Search

Background: Helsmoortel–Van der Aa syndrome (HVDAS) is a rare genetic disorder caused by variants in the activity-dependent neuroprotector homeobox (ADNP) gene; hence, it is also called ADNP syndrome. ADNP is a multitasking protein with the function as a transcription factor, playing a critical role in brain development. Furthermore, ADNP variants have been identified as one of the most common single-gene causes of autism spectrum disorder (ASD) and intellectual disability. Methods: We assembled a cohort of 15 Chinese pediatric patients, identified 13 variants in the coding region of ADNP gene, and evaluated their clinical phenotypes. Additionally, we constructed the corresponding ADNP variants and performed western blotting and immunofluorescence analysis to examine their protein expression and subcellular localization in human HEK293T and SH-SY5Y cells. Results: Our study conducted a thorough characterization of the clinical manifestations in 15 children with ADNP variants, and revealed a broad spectrum of symptoms including global developmental delay, intellectual disability, ASD, facial abnormalities, and other features. In vitro studies were carried out to check the expression of ADNP with identified variants. Two cases presented missense variants, while the remainder exhibited nonsense or frameshift variants, leading to truncated mutants in in vitro overexpression systems. Both overexpressed wildtype ADNP and all the different mutants were found to be confined to the nuclei in HEK293T cells; however, the distinctive pattern of nuclear bodies formed by the wildtype ADNP was either partially or entirely disrupted by the mutant proteins. Moreover, two variants of p.Y719* on the nuclear localization signal (NLS) of ADNP disrupted the nuclear expression pattern, predominantly manifesting in the cytoplasm in SH-SY5Y cells. Limitations: Our study was limited by a relatively small sample size and the absence of a longitudinal framework to monitor the progression of patient conditions over time. Additionally, we lacked in vivo evidence to further indicate the causal implications of the identified ADNP variants. Conclusions: Our study reported the first cohort of HVDAS patients in the Chinese population and provided systematic clinical presentations and laboratory examinations. Furthermore, we identified multiple genetic variants and validated them in vitro. Our findings offered valuable insights into the diverse genetic variants associated with HVDAS. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is an early-onset neurodevelopmental disorder in which genetics play a major role. Molecular diagnosis may lead to a more accurate prognosis, improved clinical management, and potential treatment of the condition. Both copy number variations (CNVs) and single nucleotide variations (SNVs) have been reported to contribute to the genetic etiology of ASD. The effectiveness and validity of clinical targeted panel sequencing (CTPS) designed to analyze both CNVs and SNVs can be evaluated in different ASD cohorts. CTPS was performed on 573 patients with the diagnosis of ASD. Medical records of positive CTPS cases were further reviewed and analyzed. Additional medical examinations were performed for a group of selective cases. Positive molecular findings were confirmed by orthogonal methods. The overall positive rate was 19.16% (109/569) in our cohort. About 13.89% (79/569) and 4.40% (25/569) of cases had SNVs only and CNVs only findings, respectively, while 0.9% (5/569) of cases had both SNV and CNV findings. For cases with SNVs findings, the SHANK3 gene has the greatest number of reportable variants, followed by gene MYT1L. Patients with MYT1L variants share common and specific clinical characteristics. We found a child with compound heterozygous SLC26A4 variants had an enlarged vestibular aqueduct syndrome and autistic phenotype. Our results showed that CTPS is an effective molecular diagnostic tool for ASD. Thorough clinical and genetic evaluation of ASD can lead to more accurate diagnosis and better management of the condition. [ABSTRACT FROM AUTHOR]

Objective: Early screening contributes to the early detection of children with autism spectrum disorder (ASD). We conducted a longitudinal ASD screening study in a large community setting. The study was designed to investigate the diagnostic rate of ASD screening and determine the effectiveness of ASD screening model in a community-based sample. Methods: We enrolled children who attended 18- and 24-month well-child care visits in Shanghai Xuhui District. Modified Checklist for Autism in Toddlers, Revised with Follow-up (M-CHAT-R/F) and Binomial Observation Test (BOT) were selected as screening instruments. Screen-positive children were referred to a tertiary diagnostic center for comprehensive ASD diagnostic evaluation. Screen-negative children received well-child checkups and follow-up every 3–6 months until age three and were referred if they were suspected of having ASD. Results: A total of 11,190 toddlers were screened, and 36 screen-positive toddlers were diagnosed with ASD. The mean age at diagnosis for these children was 23.1 ± 4.55 months, diagnosed 20 months earlier than ASD children not screened. The diagnostic rate of ASD was 0.32% (95% CI: 0.23–0.45%) in this community-based sample. In addition, 12 screen-negative children were diagnosed with ASD during subsequent well-child visit and follow-up. The average diagnostic rate of ASD rose to 0.43% (95% CI: 0.32–0.57%) when toddlers were followed up to 3 years old. The positive predictive values (PPVs) of M-CHAT-R/F, M-CHAT-R high risk, and BOT for ASD were 0.31, 0.43, and 0.38 respectively. Conclusion: Our findings provide reliable data for estimating the rate of ASD detection and identifying the validity of community-based screening model. M-CHAT-R/F combined with BOT can be an effective tool for early detection of ASD. This community-based screening model is worth replicating. [ABSTRACT FROM AUTHOR]

