1. Badhe S, Nivins S, Kulkarni P, Jose A, Manek D, Badhe S, Sane H, Gokulchandran N, Badhe P, Sharma A. Abnormal Development of the Corpus Callosum in Autism Spectrum Disorder: An MRI Study. Top Magn Reson Imaging;2024 (Jun 1);33(3):e0312.

BACKGROUND: Altered size in the corpus callosum (CC) has been reported in individuals with autism spectrum disorder (ASD), but few studies have investigated younger children. Moreover, knowledge about the age-related changes in CC size in individuals with ASD is limited. OBJECTIVES: Our objective was to investigate the age-related size of the CC and compare them with age-matched healthy controls between the ages of 2 and 18 years. METHODS: Structural-weighted images were acquired in 97 male patients diagnosed with ASD; published data were used for the control group. The CC was segmented into 7 distinct subregions (rostrum, genu, rostral body, anterior midbody, posterior midbody, isthmus, and splenium) as per Witelson’s technique using ITK-SNAP software. We calculated both the total length and volume of the CC as well as the length and height of its 7 subregions. The length of the CC measures was studied as both continuous and categorical forms. For the continuous form, Pearson’s correlation was used, while categorical forms were based on age ranges reflecting brain expansion during early postnatal years. Differences in CC measures between adjacent age groups in individuals with ASD were assessed using a Student t-test. Mean and standard deviation scores were compared between ASD and control groups using the Welch t-test. RESULTS: Age showed a moderate positive association with the total length of the CC (r = 0.43; Padj = 0.003) among individuals with ASD. Among the subregions, a positive association was observed only in the anterior midbody of the CC (r = 0.41; Padj = 0.01). No association was found between the age and the height of individual subregions or with the total volume of the CC. In comparison with healthy controls, individuals with ASD exhibited shorter lengths and heights of the genu and splenium of the CC across wide age ranges. CONCLUSION: Overall, our results highlight a distinct abnormal developmental trajectory of CC in ASD, particularly in the genu and splenium structures, potentially reflecting underlying pathophysiological mechanisms that warrant further investigation.

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2. Bloomfield M, Lautarescu A, Heraty S, Douglas S, Violland P, Plas R, Ghosh A, Van den Bosch K, Eaton E, Absoud M, Battini R, Blázquez Hinojosa A, Bolshakova N, Bölte S, Bonanni P, Borg J, Calderoni S, Calvo Escalona R, Castelo-Branco M, Castro-Fornieles J, Caro P, Cliquet F, Danieli A, Delorme R, Elia M, Hempel M, Leblond CS, Madeira N, McAlonan G, Milone R, Molloy CJ, Mouga S, Montiel V, Pina Rodrigues A, Schaaf CP, Serrano M, Tammimies K, Tye C, Vigevano F, Oliveira G, Mazzone B, O’Neill C, Pender J, Romero V, Tillmann J, Oakley B, Murphy DGM, Gallagher L, Bourgeron T, Chatham C, Charman T. European Autism GEnomics Registry (EAGER): protocol for a multicentre cohort study and registry. BMJ Open;2024 (Jun 4);14(6):e080746.

INTRODUCTION: Autism is a common neurodevelopmental condition with a complex genetic aetiology that includes contributions from monogenic and polygenic factors. Many autistic people have unmet healthcare needs that could be served by genomics-informed research and clinical trials. The primary aim of the European Autism GEnomics Registry (EAGER) is to establish a registry of participants with a diagnosis of autism or an associated rare genetic condition who have undergone whole-genome sequencing. The registry can facilitate recruitment for future clinical trials and research studies, based on genetic, clinical and phenotypic profiles, as well as participant preferences. The secondary aim of EAGER is to investigate the association between mental and physical health characteristics and participants’ genetic profiles. METHODS AND ANALYSIS: EAGER is a European multisite cohort study and registry and is part of the AIMS-2-TRIALS consortium. EAGER was developed with input from the AIMS-2-TRIALS Autism Representatives and representatives from the rare genetic conditions community. 1500 participants with a diagnosis of autism or an associated rare genetic condition will be recruited at 13 sites across 8 countries. Participants will be given a blood or saliva sample for whole-genome sequencing and answer a series of online questionnaires. Participants may also consent to the study to access pre-existing clinical data. Participants will be added to the EAGER registry and data will be shared externally through established AIMS-2-TRIALS mechanisms. ETHICS AND DISSEMINATION: To date, EAGER has received full ethical approval for 11 out of the 13 sites in the UK (REC 23/SC/0022), Germany (S-375/2023), Portugal (CE-085/2023), Spain (HCB/2023/0038, PIC-164-22), Sweden (Dnr 2023-06737-01), Ireland (230907) and Italy (CET_62/2023, CEL-IRCCS OASI/24-01-2024/EM01, EM 2024-13/1032 EAGER). Findings will be disseminated via scientific publications and conferences but also beyond to participants and the wider community (eg, the AIMS-2-TRIALS website, stakeholder meetings, newsletters).

