Mixing of moiré-surface and bulk states in graphite.

Van der Waals assembly enables the design of electronic states in two-dimensional (2D) materials, often by superimposing a long-wavelength periodic potential on a crystal lattice using moiré superlattices1-9. This twistronics approach has resulted in numerous previously undescribed physics, including strong correlations and superconductivity in twisted bilayer graphene10-12, resonant excitons, charge ordering and Wigner crystallization in transition-metal chalcogenide moiré structures13-18 and Hofstadter's butterfly spectra and Brown-Zak quantum oscillations in graphene superlattices19-22. Moreover, twistronics has been used to modify near-surface states at the interface between van der Waals crystals23,24. Here we show that electronic states in three-dimensional (3D) crystals such as graphite can be tuned by a superlattice potential occurring at the interface with another crystal-namely, crystallographically aligned hexagonal boron nitride. This alignment results in several Lifshitz transitions and Brown-Zak oscillations arising from near-surface states, whereas, in high magnetic fields, fractal states of Hofstadter's butterfly draw deep into the bulk of graphite. Our work shows a way in which 3D spectra can be controlled using the approach of 2D twistronics.

Electronic phase separation in multilayer rhombohedral graphite.

Of the two stable forms of graphite, hexagonal and rhombohedral, the former is more common and has been studied extensively. The latter is less stable, which has so far precluded its detailed investigation, despite many theoretical predictions about the abundance of exotic interaction-induced physics1-6. Advances in van der Waals heterostructure technology7 have now allowed us to make high-quality rhombohedral graphite films up to 50 graphene layers thick and study their transport properties. Here we show that the bulk electronic states in such rhombohedral graphite are gapped8 and, at low temperatures, electron transport is dominated by surface states. Because of their proposed topological nature, the surface states are of sufficiently high quality to observe the quantum Hall effect, whereby rhombohedral graphite exhibits phase transitions between a gapless semimetallic phase and a gapped quantum spin Hall phase with giant Berry curvature. We find that an energy gap can also be opened in the surface states by breaking their inversion symmetry by applying a perpendicular electric field. Moreover, in rhombohedral graphite thinner than four nanometres, a gap is present even without an external electric field. This spontaneous gap opening shows pronounced hysteresis and other signatures characteristic of electronic phase separation, which we attribute to emergence of strongly correlated electronic surface states.

Association between Homologous Recombination Repair Defect Status and Long-Term Prognosis of Early HER2-Low Breast Cancer: A Retrospective Cohort Study.

BACKGROUND: As a newly identified subtype of HER2-negative tumors associated with a less favorable prognosis, it remains crucial to evaluate potential prognostic and predictive factors, particularly non-invasive biomarkers, for individuals with human epidermal growth factor 2 (HER2) low early-stage breast cancer (EBC). Multiple investigations have highlighted that HER2-negative patients with EBC exhibiting high homologous recombination deficiency (HRD) scores display lower rates of pathological complete response (PCR) to neoadjuvant chemotherapy (NAC). Nevertheless, no study to date has explored the correlation between HRD and the long-term prognosis in HER2-low patients with EBC. PATIENTS AND METHODS: This retrospective observational study focuses on primary EBC sourced from The Cancer Genome Atlas dataset (TCGA). It reveals the gene mutation landscape in EBC with low HER2 expression and elucidates the tumor immune landscape across different HRD states. Utilizing bioinformatics analysis and Cox proportional models, along with the Kaplan-Meier method, the study assesses the correlation between HRD status and disease-specific survival (DSS), disease-free interval (DFI), and progression-free interval (PFI). Subgroup analyses were conducted to identify potential variations in the association between HRD and prognosis. RESULTS: In the patients with HER2-low breast cancer, patients with homologous recombination related genes (HRRGs) defects had an HRD score about twice that of those without related genes mutations, and were at higher risk of acquiring ARID1A, ATM, and BRCA2 mutations. We also found that most immune cell abundances were significantly higher in EBC tumors with high HRD than in EBC tumors with low HRD or HRD-medium, particularly plasma B-cell abundance, CD8 T-cell abundance, and M1 macrophages. In addition, these tumors with HRD-high also appear to have significantly higher tumor immune scores and lower interstitial scores. Then, we analyzed the relationship between different HRD status and prognosis. There was statistical significance (P = .036 and P = .046, respectively) in DSS and PFI between the HRD-low and HRD-high groups, and patients with HRD-high EBC showed relatively poor survival outcomes. A medium HRD score (hazard ratio, HR = 2.15, 95% CI: 1.04-4.41, P = .038) was a significant risk factor for PFI. Hormone receptor positivity is an important factor in obtaining medium-high HRD score and poor prognosis. CONCLUSION: Higher HRD scores were associated with poorer PFI outcomes, particularly in people with HR+/HER2-low. Varied HRD states exhibited distinctions in HRRGs and the tumor immune landscape. These insights have the potential to assist clinicians in promptly identifying high-risk groups and tailoring personalized treatments for patients with HER2-low EBC, aiming to enhance long-term outcomes.

