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Humans with monogenic inborn errors responsible for extreme disease phenotypes can reveal essential physiological pathways. We investigated germline mutations in GNAI2, which encodes Gαi2, a key component in heterotrimeric G protein signal transduction usually thought to regulate adenylyl cyclase-mediated cyclic adenosine monophosphate (cAMP) production. Patients with activating Gαi2 mutations had clinical presentations that included impaired immunity. Mutant Gαi2 impaired cell migration and augmented responses to T cell receptor (TCR) stimulation. We found that mutant Gαi2 influenced TCR signaling by sequestering the guanosine triphosphatase (GTPase)-activating protein RASA2, thereby promoting RAS activation and increasing downstream extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)-AKT S6 signaling to drive cellular growth and proliferation.

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INTRODUCTION: Atrophy of the nucleus basalis of Meynert (NBM) is an early indicator of Alzheimer's disease (AD). However, reduced integrity of the NBM white matter tracts may be more relevant for cognitive impairment and progression to dementia than NBM volume. Research is needed to compare differences in NBM volume and integrity of the lateral and medial NBM tracts across early and later stages of AD progression. METHODS: 187 participants were included in this study who were either healthy controls (HC; n = 50) or had early mild cognitive impairment (EMCI; n = 50), late MCI (LMCI; n = 37), or AD (n = 50). NBM volume was calculated using voxel-based morphometry and mean diffusivity (MD) of the lateral and medial NBM tracts were extracted using probabilistic tractography. Between group differences in NBM volume and tract MD were compared using linear mixed models controlling for age, sex, and either total intracranial volume or MD of a control mask, respectively. Associations between NBM volume and tract MD with executive function, memory, language, and visuospatial function were also analysed. RESULTS: NBM volume was smallest in AD followed by LMCI (p < 0.0001), with no difference between EMCI and HC. AD had highest MD for both tracts compared to all other groups (p < 0.01). Both MCI groups had higher lateral tract MD compared to HC (p < 0.05). Medial tract MD was higher in LMCI (p = 0.008), but not EMCI (p = 0.09) compared to HC. Higher lateral tract MD was associated with executive function (p = 0.001) and language (p = 0.02). DISCUSSION: Integrity of the lateral NBM tract is most sensitive to the earliest stages of AD and should be considered an important therapeutic target for early detection and intervention.

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Adaptive deep brain stimulation (aDBS) is an emerging advancement in DBS technology; however, local field potential (LFP) signal rate detection sufficient for aDBS algorithms and the methods to set-up aDBS have yet to be defined. Here we summarize sensing data and aDBS programming steps associated with the ongoing Adaptive DBS Algorithm for Personalized Therapy in Parkinson's Disease (ADAPT-PD) pivotal trial (NCT04547712). Sixty-eight patients were enrolled with either subthalamic nucleus or globus pallidus internus DBS leads connected to a Medtronic PerceptTM PC neurostimulator. During the enrollment and screening procedures, a LFP (8-30 Hz, ≥1.2 µVp) control signal was identified by clinicians in 84.8% of patients on medication (65% bilateral signal), and in 92% of patients off medication (78% bilateral signal). The ADAPT-PD trial sensing data indicate a high LFP signal presence in both on and off medication states of these patients, with bilateral signal in the majority, regardless of PD phenotype.