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3. Brunklaus A. Autism and attention-deficit/hyperactivity disorder in Dravet syndrome. Dev Med Child Neurol;2024 (Jun 5)

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4. Dwyer P, Sillas A, Prieto M, Camp E, Nordahl CW, Rivera SM. Hyper-focus, sticky attention, and springy attention in young autistic children: Associations with sensory behaviors and cognitive ability. Autism Res;2024 (Jun 5)

The autistic-developed monotropism account suggests that atypical, domain-general attentional hyper-focus on interests is a central aspect of autism, but domain-general attention differences in autism can manifest differently. Prior research suggests autistic children are often slow to disengage attention from stimuli-a pattern often called « sticky attention »-and that they can show reduced novelty preference. These attentional patterns could influence sensory experiences and learning. We used eye-tracking to investigate novelty preference and « sticky attention » in young autistic children; we also examined whether attentional patterns were related to cognitive abilities and caregiver-reported sensory responsiveness. A total of 46 autistic and 28 nonautistic participants, aged between 2 and 4 years, provided usable data. We found no evidence that autistic children exhibited greater « sticky attention » than nonautistics, but « sticky attention » in autism was associated with more caregiver-reported sensory hyper-responsiveness, seeking/interests, and enhanced perception. Autistic children also nonsignificantly trended toward exhibiting reduced novelty preference. Unexpectedly, the time-course of this trending novelty preference difference implied it was not driven by reduced orienting to novelty, but increased returning to already-familiarized stimuli: what we call « springy attention. » Exploratory analyses of data from the attentional disengagement task suggest autistic participants may have exhibited greater « springy attention, » though further research with paradigms optimized for measuring this construct should confirm this. Importantly, « springy attention » was robustly related to reduced cognitive abilities and greater caregiver-reported hypo-responsiveness. Thus, this study illuminates two distinct domain-general attentional patterns, each with distinct correlates in young autistic children, which could have important implications for understanding autistic children’s learning, development, and experiences.

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5. Falcão M, Monteiro P, Jacinto L. Tactile sensory processing deficits in genetic mouse models of autism spectrum disorder. J Neurochem;2024 (Jun 4)

Altered sensory processing is a common feature in autism spectrum disorder (ASD), as recognized in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Although altered responses to tactile stimuli are observed in over 60% of individuals with ASD, the neurobiological basis of this phenomenon is poorly understood. ASD has a strong genetic component and genetic mouse models can provide valuable insights into the mechanisms underlying tactile abnormalities in ASD. This review critically addresses recent findings regarding tactile processing deficits found in mouse models of ASD, with a focus on behavioral, anatomical, and functional alterations. Particular attention was given to cellular and circuit-level functional alterations, both in the peripheral and central nervous systems, with the objective of highlighting possible convergence mechanisms across models. By elucidating the impact of mutations in ASD candidate genes on somatosensory circuits and correlating them with behavioral phenotypes, this review significantly advances our understanding of tactile deficits in ASD. Such insights not only broaden our comprehension but also pave the way for future therapeutic interventions.

