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Mutations in methyl-CpG binding protein 2 (MeCP2), such as the T158M, P152R, R294X, and R306C mutations, are responsible for most Rett syndrome (RTT) cases. These mutations often result in altered protein expression that appears to correlate with changes in the nuclear size; however, the molecular details of these observations are poorly understood. Using a C2C12 cellular system expressing human MeCP2-E1 isoform as well as mouse models expressing these mutations, we show that T158M and P152R result in a decrease in MeCP2 protein, whereas R306C has a milder variation, and R294X resulted in an overall 2.5 to 3 fold increase. We also explored the potential involvement of the MeCP2 PEST domains in the proteasome-mediated regulation of MeCP2. Finally, we used the R294X mutant to gain further insight into the controversial competition between MeCP2 and histone H1 in the chromatin context. Interestingly, in R294X, MeCP2 E1 and E2 isoforms were differently affected, where the E1 isoform contributes to much of the overall protein increase observed, while E2 decreases by half. The modes of MeCP2 regulation, thus, appear to be differently regulated in the two isoforms.

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Chromium as the trivalent ion is believed to pharmaceutically active, increasing insulin sensitivity in high doses in genetic rodent models of diabetes. However, contradictory results have been obtained chemical rodent models of diabetes. The current review analyses the effects of dietary Cr supplementation of rodent models of prediabetes, where the condition is administered using a high-fat or high-sugar diet. Rat model studies display a range of quality, with studies utilizing basal diets of known Cr content suggesting Cr beneficially affects insulin sensitivity. Mouse model studies display too much heterogeneity in results for any firm conclusions to be drawn. Comparison of these results with those of clinical trials suggest that the effective dose of Cr may be proportionally lower for rodents than humans, if one exists for humans.

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With its high rate of consanguineous marriages and diverse ethnic population, little is currently understood about the genetic architecture of autism spectrum disorder (ASD) in Pakistan. Pakistan has a highly ethnically diverse population, yet with a high proportion of endogamous marriages, and is therefore anticipated to be enriched for biallelic disease-relate variants. Here, we attempt to determine the underlying genetic abnormalities causing ASD in thirty-six small simplex or multiplex families from Pakistan. Microarray genotyping followed by homozygosity mapping, copy number variation analysis, and whole exome sequencing were used to identify candidate. Given the high levels of consanguineous marriages among these families, autosomal recessively inherited variants were prioritized, however de novo/dominant and X-linked variants were also identified. The selected variants were validated using Sanger sequencing. Here we report the identification of sixteen rare or novel coding variants in fifteen genes (ARAP1, CDKL5, CSMD2, EFCAB12, EIF3H, GML, NEDD4, PDZD4, POLR3G, SLC35A2, TMEM214, TMEM232, TRANK1, TTC19, and ZNF292) in affected members in eight of the families, including ten homozygous variants in four families (nine missense, one loss of function). Three heterozygous de novo mutations were also identified (in ARAP1, CSMD2, and NEDD4), and variants in known X-linked neurodevelopmental disorder genes CDKL5 and SLC35A2. The current study offers information on the genetic variability associated with ASD in Pakistan, and demonstrates a marked enrichment for biallelic variants over that reported in outbreeding populations. This information will be useful for improving approaches for studying ASD in populations where endogamy is commonly practiced.

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A decade ago, the author assessed the status of chromium as the trivalent ion as an essential element and as a therapeutic agent based on rodent studies for this journal. The current review was undertaken to update considerations regarding the status of chromium, focusing on studies of Cr supplementation of diabetic rodent models over the last decade. Cr can no longer be considered an essential trace element for humans. Observed effects of Cr on rodent models of insulin resistance and diabetes are best interpreted in terms of a pharmacological role for Cr. The review of studies on the effects of Cr on rat models of diabetes is updated, and the results continue to suggest Cr increases insulin sensitivity in peripheral tissues of the rodent models. The lack of effects in human studies may stem from humans receiving a comparably smaller dose than the rodent models. However, given the different responses to Cr in the rodent models, humans could potentially have different responses to Cr. Recent studies primary utilizing rodents suggest two potential complementary but also contradictory modes of action for Cr(III) at a molecular level.