Association of FTH1-Expressing Circulating Tumor Cells With Efficacy of Neoadjuvant Chemotherapy for Patients With Breast Cancer: A Prospective Cohort Study.

BACKGROUND: The association between different phenotypes and genotypes of circulating tumor cells (CTCs) and efficacy of neoadjuvant chemotherapy (NAC) remains uncertain. This study was conducted to evaluate the relationship of FTH1 gene-associated CTCs (F-CTC) with/without epithelial-mesenchymal transition (EMT) markers, or their dynamic changes with the efficacy of NAC in patients with non-metastatic breast cancer. PATIENTS AND METHODS: This study enrolled 120 patients with non-metastatic breast cancer who planned to undergo NAC. The FTH1 gene and EMT markers in CTCs were detected before NAC (T0), after 2 cycles of chemotherapy (T1), and before surgery (T2). The associations of these different types of CTCs with rates of pathological complete response (pCR) and breast-conserving surgery (BCS) were evaluated using the binary logistic regression analysis. RESULTS: F-CTC in peripheral blood ≥1 at T0 was an independent factor for pCR rate in patients with HER2-positive (odds ratio [OR]=0.08, 95% confidence interval [CI], 0.01-0.98, P = .048). The reduction in the number of F-CTC at T2 was an independent factor for BCS rate (OR = 4.54, 95% CI, 1.14-18.08, P = .03). CONCLUSIONS: The number of F-CTC prior to NAC was related to poor response to NAC. Monitoring of F-CTC may help clinicians formulate personalized NAC regimens and implement BCS for patients with non-metastatic breast cancer.

Chirality-dependent topological edge states in photonic metacrystal.

Topological edge state, a unique mode for manipulating electromagnetic waves (EMs), has been extensively studied in both fundamental and applied physics. Up to now, the work on topological edge states has focused on manipulating linearly polarized waves. Here, we realize chirality-dependent topological edge states in one-dimensional photonic crystals (1DPCs) to manipulate circularly polarized waves. By introducing the magneto-electric coupling term (chirality), the degeneracy Dirac point (DP) is opened in PCs with symmetric unit cells. The topological properties of the upper and lower bands are different in the cases of left circularly polarized (LCP) and right circularly polarized (RCP) waves by calculating the Zak phase. Moreover, mapping explicitly 1D Maxwell's equations to the Dirac equation, we demonstrate that the introduction of chirality can lead to different topological properties of bandgaps for RCP and LCP waves. Based on this chirality-dependent topology, we can further realize chirality-dependent topological edge states in photonic heterostructures composed of two kinds of PCs. Finally, we propose a realistic structure for the chirality-dependent topological edge states by placing metallic helixes in host media. Our work provides a method for manipulating topological edge states for circularly polarized waves, which has a broad range of potential applications in designing optical devices including polarizers, filters, and sensors with robustness against disorder.