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6. Fard YA, Sadeghi EN, Pajoohesh Z, Gharehdaghi Z, Khatibi DM, Khosravifar S, Pishkari Y, Nozari S, Hijazi A, Pakmehr S, Shayan SK. Epigenetic underpinnings of the autistic mind: Histone modifications and prefrontal excitation/inhibition imbalance. Am J Med Genet B Neuropsychiatr Genet;2024 (Jun 4):e32986.

Autism spectrum disorder (ASD) is complex neurobehavioral condition influenced by several cellular and molecular mechanisms that are often concerned with synaptogenesis and synaptic activity. Based on the excitation/inhibition (E/I) imbalance theory, ASD could be the result of disruption in excitatory and inhibitory synaptic transmission across the brain. The prefrontal cortex (PFC) is the chief regulator of executive function and can be affected by altered neuronal excitation and inhibition in the course of ASD. The molecular mechanisms involved in E/I imbalance are subject to epigenetic regulation. In ASD, altered enrichment and spreading of histone H3 and H4 modifications such as the activation-linked H3K4me2/3, H3K9ac, and H3K27ac, and repression-linked H3K9me2, H3K27me3, and H4K20me2 in the PFC result in dysregulation of molecules mediating synaptic excitation (ARC, EGR1, mGluR2, mGluR3, GluN2A, and GluN2B) and synaptic inhibition (BSN, EphA7, SLC6A1). Histone modifications are a dynamic component of the epigenetic regulatory elements with a pronounced effect on patterns of gene expression with regards to any biological process. The excitation/inhibition imbalance associated with ASD is based on the excitatory and inhibitory synaptic activity in different regions of the brain, including the PFC, the ultimate outcome of which is highly influenced by transcriptional activity of relevant genes.

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7. Lee HK, Tong SX. Impaired inhibitory control when processing real but not cartoon emotional faces in autistic children: Evidence from an event-related potential study. Autism Res;2024 (Jun 5)

Impaired socioemotional functioning characterizes autistic children, but does weak inhibition control underlie their socioemotional difficulty? This study addressed this question by examining whether and, if so, how inhibition control is affected by face realism and emotional valence in school-age autistic and neurotypical children. Fifty-two autistic and 52 age-matched neurotypical controls aged 10-12 years completed real and cartoon emotional face Go/Nogo tasks while event-related potentials (ERPs) were recorded. The analyses of inhibition-emotion components (i.e., N2, P3, and LPP) and a face-specific N170 revealed that autistic children elicited greater N2 while inhibiting Nogo trials and greater P3/LPP and late LPP for real but not cartoon emotional faces. Moreover, autistic children exhibited a reduced N170 to real face emotions only. Furthermore, correlation results showed that better behavioral inhibition and emotion recognition in autistic children were associated with a reduced N170. These findings suggest that neural mechanisms of inhibitory control in autistic children are less efficient and more disrupted during real face processing, which may affect their age-appropriate socio-emotional development.

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8. Mavritsakis D. Augmentative and alternative communication in autism spectrum disorder: transitioning from letter board to iPad – a case study. Front Psychiatry;2024;15:1345447.

This case study examines the effective use of Augmentative and Alternative Communication (AAC) tools in enhancing communication skills in a 15-year-old male with Autism Spectrum Disorder (ASD). Initially exhibiting non-verbal tendencies, the subject experienced significant improvements in communication and social interaction following the introduction of a letter board and subsequent transition to an iPad. These AAC tools facilitated a marked development in his ability to articulate thoughts, engage in academic activities, and express complex ideas, particularly in science. The study highlights the role of AAC in expanding the communicative capabilities of individuals with limited or no verbal language, demonstrating notable advancements in both verbal expression and cognitive engagement. The findings underscore the transformative impact of personalized AAC interventions and suggest the potential for broader application in ASD support strategies. This case highlights the need for further research, including randomized controlled trials, to explore the efficacy of AAC tools in diverse ASD contexts.

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9. Najm R, Knoblich JA. Making sense of Timothy syndrome with 3D human neuronal models. Neuron;2024 (Jun 5);112(11):1730-1732.