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Emergent tremor in Parkinson's disease (PD) can occur during sustained postures or movements that are different from action tremor. Tremor can contaminate the clinical rating of bradykinesia during finger tapping. Currently, there is no reliable way of isolating emergent tremor and measuring the cardinal motor symptoms based on voluntary movements only. In this study, we investigated whether emergent tremor during repetitive alternating finger tapping (RAFT) on a quantitative digitography (QDG) device could be reliably identified and distinguished from voluntary tapping. Ninety-six individuals with PD and forty-two healthy controls performed a thirty-second QDG-RAFT task and the Movement Disorders Society - Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III). Visual identification of tremor during QDG-RAFT was labeled by an experienced movement disorders specialist. Two methods of identifying tremor were investigated: 1) physiologically informed temporal thresholds 2) XGBoost model using temporal and amplitude features of tapping. The XGBoost model showed high accuracy for identifying tremor (area under the precision-recall curve of 0.981) and outperformed temporal-based thresholds. Percent time duration of classifier-identified tremor showed significant correlations with MDS-UPDRS III tremor subscores (r = 0.50, p < 0.0001). There was a significant change in QDG metrics for bradykinesia, rigidity, and arrhythmicity after tremor strikes were excluded (p < 0.01). The results demonstrate that emergent tremor during QDG-RAFT has a unique digital signature and the duration of tremor correlated with the MDS-UPDRS III tremor items. When involuntary tremor strikes were excluded, the QDG metrics of bradykinesia and rigidity were significantly worse, demonstrating the importance of distinguishing tremor from voluntary movement when rating bradykinesia.

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INTRODUCTION: Atrophy of the nucleus basalis of Meynert (NBM) is an early indicator of Alzheimer's disease (AD). However, reduced integrity of the NBM white matter tracts may be more relevant for cognitive impairment and progression to dementia than NBM volume. Research is needed to compare differences in NBM volume and integrity of the lateral and medial NBM tracts across early and later stages of AD progression. METHODS: 187 participants were included in this study who were either healthy controls (HC; n=50) or had early mild cognitive impairment (EMCI; n=50), late MCI (LMCI; n=37), or AD (n=50). NBM volume was calculated using voxel-based morphometry and mean diffusivity (MD) of the lateral and medial NBM tracts were extracted using probabilistic tractography. Between group differences in NBM volume and tract MD were compared using linear mixed models controlling for age, sex, and either total intracranial volume or MD of a control mask, respectively. Associations between NBM volume and tract MD with executive function, memory, language, and visuospatial function were also analysed. RESULTS: NBM volume was smallest in AD followed by LMCI (p<0.0001), with no difference between EMCI and HC. AD had highest MD for both tracts compared to all other groups (p<0.001). Both MCI groups had higher lateral tract MD compared to HC (p<0.05). Medial tract MD was higher in LMCI (p=0.008), but not EMCI (p=0.09) compared to HC. Higher lateral tract MD was associated with executive function (p=0.001) and language (p=0.02). DISCUSSION: Integrity of the lateral NBM tract is most sensitive to the earliest stages of AD and should be considered an important therapeutic target for early detection and intervention.

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People with Parkinson's disease (PWP) face critical challenges, including lack of access to neurological care, inadequate measurement and communication of motor symptoms, and suboptimal medication management and compliance. We have developed QDG-Care: a comprehensive connected care platform for Parkinson's disease (PD) that delivers validated, quantitative metrics of all motor signs in PD in real time, monitors the effects of adjusting therapy and medication adherence and is accessible in the electronic health record. In this article, we describe the design and engineering of all components of QDG-Care, including the development and utility of the QDG Mobility and Tremor Severity Scores. We present the preliminary results and insights from an at-home trial using QDG-Care. QDG technology has enormous potential to improve access to, equity of, and quality of care for PWP, and improve compliance with complex time-critical medication regimens. It will enable rapid "Go-NoGo" decisions for new therapeutics by providing high-resolution data that require fewer participants at lower cost and allow more diverse recruitment.