Effects of an integrated ambulatory care program on healthcare utilization and costs in older patients with multimorbidity: a propensity score-matched cohort study.

BACKGROUND: Population aging has increased the prevalence of multimorbidity, jeopardizing the sustainability and efficiency of healthcare systems. This study aimed to evaluate the effects of an integrated ambulatory care program (IACP) on healthcare utilization and costs among older patients with multimorbidity while accounting for the confounding effects of frailty. METHODS: A retrospective cohort study using propensity matching including patients aged 65 or older with two or more chronic conditions attending the outpatient clinic at our hospital between June 1 and December 31, 2019, was conducted. Exposure was defined as receipt of IACP care. Patients not undergoing the IACP comprised the unexposed group and were matched at a ratio of 1:4 to patients undergoing the IACP group according to sex, age, Charlson Comorbidity Index score, multimorbidity frailty index score, and number of outpatient visits within 6 months before the index date. Outcomes were changes in healthcare utilization and related costs between 6 months before and after receiving IACP care. Multivariate regression analyses were used for data analysis and the Generalized Estimation Equation method was used to fit the regression models. RESULTS: A total of 166 (IACP) and 664 (non-exposed) patients were analyzed. The mean participant baseline ages were 77.15 ± 7.77 (IACP) and 77.28 ± 7.90 years (unexposed). In univariate analyses, the IACP group demonstrated greater reductions than the unexposed group in the frequency of outpatient visits (-3.16 vs. -1.36, p < 0.001), number of physicians visited (-0.99 vs. -0.17, p < 0.001), diagnostic fees (-1300 New Taiwan Dollar [NTD] vs. -520 NTD, p < 0.001), drug prescription fees (-250 NTD vs. -70 NTD, p < 0.001), and examination fees (-1620 NTD vs. -700 NTD, p = 0.014). Multivariate analyses demonstrated that patients in the IACP group experienced significant reduction in the frequency of outpatient visits (95% CI: -0.357 to -0.181, p < 0.001), number of physicians visited (95% CI: -0.334 to -0.199, p < 0.001), and overall outpatient costs (95% CI: -0.082 to -0.011, p = 0.01). However, emergency department utilization, hospitalization, and costs did not differ significantly. CONCLUSIONS: Expanding IACPs may help patients with multimorbidity reduce their use of outpatient clinics at the 6-month follow-up, reduce care fragmentation, and promote sustainability of the healthcare system.

Walking Interventions and Sleep Quality of Persons Living With Dementia and Their Family Caregivers: Effects of Different Walking Companions.

PURPOSE: To examine the effect of walking interventions on sleep quality of persons with dementia (PWD) and their caregivers (dyads), and how different companions affect results. METHOD: Forty-five dyads were divided into three groups: a control group and two experimental groups (one with a care attendant, one with a family caregiver). The two experimental groups engaged in 120 minutes of walking per week for 24 weeks. RESULTS: A significant improvement in sleep quality was observed among PWD in the family caregiver group (Wald χ2 = 4.55, p = 0.033), whereas there was no improvement in the care attendant group. A slight improvement in sleep quality of family caregivers was also found. CONCLUSION: Findings suggest the importance of creating individualized walking activity plans for dyads, incorporating trust and rapport-building strategies to improve sleep quality. [Journal of Gerontological Nursing, 50(8), 46-56.].

Sequential neoadjuvant chemotherapy using pegylated liposomal doxorubicin and cyclophosphamide followed by taxanes with complete trastuzumab and pertuzumab treatment for HER2-positive breast cancer: A phase II single-arm study.