In a recent issue of Nature, Chen and colleagues(1) reveal the potential for antisense oligonucleotides (ASOs) to rescue the neuropathological mechanisms underlying Timothy syndrome (TS) using three-dimensional neuronal models. Combining in vitro and in vivo approaches, the authors present a strategy to translate disease biology findings into potential therapeutics.

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10. Ren T, Zhang L, Liu Y, Zhang Q, Sun Y, Zhou W, Huang L, Wang M, Pu Y, Huang R, Chen J, He H, Zhu T, Wang S, Chen W, Zhang Q, Du W, Luo Q, Li F. Sex-specific associations of adolescent motherhood with cognitive function, behavioral problems, and autistic-like traits in offspring and the mediating roles of family conflict and altered brain structure. BMC Med;2024 (Jun 5);22(1):226.

BACKGROUND: Previous studies have linked adolescent motherhood to adverse neurodevelopmental outcomes in offspring, yet the sex-specific effect and underlying mechanisms remain unclear. METHODS: This study included 6952 children aged 9-11 from the Adolescent Brain Cognitive Development study. The exposed group consisted of children of mothers < 20 years at the time of birth, while the unexposed group was composed of children of mothers aged 20-35 at birth. We employed a generalized linear mixed model to investigate the associations of adolescent motherhood with cognitive, behavioral, and autistic-like traits in offspring. We applied an inverse-probability-weighted marginal structural model to examine the potential mediating factors including adverse perinatal outcomes, family conflict, and brain structure alterations. RESULTS: Our results revealed that children of adolescent mothers had significantly lower cognitive scores (β, - 2.11, 95% CI, - 2.90 to - 1.31), increased externalizing problems in male offspring (mean ratio, 1.28, 95% CI, 1.08 to 1.52), and elevated internalizing problems (mean ratio, 1.14, 95% CI, 0.99 to 1.33) and autistic-like traits (mean ratio, 1.22, 95% CI, 1.01 to 1.47) in female. A stressful family environment mediated ~ 70% of the association with internalizing problems in females, ~ 30% with autistic-like traits in females, and ~ 20% with externalizing problems in males. Despite observable brain morphometric changes related to adolescent motherhood, these did not act as mediating factors in our analysis, after adjusting for family environment. No elevated rate of adverse perinatal outcomes was observed in the offspring of adolescent mothers in this study. CONCLUSIONS: Our results reveal distinct sex-specific neurodevelopmental outcomes impacts of being born to adolescent mothers, with a substantial mediating effect of family environment on behavioral outcomes. These findings highlight the importance of developing sex-tailored interventions and support the hypothesis that family environment significantly impacts the neurodevelopmental consequences of adolescent motherhood.

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11. Sanders JS, Williams K, Thompson D, Shapiro HF. Enhancing comfort of resident physicians treating adults with intellectual and developmental disabilities by facilitating meaningful interactions. Front Med (Lausanne);2024;11:1264958.

BACKGROUND: Many physicians feel uncomfortable caring for patients with intellectual and developmental disabilities (IDD). While some residency training programs include lecture content on IDD, few provide structured experiences with individuals with IDD. One strategy for improving comfort is « contact theory: » increasing interactions with « dissimilar » people can lead to decreased negative attitudes toward that population. OBJECTIVE: Evaluate the impact of an interactive session on resident physicians’ comfort with adults with IDD. METHODS: Small groups of resident physicians and artists with IDD collaborated on art projects during the noon conference. A prospective pre-post-intervention survey, including the validated Interaction with Disabled Persons Scale (IDP), evaluated residents’ comfort with patients with IDD before and after the session. RESULTS: 53 residents completed both pre- and post-conference surveys. Mean IDP scores decreased from 78.7 (10.9) to 75.8 (9.5; p < 0.01), indicating decreasing discomfort. The mean level of comfort interacting with individuals with IDD increased from uncomfortable 3.6 (1.2), before the intervention, to comfortable 4.4 (1.2) after the intervention (p = <0.01). The mean level of comfort treating individuals with IDD increased from uncomfortable 3.5 (1.1) to comfortable 4.1 (1.3) after the intervention (p < 0.01). DISCUSSION: Providing resident physicians with real-life connections with people with IDD was associated with increased comfort. If statistically significant improvements occurred after one session, future studies should evaluate if additional experiences with people with IDD could have more substantial, lasting impacts on future doctors' comfort with and willingness to care for patients with IDD.