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BACKGROUND: Sibling bullying is associated with mental health difficulties; both in the short and long term. It is commonly assumed that sibling bullying leads to mental health difficulties but additional explanations for the relationship between the two are seldom investigated. METHODS: To address this gap in knowledge, we used a genetically sensitive design with data from the Avon Longitudinal Study of Parents and Children (maximum N = 3,959, 53% female). At ages 11-13 years, individuals self-reported their involvement in sibling bullying, as a victim and perpetrator, and parents reported on their child's mental health difficulties. Polygenic scores, indices of genetic risk for psychiatric disorders (major depressive disorder and attention deficit hyperactivity disorder) were computed using children's genetic data. Regression and structural equation models were fitted to the data. RESULTS: Sibling bullying, victimisation and perpetration, and polygenic scores both predicted mental health difficulties in an additive manner but there was no interaction between them. Polygenic scores for mental health difficulties were also associated with sibling bullying. CONCLUSIONS: These findings suggest that sibling bullying, victimisation and perpetration, is associated with mental health difficulties, even after accounting for some genetic effects. Additionally, the relationship between sibling bullying and mental health difficulties may be, at least partly, due to shared genetic aetiology. One possibility is that genetic risk for mental health difficulties influences the onset of mental health difficulties which in turn make children more susceptible to sibling bullying.

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PTCHD1 has been implicated in Autism Spectrum Disorders (ASDs) and/or intellectual disability, where copy-number-variant losses or loss-of-function coding mutations segregate with disease in an X-linked recessive fashion. Missense variants of PTCHD1 have also been reported in patients. However, the significance of these mutations remains undetermined since the activities, subcellular localization, and regulation of the PTCHD1 protein are currently unknown. This paucity of data concerning PTCHD1 prevents the effective evaluation of sequence variants identified during diagnostic screening. Here, we characterize PTCHD1 protein binding partners, extending previously reported interactions with postsynaptic scaffolding protein, SAP102. Six rare missense variants of PTCHD1 were also identified from patients with neurodevelopmental disorders. After modelling these variants on a hypothetical three-dimensional structure of PTCHD1, based on the solved structure of NPC1, PTCHD1 variants harboring these mutations were assessed for protein stability, post-translational processing, and protein trafficking. We show here that the wild-type PTCHD1 post-translational modification includes complex N-glycosylation and that specific mutant proteins disrupt normal N-link glycosylation processing. However, regardless of their processing, these mutants still localized to PSD95-containing dendritic processes and remained competent for complexing SAP102.

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BACKGROUND: Although genetic and environmental factors are involved in the aetiology of bipolar disorder [BD], studies focused on their interplay are lacking. The current investigation examines interactions and correlations between polygenic risk scores [PRS] for BD and major depressive disorder [MDD] with stressful life events [SLEs] in liability for BD. METHODS: This study used data from 1715 participants (862 bipolar cases and 853 controls) taken from UK and Canadian samples. The List of Threatening Experiences Questionnaire recorded SLEs that occurred 6 months before interview for controls and 6 months prior to the first (Canadian sample) and worst (UK sample) depressive and manic episodes for bipolar cases. PRS-BD and PRS-MDD were calculated from the Psychiatric Genomics Consortium. RESULTS: For the worst depressive episode, the PRS-MDD was significantly correlated with total number of SLEs (ß = 0.13, 95 % CI:0.04-0.22, p = 0.003) and dependent SLEs (ß = 0.09, 95 % CI:0.02-0.16, p = 0.007). After correction for multiple testing nominally significant correlations were detected for PRS-BD with total number of SLEs (ß = 0.11, 95 % CI:0.02-0.20, p = 0.015) and dependent SLEs (ß = 0.08, 95 % CI:0.01-0.15, p = 0.019). Among bipolar cases, these associations were slightly stronger but were only of nominal significance for total number of SLEs (PRS-MDD: ß = 0.19, 95 % CI:0.04-0.35, p = 0.015; PRS-BD: ß = 0.16, 95 % CI:0.01-0.32, p = 0.042) and dependent SLEs (PRS-MDD: ß = 0.14, 95 % CI:0.03-0.26, p = 0.015; PRS-BD: ß = 0.12, 95 % CI:0.004-0.24, p = 0.043). No other significant gene-environment correlations or interactions were found. LIMITATIONS: Use of a larger sample size would be beneficial. CONCLUSIONS: The relationship between SLEs and genetic risk for mood disorders may be best explained through correlations rather than interactions.