Objective: Despite cardiotoxicity overlap, the trastuzumab/pertuzumab and anthracycline combination remains crucial due to significant benefits. Pegylated liposomal doxorubicin (PLD), a less cardiotoxic anthracycline, was evaluated for efficacy and cardiac safety when combined with cyclophosphamide and followed by taxanes with trastuzumab/pertuzumab in human epidermal growth factor receptor-2 (HER2)-positive early breast cancer (BC). Methods: In this multicenter, phase II study, patients with confirmed HER2-positive early BC received four cycles of PLD (30-35 mg/m2) and cyclophosphamide (600 mg/m2), followed by four cycles of taxanes (docetaxel, 90-100 mg/m2 or nab-paclitaxel, 260 mg/m2), concomitant with eight cycles of trastuzumab (8 mg/kg loading dose, then 6 mg/kg) and pertuzumab (840 mg loading dose, then 420 mg) every 3 weeks. The primary endpoint was total pathological complete response (tpCR, ypT0/is ypN0). Secondary endpoints included breast pCR (bpCR), objective response rate (ORR), disease control rate, rate of breast-conserving surgery (BCS), and safety (with a focus on cardiotoxicity). Results: Between May 27, 2020 and May 11, 2022, 78 patients were treated with surgery, 42 (53.8%) of whom had BCS. After neoadjuvant therapy, 47 [60.3%, 95% confidence interval (95% CI), 48.5%-71.2%] patients achieved tpCR, and 49 (62.8%) achieved bpCR. ORRs were 76.9% (95% CI, 66.0%-85.7%) and 93.6% (95% CI, 85.7%-97.9%) after 4-cycle and 8-cycle neoadjuvant therapy, respectively. Nine (11.5%) patients experienced asymptomatic left ventricular ejection fraction (LVEF) reductions of ≥10% from baseline, all with a minimum value of >55%. No treatment-related abnormal cardiac function changes were observed in mean N-terminal pro-BNP (NT-proBNP), troponin I, or high-sensitivity troponin. Conclusions: This dual HER2-blockade with sequential polychemotherapy showed promising activity with rapid tumor regression in HER2-positive BC. Importantly, this regimen showed an acceptable safety profile, especially a low risk of cardiac events, suggesting it as an attractive treatment approach with a favorable risk-benefit balance.

Self-focusing effect analysis of a perfect optical vortex beam in atmospheric turbulence.

The correlation function and the detection probability of orbital angular momentum (OAM) of a perfect optical vortex beam (POVB) were obtained under atmospheric turbulence conditions and then used to estimate the POVB propagation model through atmospheric turbulence. The POVB propagation in a turbulence-free channel can be divided into anti-diffraction and self-focusing stages. The beam profile size can be well preserved in the anti-diffraction stage as the transmission distance increases. After shrinking and focusing the POVB in the self-focusing region, the beam profile size expands in the self-focusing stage. The influence of topological charge on the beam intensity and profile size differs depending on the propagation stage. The POVB degenerates into a Bessel-Gaussian beam (BGB)-like when the ratio of the ring radius to the Gaussian beam waist approaches 1. The unique self-focusing effect of the POVB enables higher received probability compared to the BGB when propagating over long distances in atmospheric turbulence. However, the property of the POVB that its initial beam profile size is not affected by topological charge does not contribute to the POVB achieving a higher received probability than the BGB in short-range transmission application scenarios. The BGB anti-diffraction is stronger than that of the POVB, assuming a similar initial beam profile size at short-range transmission.

Nonlinear topological laser on the non-Hermitian Haldane model with higher-order corner states.

The non-Hermitian skin effect (NHSE) on the non-Hermitian Haldane model with gain and loss on the honeycomb lattice with the outline of a triangle is discussed. The NHSE only occurs on the edge of the lattice, transforming the edge modes into the higher-order corner modes. The NHSE can also occur on a lattice with only loss, which can be treated as a lattice with gain and loss as well as a global loss added to it. When the saturated gain is added to the three corner sites of the dissipative lattice, a single-mode laser system is obtained. When any one site is stimulated initially, the system will reach a saturated state depending on the distribution of the corner modes, and the stable laser light is emitted by sites at the corners.