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12. Simarro Gonzalez M, Ni G, Lam V, Demopoulos C. Beyond words: an investigation of fine motor skills and the verbal communication spectrum in autism. Front Psychiatry;2024;15:1379307.

INTRODUCTION: This study investigated the associations between fine motor skills and expressive verbal abilities in a group of 97 autistic participants (age 8-17, mean=12.41) and 46 typically developing youth (age 8-17, mean=12.48). METHODS: Participants completed assessments of motor and verbal communication skills, including finger tapping speed, grooved pegboard, grip strength, visual-motor integration tasks, and measures of speech and communication skills. ASD group performance on motor tests was compared to controls. Non-parametric tests were used to analyze group differences and correlations between motor and verbal communication skills. Based on prior research, we hypothesized that individuals on the autism spectrum would exhibit deficits in fine motor speed, dexterity, pencil motor control, but not manual motor strength. Additionally, we expected that impaired fine motor skills would be linked to poorer performance on standardized measures of verbal abilities. RESULTS: The results indicated that 80% of autistic participants demonstrated an impairment on at least one measure of motor skills, and as a group, they exhibited significantly poorer fine motor performance compared to the non-ASD group in dominant hand finger tapping speed, bilateral fine motor dexterity measured via the grooved pegboard task, and pencil motor coordination and visual-motor integration measured on the Beery-Buktenica Developmental Test of Visual-Motor Integration-Sixth Edition. Moreover, impaired fine motor skills were associated with poorer performance on standardized clinical measures of verbal abilities, including articulation errors, receptive and expressive language and vocabulary, rapid naming, oromotor sequencing, and parent reported functional communication skills and social communication symptoms. DISCUSSION: Overall,our findings suggest there is a high prevalence of fine motor impairments in ASD, and these impairments were associated with a range of verbal abilities. Further research is warranted to better understand the underlying mechanisms of these associations and develop targeted interventions to address both fine motor and verbal impairments in ASD.

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13. Tian Y, Ai R, Xiao X, Liu W, Cheng S, Zhu X. Mechanism of the effect of TREM2 on cognitive function in autistic mice. Cell Mol Biol (Noisy-le-grand);2024 (Jun 5);70(6):66-72.

This study aimed to investigate the mechanism of the effect of TREM2 on cognitive function in autistic mice. TREM2 overexpression and knockdown viruses were given to autism spectrum disorder (ASD) mice and BV2 microglia cell line. To assess cognitive performance, all groups of mice took part in the open field, new object recognition, Morris water maze, and three-box social experiments. Double immunofluorescence labeling demonstrated co-localization of LC3II and NeuN. Proteins from the PI3K/Akt/mTOR pathway were identified. In vivo, behavior studies revealed that TREM2 could successfully improve ASD mice’s social interaction and cognitive performance. Besides, we discovered that TREM2 could increase autophagy in ASD mice. In vitro, overexpressing TREM2 reduced the expression of PI3K/AKT/mTOR pathway proteins, whereas knocking down TREM2 increased the expression of PI3K/AKT/mTOR pathway proteins. In conclusion, TREM2 could inhibit PI3K/Akt/mTOR signaling pathway, enhance autophagy, and improve the social communication ability and cognitive function of ASD mice.

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14. Umapathy N, Thirugnana Sambanda Moorthy B, Azhagar Nambi Santhi V, Nair LDV. Microcornea, cerebellar hypoplasia and hyperlax joints-unusual combo in rare Ehlers-Danlos syndrome-musculocontractural type 1. BMJ Case Rep;2024 (Jun 4);17(6)

Ehlers-Danlos syndrome is a group of connective tissue disorders with 14 subtypes, involving joint hyperlaxity, tissue fragility, hypertensive skin and other systemic organs with an incidence of 1 in 1 000 000 worldwide. We report a middle childhood female born of second degree consanguineous marriage with limping gait with muscle weakness, with normal development and IQ. Examination revealed microcornea, distal joint laxity of fingers and wrist, hypotonia and broad-based limping gait. Fracture dislocation right hip was managed by fixation. With the atypical neuroimaging finding of cerebellar vermis hypoplasia, exome sequencing was ordered and confirmed as Ehlers-Danlos syndrome (musculocontractural type-1). Hence, genetic counselling was done and prognosis of the child was explained.