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Detection of structural variants (SVs) is currently biased toward those that alter copy number. The relative contribution of inversions toward genetic disease is unclear. In this study, we analyzed genome sequencing data for 33,924 families with rare disease from the 100,000 Genomes Project. From a database hosting >500 million SVs, we focused on 351 genes where haploinsufficiency is a confirmed disease mechanism and identified 47 ultra-rare rearrangements that included an inversion (24 bp to 36.4 Mb, 20/47 de novo). Validation utilized a number of orthogonal approaches, including retrospective exome analysis. RNA-seq data supported the respective diagnoses for six participants. Phenotypic blending was apparent in four probands. Diagnostic odysseys were a common theme (>50 years for one individual), and targeted analysis for the specific gene had already been performed for 30% of these individuals but with no findings. We provide formal confirmation of a European founder origin for an intragenic MSH2 inversion. For two individuals with complex SVs involving the MECP2 mutational hotspot, ambiguous SV structures were resolved using long-read sequencing, influencing clinical interpretation. A de novo inversion of HOXD11-13 was uncovered in a family with Kantaputra-type mesomelic dysplasia. Lastly, a complex translocation disrupting APC and involving nine rearranged segments confirmed a clinical diagnosis for three family members and resolved a conundrum for a sibling with a single polyp. Overall, inversions play a small but notable role in rare disease, likely explaining the etiology in around 1/750 families across heterogeneous clinical cohorts.

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Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare multisystem disorders arising from pathogenic variants in glycosylphosphatidylinositol anchor pathway (GPI-AP) genes. Despite associating 24 of at least 31 GPI-AP genes with human neurogenetic disease, prior reports are limited to single genes without consideration of the GPI-AP as a whole and with limited natural history data. In this multinational retrospective observational study, we systematically analyse the molecular spectrum, phenotypic characteristics and natural history of 83 individuals from 75 unique families with IGDs, including 70 newly reported individuals; the largest single cohort to date. Core clinical features were developmental delay or intellectual disability (DD/ID, 90%), seizures (83%), hypotonia (72%) and motor symptoms (64%). Prognostic and biologically significant neuroimaging features included cerebral atrophy (75%), cerebellar atrophy (60%), callosal anomalies (57%) and symmetric restricted diffusion of the central tegmental tracts (60%). Sixty-one individuals had multisystem involvement including gastrointestinal (66%), cardiac (19%) and renal (14%) anomalies. Though dysmorphic features were appreciated in 82%, no single dysmorphic feature had a prevalence >30%, indicating substantial phenotypic heterogeneity. Follow-up data were available for all individuals, 15 of whom were deceased at the time of writing. Median age at seizure onset was 6 months. Individuals with variants in synthesis stage genes of the GPI-AP exhibited a significantly shorter time to seizure onset than individuals with variants in transamidase and remodelling stage genes of the GPI-AP (P = 0.046). Forty individuals had intractable epilepsy. The majority of individuals experienced delayed or absent speech (95%), motor delay with non-ambulance (64%), and severe-to-profound DD/ID (59%). Individuals with a developmental epileptic encephalopathy (51%) were at greater risk of intractable epilepsy (P = 0.003), non-ambulance (P = 0.035), ongoing enteral feeds (P < 0.001) and cortical visual impairment (P = 0.007). Serial neuroimaging showed progressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in 70.8%, indicating a neurodegenerative process. Genetic analyses identified 93 unique variants (106 total), including 22 novel variants. Exploratory analyses of genotype-phenotype correlations using unsupervised hierarchical clustering identified novel genotypic predictors of clinical phenotype and long-term outcome with meaningful implications for management. In summary, we expand both the mild and severe phenotypic extremities of the IGDs, provide insights into their neurological basis, and vitally, enable meaningful genetic counselling for affected individuals and their families.

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The Deep Brain Stimulation (DBS) Think Tank XI was held on August 9-11, 2023 in Gainesville, Florida with the theme of "Pushing the Forefront of Neuromodulation". The keynote speaker was Dr. Nico Dosenbach from Washington University in St. Louis, Missouri. He presented his research recently published in Nature inn a collaboration with Dr. Evan Gordon to identify and characterize the somato-cognitive action network (SCAN), which has redefined the motor homunculus and has led to new hypotheses about the integrative networks underpinning therapeutic DBS. The DBS Think Tank was founded in 2012 and provides an open platform where clinicians, engineers, and researchers (from industry and academia) can freely discuss current and emerging DBS technologies, as well as logistical and ethical issues facing the field. The group estimated that globally more than 263,000 DBS devices have been implanted for neurological and neuropsychiatric disorders. This year's meeting was focused on advances in the following areas: cutting-edge translational neuromodulation, cutting-edge physiology, advances in neuromodulation from Europe and Asia, neuroethical dilemmas, artificial intelligence and computational modeling, time scales in DBS for mood disorders, and advances in future neuromodulation devices.