Omnidirectional defect mode in one-dimensional photonic crystal with a (chiral) hyperbolic metamaterial defect.

The wavelength of defect mode in all-dielectric photonic crystals (PCs) with a dielectric defect are blue-shifted as incident angle increases for both transverse electric and transverse magnetic (TM) polarized waves. The blue-shifted property of defect mode limits the design of some optical devices including omnidirectional optical filters and wide-angle polarization selectors. Here we introduce a hyperbolic metamaterial (HMM) layer as a defect into dielectric one-dimensional photonic crystals (1DPCs) to obtain an omnidirectional defect mode for TM polarized waves at near-infrared regimes. Since only one HMM layer is introduced, omnidirectional defect mode with transmittance as high as 71% can be realized. Because of the unusual angle-dependence of propagating phase in the HMM defect, the total phase for satisfying the resonance condition of defect mode can be unchanged in a wide-angle range at a fixed wavelength, which leads to the omnidirectional defect mode. Moreover, the manipulation of propagating phase can be generalized to the case of circularly polarized waves, and we obtain an omnidirectional defect mode for left-handed circularly polarized waves in 1DPCs with a chiral hyperbolic metamaterial defect. Nevertheless, the defect mode for right-handed circularly polarized waves is still blue-shifted. Such spin-selective omnidirectional defect mode can be utilized to greatly enhance circular dichroism in a wide-angle range up to 64.1°. Our structure facilitates the design of omnidirectional optical filters with a high transmittance and circular polarization selectors working in a wide-angle range.

Topological laser with higher-order corner states in the 2-dimensional Su-Schrieffer-Heeger model.

A nonlinear non-Hermitian topological laser system based on the higher-order corner states of the 2-dimensional (2D) Su-Schrieffer-Heeger (SSH) model is investigated. The topological property of this nonlinear non-Hermitian system described by the quench dynamics is in accordance with that of a normal 2D SSH model. In the topological phase, all sites belonging to the topological corner states begin to emit stable laser light when a pulse is given to any one site of the lattice, while no laser light is emitted when the lattice is in the trivial phase. Furthermore, the next-nearest-neighbor (NNN) couplings are introduced into the strong-coupling unit cells of the 2D SSH model, which open a band gap in the continuous band structure. In the topological phase, similar to the case of 2D SSH model without NNN couplings, the corner sites can emit stable laser light due to the robustness of the higher-order corner states when the NNN couplings are regarded as the perturbation. However, amplitude of the stimulated site does not decay to zero in the trivial phase, because the existence of the NNN couplings in the strong-coupling unit cells make the lattice like one in the tetramer limit, and a weaker laser light is emitted by each corner.

Passive white light cavities with metal coatings.

White light cavities with broadband resonance are usually filled with negative dispersion medium, which inevitably leads to gain. In this article, pure passive white light cavities are designed, in which negative dispersion medium is no longer necessary. Theoretically, if the reflection phase of the cavity wall can exhibit a negative dispersion slope, then it can also satisfy white light cavities conditions without medium. In practice, the negative dispersion property of the cavity wall can be realized by two metal coatings with different reflection coefficients. Therefore, our white light cavities are composite cavities, in which the main cavity provides resonance while the auxiliary cavity forms the cavity wall, providing negative dispersion reflection phase. Further, atomic gas can be employed to improve the performance of the white light cavities. Atomic gas exploits effects such as Electromagnetic Induced Transparency (EIT), enabling the white light cavities to be controlled by coherent driving field. With the passive characters, our design can be realized and implemented much more easily.

Influence of a topological artificial atom chain on the transmission properties of a cavity.