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The Cognitive Bias (CogBIAS) hypothesis proposes that cognitive biases develop as a function of environmental influences (which determine the valence of biases) and the genetic susceptibility to those influences (which determines the potency of biases). The current study employed a longitudinal, polygenic-by-environment approach to examine the CogBIAS hypothesis. To this end, measures of life experiences and polygenic scores for depression were used to assess the development of memory and interpretation biases in a three-wave sample of adolescents (12-16 years) (N = 337). Using mixed effects modeling, three patterns were revealed. First, positive life experiences (PLEs) were found to diminish negative and enhance positive forms of memory and social interpretation biases. Second, and against expectation, negative life experiences and depression polygenic scores were not associated with any cognitive outcomes, upon adjusting for psychopathology. Finally, and most importantly, the interaction between high polygenic risk and greater PLEs was associated with a stronger positive interpretation bias for social situations. These results provide the first line of polygenic evidence in support of the CogBIAS hypothesis, but also extend this hypothesis by highlighting positive genetic and nuanced environmental influences on the development of cognitive biases across adolescence.

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A recent report has shown the active site of the beta subunit of mitochondrial ATP synthase is probably the site of action of Cr(III) action, independent of the insulin signaling pathway. This works appears to answer an important question about the mode of action of Cr(III) at a molecular level when supplied in supra-nutritional levels to rodents. However, as with any good research, the research also raises several questions. The relationship between this study and the results of rodent studies of chromium supplementation and between this study and the current understanding the chromium(III) transport and detoxification system are put into perspective.

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Highly conserved transport protein particle (TRAPP) complexes regulate subcellular trafficking pathways. Accurate protein trafficking has been increasingly recognized to be critically important for normal development, particularly in the nervous system. Variants in most TRAPP complex subunits have been found to lead to neurodevelopmental disorders with diverse but overlapping phenotypes. We expand on limited prior reports on TRAPPC6B with detailed clinical and neuroradiologic assessments, and studies on mechanisms of disease, and new types of variants. We describe 29 additional patients from 18 independent families with biallelic variants in TRAPPC6B. We identified seven homozygous nonsense (n = 12 patients) and eight canonical splice-site variants (n = 17 patients). In addition, we identified one patient with compound heterozygous splice-site/missense variants with a milder phenotype and one patient with homozygous missense variants. Patients displayed non-progressive microcephaly, global developmental delay/intellectual disability, epilepsy and absent expressive language. Movement disorders including stereotypies, spasticity and dystonia were also observed. Brain imaging revealed reductions in cortex, cerebellum and corpus callosum size with frequent white matter hyperintensity. Volumetric measurements indicated globally diminished volume rather than specific regional losses. We identified a reduced rate of trafficking into the Golgi apparatus and Golgi fragmentation in patient-derived fibroblasts that was rescued by wild-type TRAPPC6B. Molecular studies revealed a weakened interaction between mutant TRAPPC6B (c.454C>T, p.Q152*) and its TRAPP binding partner TRAPPC3. Patient-derived fibroblasts from the TRAPPC6B (c.454C>T, p.Q152*) variant displayed reduced levels of TRAPPC6B as well as other TRAPP II complex-specific members (TRAPPC9 and TRAPPC10). Interestingly, the levels of the TRAPPC6B homologue TRAPPC6A were found to be elevated. Moreover, co-immunoprecipitation experiments showed that TRAPPC6A co-precipitates equally with TRAPP II and TRAPP III, while TRAPPC6B co-precipitates significantly more with TRAPP II, suggesting enrichment of the protein in the TRAPP II complex. This implies that variants in TRAPPC6B may preferentially affect TRAPP II functions compared to TRAPP III functions. Finally, we assessed phenotypes in a Drosophila TRAPPC6B-deficiency model. Neuronal TRAPPC6B knockdown impaired locomotion and led to wing posture defects, supporting a role for TRAPPC6B in neuromotor function. Our findings confirm the association of damaging biallelic TRAPPC6B variants with microcephaly, intellectual disability, language impairments, and epilepsy. A subset of patients also exhibited dystonia and/or spasticity with impaired ambulation. These features overlap with disorders arising from pathogenic variants in other TRAPP subunits, particularly components of the TRAPP II complex. These findings suggest that TRAPPC6B is essential for brain development and function, and TRAPP II complex activity may be particularly relevant for mediating this function.