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People with Parkinson's disease (PWP) face critical challenges, including lack of access to neurological care, inadequate measurement and communication of motor symptoms, and suboptimal medication management and compliance. We have developed QDG-Care: a comprehensive connected care platform for Parkinson's disease (PD) that delivers validated, quantitative metrics of all motor signs in PD in real time, monitors the effects of adjusting therapy and medication adherence and is accessible in the electronic health record. In this article, we describe the design and engineering of all components of QDG-Care, including the development and utility of the QDG Mobility and Tremor Severity Scores. We present the preliminary results and insights from the first at-home trial using QDG-Care. QDG technology has enormous potential to improve access to, equity of, and quality of care for PWP, and improve compliance with complex time-critical medication regimens. It will enable rapid "Go-NoGo" decisions for new therapeutics by providing high-resolution data that require fewer participants at lower cost and allow more diverse recruitment.

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BACKGROUND: The ITPR1 gene encodes the inositol 1,4,5-trisphosphate (IP3 ) receptor type 1 (IP3 R1), a critical player in cerebellar intracellular calcium signaling. Pathogenic missense variants in ITPR1 cause congenital spinocerebellar ataxia type 29 (SCA29), Gillespie syndrome (GLSP), and severe pontine/cerebellar hypoplasia. The pathophysiological basis of the different phenotypes is poorly understood. OBJECTIVES: We aimed to identify novel SCA29 and GLSP cases to define core phenotypes, describe the spectrum of missense variation across ITPR1, standardize the ITPR1 variant nomenclature, and investigate disease progression in relation to cerebellar atrophy. METHODS: Cases were identified using next-generation sequencing through the Deciphering Developmental Disorders study, the 100,000 Genomes project, and clinical collaborations. ITPR1 alternative splicing in the human cerebellum was investigated by quantitative polymerase chain reaction. RESULTS: We report the largest, multinational case series of 46 patients with 28 unique ITPR1 missense variants. Variants clustered in functional domains of the protein, especially in the N-terminal IP3 -binding domain, the carbonic anhydrase 8 (CA8)-binding region, and the C-terminal transmembrane channel domain. Variants outside these domains were of questionable clinical significance. Standardized transcript annotation, based on our ITPR1 transcript expression data, greatly facilitated analysis. Genotype-phenotype associations were highly variable. Importantly, while cerebellar atrophy was common, cerebellar volume loss did not correlate with symptom progression. CONCLUSIONS: This dataset represents the largest cohort of patients with ITPR1 missense variants, expanding the clinical spectrum of SCA29 and GLSP. Standardized transcript annotation is essential for future reporting. Our findings will aid in diagnostic interpretation in the clinic and guide selection of variants for preclinical studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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PURPOSE: The UK 100,000 Genomes Project offered participants screening for additional findings (AFs) in genes associated with familial hypercholesterolemia (FH) or hereditary cancer syndromes including breast/ovarian cancer (HBOC), Lynch, familial adenomatous polyposis, MYH-associated polyposis, multiple endocrine neoplasia (MEN), and von Hippel-Lindau. Here, we report disclosure processes, manifestation of AF-related disease, outcomes, and costs. METHODS: An observational study in an area representing one-fifth of England. RESULTS: Data were collected from 89 adult AF recipients. At disclosure, among 57 recipients of a cancer-predisposition-associated AF and 32 recipients of an FH-associated AF, 35% and 88%, respectively, had personal and/or family history evidence of AF-related disease. During post-disclosure investigations, 4 cancer-AF recipients had evidence of disease, including 1 medullary thyroid cancer. Six women with an HBOC AF, 3 women with a Lynch syndrome AF, and 2 individuals with a MEN AF elected for risk-reducing surgery. New hyperlipidemia diagnoses were made in 6 FH-AF recipients and treatment (re-)initiated for 7 with prior hyperlipidemia. Generating and disclosing AFs in this region cost £1.4m; £8680 per clinically significant AF. CONCLUSION: Generation and disclosure of AFs identifies individuals with and without personal or familial evidence of disease and prompts appropriate clinical interventions. Results can inform policy toward secondary findings.