We explore the influence of the artificial atomic chain on the input-output relation of the cavity. Specifically, we extend the atom chain to the one-dimensional Su-Schrieffer-Heeger (SSH) chain to check the role of atomic topological non-trivial edge state on the transmission characteristics of the cavity. The superconducting circuits can realize the artificial atomic chain. Our results show that the atom chain is not equivalent to atom gas, and the transmission properties of the cavity containing the atom chain are entirely different from that of the cavity containing atom gas. When the atom chain is arranged in the form of topological non-trivial SSH model, the atom chain can be equivalent to the three-level atom, in which the edge state contributes to the second level and is resonant with the cavity, while the high-energy bulk state contributes to form the third level and is greatly detuned with the cavity. Therefore, the transmission spectrum shows no more than three peaks. This allows us to infer the topological phase of the atomic chain and the coupling strength between the atom and the cavity only from the profile of the transmission spectrum. Our work is helping to understand the role of topology in quantum optics.

Pramipexole inhibits astrocytic NLRP3 inflammasome activation via Drd3-dependent autophagy in a mouse model of Parkinson's disease.

Inflammation is one of the pathogenic processes in Parkinson's disease (PD). Dopamine receptor agonist pramipexole (PPX) is extensively used for PD treatment in clinics. A number of studies show that PPX exerts neuroprotection on dopaminergic (DA) neurons, but the molecular mechanisms underlying the protective effects of PPX on DA neurons are not fully elucidated. In the present study, we investigated whether PPX modulated PD-related neuroinflammation and underlying mechanisms. PD model was established in mice by bilateral striatum injection of lipopolyssaccharide (LPS). The mice were administered PPX (0.5 mg·kg-1·d-1, i.p.) 3 days before LPS injection, and for 3 or 21 days after surgery, respectively, for biochemical and histological analyses. We showed that PPX administration significantly alleviated the loss of DA neurons, and suppressed the astrocyte activation and levels of proinflammatory cytokine IL-1ß in the substantia nigra of LPS-injected mice. Furthermore, PPX administration significantly decreased the expression of NLRP3 inflammasome-associated proteins, i.e., cleaved forms of caspase-1, IL-1ß, and apoptosis-associated speck-like protein containing a caspase recruit domain (ASC) in the striatum. These results were validated in LPS+ATP-stimulated primary mouse astrocytes in vitro. Remarkably, we showed that PPX (100-400 µM) dose-dependently enhanced the autophagy activity in the astrocytes evidenced by the elevations in LC3-II and BECN1 protein expression, as well as the increase of GFP-LC3 puncta formation. The opposite effects of PPX on astrocytic NLRP3 inflammasome and autophagy were eliminated by Drd3 depletion. Moreover, we demonstrated that both pretreatment of astrocytes with autophagy inhibitor chloroquine (40 µM) in vitro and astrocyte-specific Atg5 knockdown in vivo blocked PPX-caused inhibition on NLRP3 inflammasome and protection against DA neuron damage. Altogether, this study demonstrates an anti-neuroinflammatory activity of PPX via a Drd3-dependent enhancement of autophagy activity in astrocytes, and reveals a new mechanism for the beneficial effect of PPX in PD therapy.

Nucleic acid aptasensor with magnetically induced self-assembly for the detection of EpCAM glycoprotein.

A "turn-on" aptasensor for label-free and cell-free EpCAM detection was constructed by employing magnetic α-Fe2O3/Fe3O4@Au nanocomposites as a matrix for signal amplification and double-stranded complex (SH-DNA/Apt probes) immobilization through Au-S binding. α-Fe2O3/Fe3O4@Au could be efficiently assembled into uniform and stable self-assembly films via magnetic-induced self-assembly technique on a magnetic glassy carbon electrode (MGCE). The effectiveness of the platform for EpCAM detection was confirmed through differential pulse voltammetry (DPV). Under optimized conditions, the platform exhibited excellent specificity for EpCAM, and a strong linear correlation was observed between the current and the logarithm of EpCAM protein concentration in the range 1 pg/mL-1000 pg/mL (R2 = 0.9964), with a limit of detection (LOD) of 0.27 pg/mL. Furthermore, the developed platform demonstrated good stability during a 14-day storage test, with fluctuations remaining below 93.33% of the initial current value. Promising results were obtained when detecting EpCAM in spiked serum samples, suggesting its potential as a point-of-care (POC) testing.

Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.

A set of glutamylases and deglutamylases controls levels of tubulin polyglutamylation, a prominent post-translational modification of neuronal microtubules. Defective tubulin polyglutamylation was first linked to neurodegeneration in the Purkinje cell degeneration (pcd) mouse, which lacks deglutamylase CCP1, displays massive cerebellar atrophy, and accumulates abnormally glutamylated tubulin in degenerating neurons. We found biallelic rare and damaging variants in the gene encoding CCP1 in 13 individuals with infantile-onset neurodegeneration and confirmed the absence of functional CCP1 along with dysregulated tubulin polyglutamylation. The human disease mainly affected the cerebellum, spinal motor neurons, and peripheral nerves. We also demonstrate previously unrecognized peripheral nerve and spinal motor neuron degeneration in pcd mice, which thus recapitulated key features of the human disease. Our findings link human neurodegeneration to tubulin polyglutamylation, entailing this post-translational modification as a potential target for drug development for neurodegenerative disorders.

A Genocentric Approach to Discovery of Mendelian Disorders.

The advent of inexpensive, clinical exome sequencing (ES) has led to the accumulation of genetic data from thousands of samples from individuals affected with a wide range of diseases, but for whom the underlying genetic and molecular etiology of their clinical phenotype remains unknown. In many cases, detailed phenotypes are unavailable or poorly recorded and there is little family history to guide study. To accelerate discovery, we integrated ES data from 18,696 individuals referred for suspected Mendelian disease, together with relatives, in an Apache Hadoop data lake (Hadoop Architecture Lake of Exomes [HARLEE]) and implemented a genocentric analysis that rapidly identified 154 genes harboring variants suspected to cause Mendelian disorders. The approach did not rely on case-specific phenotypic classifications but was driven by optimization of gene- and variant-level filter parameters utilizing historical Mendelian disease-gene association discovery data. Variants in 19 of the 154 candidate genes were subsequently reported as causative of a Mendelian trait and additional data support the association of all other candidate genes with disease endpoints.

Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder.

PURPOSE: SRRM2 encodes the SRm300 protein, a splicing factor of the SR-related protein family characterized by its serine- and arginine-enriched domains. It promotes interactions between messenger RNA and the spliceosome catalytic machinery. This gene, predicted to be highly intolerant to loss of function (LoF) and very conserved through evolution, has not been previously reported in constitutive human disease. METHODS: Among the 1000 probands studied with developmental delay and intellectual disability in our database, we found 2 patients with de novo LoF variants in SRRM2. Additional families were identified through GeneMatcher. RESULTS: Here, we report on 22 patients with LoF variants in SRRM2 and provide a description of the phenotype. Molecular analysis identified 12 frameshift variants, 8 nonsense variants, and 2 microdeletions of 66 kb and 270 kb. The patients presented with a mild developmental delay, predominant speech delay, autistic or attention-deficit/hyperactivity disorder features, overfriendliness, generalized hypotonia, overweight, and dysmorphic facial features. Intellectual disability was variable and mild when present. CONCLUSION: We established SRRM2 as a gene responsible for a rare neurodevelopmental disease.

MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia.

The Mediator multiprotein complex functions as a regulator of RNA polymerase II-catalyzed gene transcription. In this study, exome sequencing detected biallelic putative disease-causing variants in MED27, encoding Mediator complex subunit 27, in 16 patients from 11 families with a novel neurodevelopmental syndrome. Patient phenotypes are highly homogeneous, including global developmental delay, intellectual disability, axial hypotonia with distal spasticity, dystonic movements, and cerebellar hypoplasia. Seizures and cataracts were noted in severely affected individuals. Identification of multiple patients with biallelic MED27 variants supports the critical role of MED27 in normal human neural development, particularly for the cerebellum. ANN NEUROL 2021;89:828-833.