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The reduction of the carcinogen chromate has been proposed to lead to three Cr(III)-containing DNA lesions: binary adducts (Cr(III) and DNA), interstrand crosslinks, and ternary adducts (Cr(III) linking DNA to a small molecule or protein). Although the structures of binary adducts have recently been elucidated, the structures of interstrand crosslinks and ternary adducts are not known. Analysis of Cr(III) binding to an oligonucleotide duplex containing a 5'-CG site allows elucidation of the structure of an oxide- or hydroxide-bridged binuclear Cr(III) assembly bridging the two strands of DNA. One Cr(III) is directly coordinated by the N-7 atom of a guanine residue, and the complex straddles the helix to form a hydrogen bond between another guanine residue and a Cr(III)-bound aquo ligand. No involvement of the phosphate backbone was observed. The properties and stability of this Cr-O(H)-Cr-bridged complex differ significantly from those reported for Cr-induced interstrand crosslinks, suggesting that interstrand crosslinks resulting from chromate reduction may be organic in nature.

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A pivotal concept in the field of mood disorders is the dichotomy between unipolar depression and bipolar disorder. Due to the unique treatment in older age bipolar disorder and the scarcity of research in this area, it is clinically important to raise the awareness of the diagnostic conversion of unipolar depression to bipolar disorder in the elderly population. We present a case of a 71-year-old Chinese man whose diagnosis was revised to bipolar disorder after 9 years of treatment for unipolar depression. Organic workup, including blood tests and brain imaging, was performed to rule out organic causes. This patient eventually responded well to the combined treatment of an antipsychotic and a mood stabilizer. This case report adds to the growing literature of challenges in identifying and managing bipolar disorder in the elderly. As unipolar depression and bipolar disorder have different disease courses and different treatment strategies, it is essential for clinicians to be aware of diagnostic conversion. Further research is needed to delineate bipolar disorder from unipolar depression in the elderly population.

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Patched domain-containing 1 (PTCHD1) is a well-established susceptibility gene for autism spectrum disorder (ASD) and intellectual disability (ID). Previous studies have suggested that alterations in the dosage of PTCHD1 may contribute to the etiology of both ASD and ID. However, there has not yet been a thorough investigation regarding mechanisms that regulate PTCHD1 expression. We sought to characterize the Ptchd1 promoter in a mouse neuronal model, as well as to identify and validate cis regulatory elements. We defined specific regions of the Ptchd1 promoter essential for robust expression in P19-induced neurons. Evolutionarily-conserved putative transcription factor binding sites within these regions were subsequently identified. Using a pairwise comparison of chromatin accessibility between mouse forebrain and liver tissues, a candidate regulatory region, ~ 9.1 kbp downstream of the Ptchd1 stop codon was defined. This region harbours two ENCODE-predicted enhancer cis-regulatory elements. Further, using DNase footprint analysis, a putative YY1-binding motif was also identified. Genomic deletion of the entire 8 kbp downstream open chromatin region attenuated Ptchd1 transcription by over 60% in our neuronal model, corroborating its predicted regulatory function. This study provides mechanistic insights related to the expression of PTCHD1, and provides important context to interpret genetic and genomic variation at this locus which may influence neurodevelopment.