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Over the past three decades, deep brain stimulation (DBS) for Parkinson's disease (PD) has been applied in a continuous open loop fashion, unresponsive to changes in a given patient's state or symptoms over the course of a day. Advances in recent neurostimulator technology enable the possibility for closed loop adaptive DBS (aDBS) for PD as a treatment option in the near future in which stimulation adjusts in a demand-based manner. Although aDBS offers great clinical potential for treatment of motor symptoms, it also brings with it the need for better understanding how to implement it in order to maximize its benefits. In this perspective, we outline considerations for programing several key parameters for aDBS based on our experience across several aDBS-capable research neurostimulators. At its core, aDBS hinges on successful identification of relevant biomarkers that can be measured reliably in real-time working in cohesion with a control policy that governs stimulation adaption. However, auxiliary parameters such as the window in which stimulation is allowed to adapt, as well as the rate it changes, can be just as impactful on performance and vary depending on the control policy and patient. A standardize protocol for programming aDBS will be crucial to ensuring its effective application in clinical practice.

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Converging evidence indicates that impairments in executive function and information-processing speed limit quality of life and social reentry after moderate-to-severe traumatic brain injury (msTBI). These deficits reflect dysfunction of frontostriatal networks for which the central lateral (CL) nucleus of the thalamus is a critical node. The primary objective of this feasibility study was to test the safety and efficacy of deep brain stimulation within the CL and the associated medial dorsal tegmental (CL/DTTm) tract.Six participants with msTBI, who were between 3 and 18 years post-injury, underwent surgery with electrode placement guided by imaging and subject-specific biophysical modeling to predict activation of the CL/DTTm tract. The primary efficacy measure was improvement in executive control indexed by processing speed on part B of the trail-making test.All six participants were safely implanted. Five participants completed the study and one was withdrawn for protocol non-compliance. Processing speed on part B of the trail-making test improved 15% to 52% from baseline, exceeding the 10% benchmark for improvement in all five cases.CL/DTTm deep brain stimulation can be safely applied and may improve executive control in patients with msTBI who are in the chronic phase of recovery.ClinicalTrials.gov identifier: NCT02881151 .

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Background: Emergent tremor in Parkinson's disease (PD) can occur during sustained postures or movement that is different from action tremor. Tremor can contaminate the clinical rating of bradykinesia during finger tapping. Currently, there is no reliable way of isolating emergent tremor and measuring the cardinal motor symptoms based on voluntary movements only. Objective: Investigate whether emergent tremor during repetitive alternating finger tapping (RAFT) on a quantitative digitography (QDG) device can be reliably identified and distinguished from voluntary tapping. Methods: Ninety-six individuals with PD and forty-two healthy controls performed a thirty-second QDG-RAFT task and the Movement Disorders Society - Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III). Visual identification of tremor during QDG-RAFT was labelled by an experienced movement disorders specialist. Two methods of identifying tremor were investigated: 1) physiologically-informed temporal thresholds 2) XGBoost model using temporal and amplitude features of tapping. Results: The XGBoost model showed high accuracy for identifying tremor (area under the precision-recall curve of 0.981) and outperformed temporal-based thresholds. Percent time duration of classifier-identified tremor showed significant correlations with MDS-UPDRS III tremor subscores (r = 0.50, P < 0.0001). There was a significant change in QDG metrics for bradykinesia, rigidity and arrhythmicity after tremor strikes were excluded (p < 0.01). Conclusions: Emergent tremor during QDG-RAFT has a unique digital signature and the duration of tremor correlated with the MDS-UPDRS III tremor items. When involuntary tremor strikes were excluded, the QDG metrics of bradykinesia and rigidity were significantly worse, demonstrating the importance of distinguishing tremor from voluntary movement when rating bradykinesia.

