrum conditions (ASC) is language development and ability. In 80 high-functioning male adults with ASC, we tested if variations in developmental and current structural language are associated with current neuroanatomy. Groups with and without language delay differed behaviorally in early social reciprocity, current language, but not current autistic features. Language delay was associated with larger total gray matter (GM) volume, smaller relative volume at bilateral insula, ventral basal ganglia, and right superior, middle, and polar temporal structures, and larger relative volume at pons and medulla oblongata in adulthood. Despite this heterogeneity, those with and without language delay showed significant commonality in morphometric features when contrasted with matched neurotypical individuals (n = 57). In ASC, better current language was associated with increased GM volume in bilateral temporal pole, superior temporal regions, dorsolateral fronto-parietal and cerebellar structures, and increased white matter volume in distributed frontal and insular regions. Furthermore, current language-neuroanatomy correlation patterns were similar across subgroups with or without language delay. High-functioning adult males with ASC show neuroanatomical variations associated with both developmental and current language characteristics. This underscores the importance of including both developmental and current language as specifiers for ASC, to help clarify heterogeneity., (© The Author 2014. Published by Oxford University Press.)

Autism spectrum disorders (ASD) are a group of conditions that show abnormalities in the neuroanatomy of multiple brain regions. The variability in the development of intelligence and language among individuals on the autism spectrum has long been acknowledged, but it remains unknown whether these differences impact on the neuropathology of ASD. In this study, we aimed to compare associations between surface-based regional brain measures and general intelligence (IQ) scores in ASD individuals with and without a history of language delay. We included 64 ASD adults of normal intelligence (37 without a history of language delay and 27 with a history of language delay and 80 neurotypicals). Regions with a significant association between verbal and nonverbal IQ and measures of cortical thickness (CT), surface area, and cortical volume were first identified in the combined sample of individuals with ASD and controls. Thicker dorsal frontal and temporal cortices, and thinner lateral orbital frontal and parieto-occipital cortices were associated with greater and lower verbal IQ scores, respectively. Correlations between cortical volume and verbal IQ were observed in similar regions as revealed by the CT analysis. A significant difference between ASD individuals with and without a history of language delay in the association between CT and verbal IQ was evident in the parieto-occipital region. These results indicate that ASD subgroups defined on the basis of differential language trajectories in childhood can have different associations between verbal IQ and brain measures in adulthood despite achieving similar levels of cognitive performance., (© 2015 International Society for Autism Research, Wiley Periodicals, Inc.)

We detail here the clinical description and the family genetic study of a male patient with global developmental delay, disruptive and obsessive behaviors and minor dysmorphic features and a combination of two rare genetic variants: a maternally inherited 16p13.11-p12.3 duplication and a de novo 12p12.1 deletion affecting SOX5. The 16p13.11 microduplication has been implicated in several neurodevelopmental and behavioral disorders and is characterized by variable expressivity and incomplete penetrance. The causes of this variation in phenotypic expression are not fully clear, representing a challenge in genetic diagnosis and counseling. However, several authors have proposed the two-hit model as one of the underlying mechanisms for this phenotypic heterogeneity. Our data could also support this two-hit model in which the 16p13.11-p12.3 duplication might contribute to the phenotype, not only as a single event but also in association with the SOX5 deletion. The SOX5 gene plays important roles in various developmental processes and has been associated with several neurodevelopmental disorders, mainly intellectual disability, developmental delay and language and/or speech delay as well as with behavior problems and dysmorphic features. However, many of the physical features and behavioral manifestations as well as language deficiencies present in our patient are consistent with those previously reported for SOX5 deletions. Patients carrying multiple genomic variants, as the one presented here, illustrate the difficulty in analyzing genotypes when the contribution of each variant results in overlapping phenotypes and/or, alternatively, in the modification of the clinical manifestations defined by the coexisting variant., (© 2015 Wiley Periodicals, Inc.)

Isolated mitochondrial respiratory chain complex III deficiency has been described in a heterogeneous group of clinical presentations in children and adults. It has been associated with mutations in MT-CYB, the only mitochondrial DNA encoded subunit, as well as in nine nuclear genes described thus far: BCS1L, TTC19, UQCRB, UQCRQ, UQCRC2, CYC1, UQCC2, LYRM7, and UQCC3. BCS1L, TTC19, UQCC2, LYRM7, and UQCC3 are complex III assembly factors. We report on an 8-year-old girl born to consanguineous Iraqi parents presenting with slowly progressive encephalomyopathy, severe failure to thrive, significant delays in verbal and communicative skills and bilateral retinal cherry red spots on fundoscopy. SNP array identified multiple regions of homozygosity involving 7.5% of the genome. Mutations in the TTC19 gene are known to cause complex III deficiency and TTC19 was located within the regions of homozygosity. Sequencing of TTC19 revealed a homozygous nonsense mutation at exon 6 (c.937C > T; p.Q313X). We reviewed the phenotypes and genotypes of all 11 patients with TTC19 mutations leading to complex III deficiency (including our case). The consistent features noted are progressive neurodegeneration with Leigh-like brain MRI abnormalities. Significant variability was observed however with the age of symptom onset and rate of disease progression. The bilateral retinal cherry red spots and failure to thrive observed in our patient are unique features, which have not been described, in previously reported patients with TTC19 mutations. Interestingly, all reported TTC19 mutations are nonsense mutations. The severity of clinical manifestations however does not specifically correlate with the residual complex III enzyme activities., (© 2015 Wiley Periodicals, Inc.)

Primary care pediatricians and a variety of specialist physicians strive to define an accurate diagnosis for children presenting with impairment of expressive speech and delay in achieving developmental milestones. Within the past two decades, a group of disorders featuring this presentation have been identified as cerebral creatine deficiency syndromes (CCDS). Patients with these disorders were initially discerned using proton magnetic resonance spectroscopy of the brain within a magnetic resonance imaging (MRI) examination. The objective of this review is to provide the clinician with an overview of the current information available on identifying and treating these conditions. We explain the salient features of creatine metabolism, synthesis, and transport required for normal development. We propose diagnostic approaches for confirming a CCDS diagnosis. Finally, we describe treatment approaches for managing patients with these conditions.