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Transferrin, Tf, the protein that transports iron as Fe(III) from the blood to the tissues via endocytosis, is believed to also transport Cr(III). Under physiological conditions, Tf binds and releases Cr(III) rapidly from Cr(III)2-Tf; however, the major form of Tf in the bloodstream is mono-ferric Tf (Fe(III)-Tf). Given the low concentration of Cr(III) in the bloodstream, the form of Cr(III)-containing Tf that is transported is probably monochromic, monoferric-Tf (Cr(III),Fe(III)-Tf). Given that Tf has two specific metal-binding sites, one in both its C-terminal and its N-terminal lobe, two forms of Cr(III),Fe(III)-Tf can form. The binding of Cr(III) to mono-ferric Tf to generate both forms of Cr(III),Fe(III)-Tf has been examined in detail for the first time. The addition of Cr(III) to monoferric Tfs in 100 mM HEPES and 25 mM bicarbonate solution, pH 7.4, resulted in a rapid binding of Cr(III) to the open metal-binding site of the Tfs. Titrations of the monoferric Tfs with Cr(III) indicate the tight binding on one Cr(III) in each case. The binding of Cr(III) to monoferric Tfs is accompanied by conformational changes similar to adding two equivalents of Cr(III) to apoTf. Thus, mono-ferric Tfs bind one equivalent of Cr(III) rapidly and tightly to form mixed Cr(III),Fe(III)-Tfs. Cr(III) is probably transported as mixed Cr(III),Fe(III)-Tfs.

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Chromatin, a protein-DNA complex, is a dynamic structure that stores genetic information within the nucleus and responds to molecular/cellular changes in its structure, providing conditional access to the genetic machinery. ATP-dependent chromatin modifiers regulate access of transcription factors and RNA polymerases to DNA by either "opening" or "closing" the structure of chromatin, and its aberrant regulation leads to a variety of neurodevelopmental disorders. The chromodomain helicase DNA-binding (CHD) proteins are ATP-dependent chromatin modifiers involved in the organization of chromatin structure, act as gatekeepers of genomic access, and deposit histone variants required for gene regulation. In this review, we first discuss the structural and functional domains of the CHD proteins, and their binding sites, and phosphorylation, acetylation, and methylation sites. The conservation of important amino acids in SWItch/sucrose non-fermenting (SWI/SNF) domains, and their protein and mRNA tissue expression profiles are discussed. Next, we convey the important binding partners of CHD proteins, their protein complexes and activities, and their involvements in epigenetic regulation. We also show the ChIP-seq binding dynamics for CHD1, CHD2, CHD4, and CHD7 proteins at promoter regions of histone genes, as well as several genes that are critical for neurodevelopment. The role of CHD proteins in development is also discussed. Finally, this review provides information about CHD protein mutations reported in autism and neurodevelopmental disorders, and their pathogenicity. Overall, this review provides information on the progress of research into CHD proteins, their structural and functional domains, epigenetics, and their role in stem cell, development, and neurological disorders.

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MeCP2 (Methyl CpG binding protein 2) is an intrinsically disordered protein that binds to methylated genome regions. The protein is a critical transcriptional regulator of the brain, and its mutations account for 95% of Rett syndrome (RTT) cases. Early studies of this neurodevelopmental disorder revealed a close connection with dysregulations of the ubiquitin system (UbS), notably as related to UBE3A, a ubiquitin ligase involved in the proteasome-mediated degradation of proteins. MeCP2 undergoes numerous post-translational modifications (PTMs), including ubiquitination and sumoylation, which, in addition to the potential functional outcomes of their monomeric forms in gene regulation and synaptic plasticity, in their polymeric organization, these modifications play a critical role in proteasomal degradation. UbS-mediated proteasomal degradation is crucial in maintaining MeCP2 homeostasis for proper function and is involved in decreasing MeCP2 in some RTT-causing mutations. However, regardless of all these connections to UbS, the molecular details involved in the signaling of MeCP2 for its targeting by the ubiquitin-proteasome system (UPS) and the functional roles of monomeric MeCP2 ubiquitination and sumoylation remain largely unexplored and are the focus of this review.