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Background: Transcutaneous afferent patterned stimulation (TAPS) is a non-invasive neuromodulation therapy for the treatment of hand tremor in patients with essential tremor (ET). This retrospective post-market analysis evaluated the usage, effectiveness, and safety of TAPS in patients using TAPS beyond a 90-day trial period in a real-world setting. Methods: Study personnel screened a manufacturer's database for TAPS devices that had been prescribed for the treatment of ET and used beyond a 90-day trial period between August 2019 and January 2023. The device logs were collected to extract the therapy usage, accelerometry measurements, and on-board ratings of tremor improvement. Study personnel also evaluated results of a voluntary survey requested by the manufacturer after the 90-day trial period. Adverse events were assessed from patients' complaints reported to the manufacturer. Results: A total of 1,223 patients in the manufacturer's database met the study criteria. The patients had used therapy between 90 and 1,233 days, with average usage of 5.6 sessions per week. Accelerometry data indicated 89% of patients experienced tremor improvement, with an average 64% improvement. 63% of patients rated at least half of their sessions as improved. No significant habituation was observed in patients who used therapy for more than one year. Approximately 62% of survey respondents either had reduced medication or planned to consult physicians about their medication usage. No serious safety events were reported, and 10% of patients reported minor safety complaints. Discussion: The analysis demonstrates the real-world effectiveness and safety of TAPS beyond a 90-day trial period over a longer timeframe and in a larger population size than previously published evidence.

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Background: At the center of the cortical cholinergic network, the nucleus basalis of Meynert (NBM) is crucial for the cognitive domains most vulnerable in PD. Preclinical evidence has demonstrated the positive impact of NBM deep brain stimulation (DBS) on cognition but early human trials have had mixed results. It is possible that DBS of the lateral NBM efferent white matter fiber bundle may be more effective at improving cognitive-motor function. However, precise tractography modelling is required to identify the optimal target for neurosurgical planning. Individualized tractography approaches have been shown to be highly effective for accurately identifying DBS targets but have yet to be developed for the NBM. Methods: Using structural and diffusion weighted imaging, we developed a tractography pipeline for precise individualized identification of the lateral NBM target tract. Using dice similarity coefficients, the reliability of the tractography outputs was assessed across three cohorts to investigate: 1) whether this manual pipeline is more reliable than an existing automated pipeline currently used in the literature; 2) the inter- and intra-rater reliability of our pipeline in research scans of patients with PD; and 3) the reliability and practicality of this pipeline in clinical scans of DBS patients. Results: The individualized manual pipeline was found to be significantly more reliable than the existing automated pipeline for both the segmentation of the NBM region itself (p<0.001) and the reconstruction of the target lateral tract (p=0.002). There was also no significant difference between the reliability of two different raters in the PD cohort (p=0.25), which showed high inter- (mean Dice coefficient >0.6) and intra-rater (mean Dice coefficient >0.7) reliability across runs. Finally, the pipeline was shown to be highly reliable within the clinical scans (mean Dice coefficient = 0.77). However, accurate reconstruction was only evident in 7/10 tracts. Conclusion: We have developed a reliable tractography pipeline for the identification and analysis of the NBM lateral tract in research and clinical grade imaging of healthy young adult and PD patient scans.