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15. Voltaire S, Steinberg H, Garfield T, Chvasta K, Ardeleanu K, Brown M, Shea L. Inextricably tied: Nonbinary autistic individuals’ views on how their gender identity and autism are connected. Autism;2024 (Jun 5):13623613241257600.

This study explores the experiences and identities of nonbinary autistic people. The relationship between autistic and nonbinary identities has not been researched in detail. Few studies focus specifically on nonbinary autistic adults. We interviewed 44 nonbinary individuals for this study. Participants had thought-out opinions on gender identity and emphasized identifying with fluidity rather than traditional gender roles. Participants discussed the connection of their autistic and nonbinary identities and how it affected how people saw them and how they saw themselves. We have recommendations for programming, policy, and research from these findings.

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16. Zhang J, Xu Y, Liu Y, Yue L, Jin H, Chen Y, Wang D, Wang M, Chen G, Yang L, Zhang G, Zhang X, Li S, Zhao H, Zhao Y, Niu G, Gao Y, Cai Z, Yang F, Zhu C, Zhu D. Genetic Testing for Global Developmental Delay in Early Childhood. JAMA Netw Open;2024 (Jun 3);7(6):e2415084.

IMPORTANCE: Global developmental delay (GDD) is characterized by a complex etiology, diverse phenotypes, and high individual heterogeneity, presenting challenges for early clinical etiologic diagnosis. Cognitive impairment is the core symptom, and despite the pivotal role of genetic factors in GDD development, the understanding of them remains limited. OBJECTIVES: To assess the utility of genetic detection in patients with GDD and to examine the potential molecular pathogenesis of GDD to identify targets for early intervention. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, prospective cohort study enrolled patients aged 12 to 60 months with GDD from 6 centers in China from July 4, 2020, to August 31, 2023. Participants underwent trio whole exome sequencing (trio-WES) coupled with copy number variation sequencing (CNV-seq). Bioinformatics analysis was used to unravel pathogenesis and identify therapeutic targets. MAIN OUTCOMES AND MEASURES: The main outcomes of this study involved enhancing the rate of positive genetic diagnosis for GDD, broadening the scope of genetic testing indications, and investigating the underlying pathogenesis. The classification of children into levels of cognitive impairment was based on the developmental quotient assessed using the Gesell scale. RESULTS: The study encompassed 434 patients with GDD (262 [60%] male; mean [SD] age, 25.75 [13.24] months) with diverse degrees of cognitive impairment: mild (98 [23%]), moderate (141 [32%]), severe (122 [28%]), and profound (73 [17%]). The combined use of trio-WES and CNV-seq resulted in a 61% positive detection rate. Craniofacial abnormalities (odds ratio [OR], 2.27; 95% CI, 1.45-3.56), moderate or severe cognitive impairment (OR, 1.69; 95% CI, 1.05-2.70), and age between 12 and 24 months (OR, 1.57; 95% CI, 1.05-2.35) were associated with a higher risk of carrying genetic variants. Additionally, bioinformatics analysis suggested that genetic variants may induce alterations in brain development and function, which may give rise to cognitive impairment. Moreover, an association was found between the dopaminergic pathway and cognitive impairment. CONCLUSIONS AND RELEVANCE: In this cohort study of patients with GDD, combining trio-WES with CNV-seq was a demonstrable, instrumental strategy for advancing the diagnosis of GDD. The close association among genetic variations, brain development, and clinical phenotypes contributed valuable insights into the pathogenesis of GDD. Notably, the dopaminergic pathway emerged as a promising focal point for potential targets in future precision medical interventions for GDD.

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