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PURPOSE: Young people with developmental language disorder (DLD) have poorer mental health than those without DLD. However, not all young people with DLD are equally affected; some have more mental health difficulties than others. What explains these differences remains unclear. METHOD: Data from a community cohort study, the Avon Longitudinal Study of Parents and Children, were analyzed to investigate genetic and environmental influences on the development of mental health difficulties at five time points from childhood (7 years) to adolescence (16 years) in 6,387 young people (8.7% with DLD). Regression and latent class models were fitted to the data. RESULTS: Polygenic scores (PGSs), indices of genetic risk, for common psychiatric disorders (major depressive disorder, anxiety disorder, and attention deficit hyperactivity disorder) predicted mental health difficulties in both groups (with and without DLD). The presence of DLD, in some instances, amplified mental health difficulties for those with high genetic risk for common psychiatric disorders. Subgroups of children with similar developmental trajectories of mental health difficulties were identified. Young people with DLD were more likely than those without DLD to follow mental health subgroups characterized by consistently high levels of difficulties during development. PGSs, socioeconomic status, and the early home environment distinguished subgroups with low mental health difficulties from those characterized by high levels of difficulties, but these effects did not differ based on DLD status. CONCLUSIONS: These findings suggest that, for the most part, both genetic and environmental risk affect the development of mental health difficulties in a cumulative way for young people with DLD (and those without). Some analysis did, however, suggest that genetic risk for common psychiatric disorders might manifest more strongly in those with DLD compared with those without DLD. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.22351012.

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The mutagenic and carcinogenic properties of chromium(VI) complexes have been ascribed to the formation of ternary Cr(III)-small molecule-DNA complexes. As part of these laboratories' efforts to establish the structure and properties of discrete binary and ternary adducts of Cr(III) and DNA at a molecular level, the properties of Cr(III)-cysteine-DNA, Cr(III)-ascorbate-DNA, and Cr(III)-glutathione-DNA complexes formed from Cr(III) were examined. These studies determined the composition of previously described "pre-reacted" chromium cysteinate and chromium glutathione. Neither of these complexes nor "chromium ascorbate" form ternary complexes with DNA as previously proposed. In fact, these Cr(III) compounds do not measurably bind to DNA and cannot be responsible for the mutagenic and carcinogenic properties ascribed to ternary Cr(III)-cysteine-DNA and Cr(III)-ascorbate-DNA adducts. The results of biological studies where "ternary adducts" of Cr(III), cysteine, glutathione, or ascorbate and DNA were made from "pre-reacted" chromium cysteinate or chromium glutathione or from "chromium ascorbate" must, therefore, be interpreted with caution.

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Nearly 14% of disease-causing germline variants result from the disruption of mRNA splicing. Most (67%) DNA variants predicted in silico to disrupt splicing are classified as variants of uncertain significance. An analytic workflow-splice effect event resolver (SPEER)-was developed and validated to use mRNA sequencing to reveal significant deviations in splicing, pinpoint the DNA variants potentially involved, and measure the deleterious effects of the altered splicing on mRNA transcripts, providing evidence for assessing the pathogenicity of the variant. SPEER was used to analyze leukocyte RNA encoding 63 hereditary cancer syndrome-related genes in 20,317 patients. Among 3563 patients (17.5%) with at least one DNA variant predicted to affect splicing, 971 (4.8%) had altered splicing with a deleterious effect on the transcript, and 40 had altered splicing due to a DNA variant located outside of the reportable range of the test. Integrating SPEER results into the interpretation of variants allowed variants of uncertain significance to be reclassified as pathogenic or likely pathogenic in 0.4%, and as benign or likely benign in 5.9%, of the 20,317 patients. SPEER-based evidence was associated with a significantly greater effect on classifications of pathogenic or likely pathogenic and benign or likely benign in nonwhite versus non-Hispanic white patients, illustrating that evidence derived from mRNA splicing analysis may help to reduce ethnic/ancestral disparities in genetic testing.

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