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BACKGROUND: Approximately one third of recently diagnosed Parkinson's disease (PD) patients experience cognitive decline. The nucleus basalis of Meynert (NBM) degenerates early in PD and is crucial for cognitive function. The two main NBM white matter pathways include a lateral and medial trajectory. However, research is needed to determine which pathway, if any, are associated with PD-related cognitive decline. METHODS: Thirty-seven PD patients with no mild cognitive impairment (MCI) were included in this study. Participants either developed MCI at 1-year follow up (PD MCI-Converters; n = 16) or did not (PD no-MCI; n = 21). Mean diffusivity (MD) and fractional anisotropy (FA) of the medial and lateral NBM tracts were extracted using probabilistic tractography. Between-group differences in MD and FA for each tract was compared using ANCOVA, controlling for age, sex, and disease duration. Control comparisons of the internal capsule MD and FA were also performed. Associations between baseline MD or FA and cognitive outcomes (working memory, psychomotor speed, delayed recall, and visuospatial function) were assessed using linear mixed models. RESULTS: PD MCI-Converters had significantly greater MD and lower FA (p < .001) of both NBM tracts compared to PD no-MCI. No difference was found in the MD (p = .06) or FA (p = .31) of the control region. Trends were identified between: 1) lateral tract MD and FA with working memory decline; and 2) medial tract MD and reduced psychomotor speed. CONCLUSIONS: Reduced integrity of the NBM tracts is evident in PD patients up to one year prior to the development of MCI. Thus, deterioration of the NBM tracts in PD may be an early marker of those at risk of cognitive decline.

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KPTN-related disorder is an autosomal recessive disorder associated with germline variants in KPTN (previously known as kaptin), a component of the mTOR regulatory complex KICSTOR. To gain further insights into the pathogenesis of KPTN-related disorder, we analysed mouse knockout and human stem cell KPTN loss-of-function models. Kptn -/- mice display many of the key KPTN-related disorder phenotypes, including brain overgrowth, behavioural abnormalities, and cognitive deficits. By assessment of affected individuals, we have identified widespread cognitive deficits (n = 6) and postnatal onset of brain overgrowth (n = 19). By analysing head size data from their parents (n = 24), we have identified a previously unrecognized KPTN dosage-sensitivity, resulting in increased head circumference in heterozygous carriers of pathogenic KPTN variants. Molecular and structural analysis of Kptn-/- mice revealed pathological changes, including differences in brain size, shape and cell numbers primarily due to abnormal postnatal brain development. Both the mouse and differentiated induced pluripotent stem cell models of the disorder display transcriptional and biochemical evidence for altered mTOR pathway signalling, supporting the role of KPTN in regulating mTORC1. By treatment in our KPTN mouse model, we found that the increased mTOR signalling downstream of KPTN is rapamycin sensitive, highlighting possible therapeutic avenues with currently available mTOR inhibitors. These findings place KPTN-related disorder in the broader group of mTORC1-related disorders affecting brain structure, cognitive function and network integrity.

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HNRNPU encodes a multifunctional RNA-binding protein that plays critical roles in regulating pre-mRNA splicing, mRNA stability, and translation. Aberrant expression and dysregulation of HNRNPU have been implicated in various human diseases, including cancers and neurological disorders. We applied a next generation sequencing based assay (EPIC-NGS) to investigate genome-wide methylation profiling for >2 M CpGs for 7 individuals with a neurodevelopmental disorder associated with HNRNPU germline pathogenic loss-of-function variants. Compared to healthy individuals, 227 HNRNPU-associated differentially methylated positions were detected. Both hyper- and hypomethylation alterations were identified but the former predominated. The identification of a methylation episignature for HNRNPU-associated neurodevelopmental disorder (NDD) implicates HNPRNPU-related chromatin alterations in the aetiopathogenesis of this disorder and suggests that episignature profiling should have clinical utility as a predictor for the pathogenicity of HNRNPU variants of uncertain significance. The detection of a methylation episignaure for HNRNPU-associated NDD is consistent with a recent report of a methylation episignature for HNRNPK-associated NDD.

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