SH3 and Multiple Ankyrin Repeat Domains 3 (SHANK3)-caused autism spectrum disorder (ASD) may present a unique opportunity to clarify the heterogeneous neuropathological mechanisms of ASD. However, the specificity and commonality of disrupted large-scale brain organization in SHANK3- deficient children remain largely unknown. The present study combined genetic tests, neurobehavioral evaluations, and magnetic resonance imaging, aiming to explore the disruptions of both local and networked cortical structural organization in ASD children with and without SHANK3 deficiency. Multiple surface morphological parameters such as cortical thickness (CT) and sulcus depth were estimated, and the graph theory was adopted to characterize the topological properties of structural covariance networks (SCNs). Finally, a correlation analysis between the alterations in brain morphological features and the neurobehavioral evaluations was performed. Compared with typically developed children, increased CT and reduced nodal degree were found in both ASD children with and without SHANK3 defects mainly in the lateral temporal cortex, prefrontal cortex (PFC), temporo-parietal junction (TPJ), superior temporal gyrus (STG), and limbic/paralimbic regions. Besides commonality, our findings showed some distinct abnormalities in ASD children with SHANK3 defects compared to those without. Locally, more changes in the STG and orbitofrontal cortex were exhibited in ASD children with SHANK3 defects, while more changes in the TPJ and inferior parietal lobe (IPL) in those without SHANK3 defects were observed. For the SCNs, a trend toward regular network topology was observed in ASD children with SHANK3 defects, but not in those without. In addition, ASD children with SHANK3 defects showed more alterations of nodal degrees in the anterior and posterior cingulate cortices and right insular, while there were more disruptions in the sensorimotor areas and the left insular and dorsomedial PFC in ASD without SHANK3 defects. Our findings indicate dissociable disruptions of local and networked brain morphological features in ASD children with and without SHANK3 deficiency. Moreover, this monogenic study may provide a valuable path for parsing the heterogeneity of brain disturbances in ASD. [ABSTRACT FROM AUTHOR]

• The copy number variation of SHANK3 contributes 0.4 % to Chinese children with ASD. • Comprehensive clinical, neurobehavioral, and brain imaging assessments were reported in SHANK3 deficient Chinese children. • SHANK3 -deficient ASD patients relate to the disrupted striatum centered connectivity. SHANK3 deficiency represents one of the most replicated monogenic risk factors for autism spectrum disorder (ASD) and SHANK3 caused ASD presents a unique opportunity to understand the underlying neuropathological mechanisms of ASD. In this study, genetic tests, comprehensive clinical and neurobehavioral evaluations, as well as multimodal structural MRI using voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) were conducted in SHANK3 group (N = 14 with SHANK3 defects), ASD controls (N = 26 with idiopathic ASD without SHANK3 defects) and typically developing (TD) controls (N = 32). Phenotypically, we reported several new features in Chinese SHANK3 deficient children including anteverted nares, sensory stimulation seeking, dental abnormalities and hematological problems. In SHANK3 group, VBM revealed decreased grey matter volumes mainly in dorsal striatum, amygdala, hippocampus and parahippocampal gyrus; TBSS demonstrated decreased fractional anisotropy in multiple tracts involving projection, association and commissural fibers, including middle cerebral peduncle, corpus callosum, superior longitudinal fasciculus, corona radiata, external and internal capsule, and posterior thalamic radiation, etc. We report that the disrupted striatum centered brain structures are associated with SHANK3 deficient children. Study of subjects with monogenic cause offer specific insights into the neuroimaging studies of ASD. The discovery may support a path for future functional connectivity studies to allow for more in-depth understandings of the abnormal neural circuits and the underlying neuropathological mechanisms for ASD. [ABSTRACT FROM AUTHOR]