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Soluble TREM2 in CSF and its association with other biomarkers and cognition in autosomal-dominant Alzheimer’s disease: a longitudinal observational study
(2022) The Lancet Neurology, 21 (4), pp. 329-341. 

Morenas-Rodríguez, E.a b , Li, Y.e , Nuscher, B.a b x , Franzmeier, N.c , Xiong, C.e , Suárez-Calvet, M.i j k , Fagan, A.M.f , Schultz, S.g , Gordon, B.A.g , Benzinger, T.L.S.g , Hassenstab, J.f , McDade, E.f , Feederle, R.a l m n , Karch, C.M.h , Schlepckow, K.a b , Morris, J.C.f , Kleinberger, G.a b , Nellgard, B.o p , Vöglein, J.a d , Blennow, K.q r , Zetterberg, H.q r s t u , Ewers, M.a c , Jucker, M.v w , Levin, J.a d l , Bateman, R.J.f , Haass, C.a b l , Adams, S.x , Allegri, R.x , Araki, A.x , Barthelemy, N.x , Bechara, J.x , Berman, S.x , Bodge, C.x , Brandon, S.x , Brooks, W.B.x , Brosch, J.x , Buck, J.x , Buckles, V.x , Carter, K.x , Cash, L.x , Chen, C.x , Chhatwal, J.x , Chrem, P.x , Chua, J.x , Chui, H.x , Cruchaga, C.x , Day, G.S.x , De La Cruz, C.x , Denner, D.x , Diffenbacher, A.x , Dincer, A.x , Donahue, T.x , Douglas, J.x , Duong, D.x , Egido, N.x , Esposito, B.x , Farlow, M.x , Feldman, B.x , Fitzpatrick, C.x , Flores, S.x , Fox, N.x , Franklin, E.x , Friedrichsen, N.x , Fujii, H.x , Gardener, S.x , Ghetti, B.x , Goate, A.x , Goldberg, S.x , Goldman, J.x , Gonzalez, A.x , Gräber-Sultan, S.x , Graff-Radford, N.x , Graham, M.x , Gray, J.x , Gremminger, E.x , Grilo, M.x , Groves, A.x , Häsler, L.x , Hellm, C.x , Herries, E.x , Hoechst-Swisher, L.x , Hofmann, A.x , Holtzman, D.x , Hornbeck, R.x , Igor, Y.x , Ihara, R.x , Ikeuchi, T.x , Ikonomovic, S.x , Ishii, K.x , Jack, C.x , Jerome, G.x , Johnson, E.x , Käser, S.x , Kasuga, K.x , Keefe, S.x , Klunk, W.B.x , Koeppe, R.x , Koudelis, D.x , Kuder-Buletta, E.x , Laske, C.x , Levey, A.x , Lopez, O.x , Marsh, J.x , Martinez, R.x , Martins, R.x , Mason, N.S.x , Masters, C.x , Mawuenyega, K.x , McCullough, A.x , Mejia, A.x , MountzMD, J.x , Mummery, C.x , Nadkarni, N.x , Nagamatsu, A.x , Neimeyer, K.x , Niimi, Y.x , Noble, J.x , Norton, J.x , O’Connor, A.x , Obermüller, U.x , Patira, R.x , Perrin, R.x , Ping, L.x , Preische, O.x , Renton, A.x , Ringman, J.x , Salloway, S.x , Schofield, P.x , Senda, M.x , Seyfried, N.x , Shady, K.x , Shimada, H.x , Sigurdson, W.x , Smith, J.x , Smith, L.x , Snitz, B.x , Sohrabi, H.x , Stephens, S.x , Taddei, K.x , Thompson, S.x , Wang, P.x , Wang, Q.x , Weamer, E.x , Xu, J.x , Xu, X.x , Dominantly Inherited Alzheimer Networky

Abstract
Background: Therapeutic modulation of TREM2-dependent microglial function might provide an additional strategy to slow the progression of Alzheimer’s disease. Although studies in animal models suggest that TREM2 is protective against Alzheimer’s pathology, its effect on tau pathology and its potential beneficial role in people with Alzheimer’s disease is still unclear. Our aim was to study associations between the dynamics of soluble TREM2, as a biomarker of TREM2 signalling, and amyloid β (Aβ) deposition, tau-related pathology, neuroimaging markers, and cognitive decline, during the progression of autosomal dominant Alzheimer’s disease. Methods: We did a longitudinal analysis of data from the Dominantly Inherited Alzheimer Network (DIAN) observational study, which includes families with a history of autosomal dominant Alzheimer’s disease. Participants aged over 18 years who were enrolled in DIAN between Jan 1, 2009, and July 31, 2019, were categorised as either carriers of pathogenic variants in PSEN1, PSEN2, and APP genes (n=155) or non-carriers (n=93). We measured amounts of cleaved soluble TREM2 using a novel immunoassay in CSF samples obtained every 2 years from participants who were asymptomatic (Clinical Dementia Rating [CDR]=0) and annually for those who were symptomatic (CDR>0). CSF concentrations of Aβ40, Aβ42, total tau (t-tau), and tau phosphorylated on threonine 181 (p-tau) were measured by validated immunoassays. Predefined neuroimaging measurements were total cortical uptake of Pittsburgh compound B PET (PiB-PET), cortical thickness in the precuneus ascertained by MRI, and hippocampal volume determined by MRI. Cognition was measured using a validated cognitive composite (including DIAN word list test, logical memory delayed recall, digit symbol coding test [total score], and minimental status examination). We based our statistical analysis on univariate and bivariate linear mixed effects models. Findings: In carriers of pathogenic variants, a high amyloid burden at baseline, represented by low CSF Aβ42 (β=–4·28 × 10–2 [SE 0·013], p=0·0012), but not high cortical uptake in PiB-PET (β=–5·51 × 10–3 [0·011], p=0·63), was the only predictor of an augmented annual rate of subsequent increase in soluble TREM2. Augmented annual rates of increase in soluble TREM2 were associated with a diminished rate of decrease in amyloid deposition, as measured by Aβ42 in CSF (r=0·56 [0·22], p=0·011), in presymptomatic carriers of pathogenic variants, and with diminished annual rate of increase in PiB-PET (r=–0·67 [0·25], p=0·0060) in symptomatic carriers of pathogenic variants. Presymptomatic carriers of pathogenic variants with annual rates of increase in soluble TREM2 lower than the median showed a correlation between enhanced annual rates of increase in p-tau in CSF and augmented annual rates of increase in PiB-PET signal (r=0·45 [0·21], p=0·035), that was not observed in those with rates of increase in soluble TREM2 higher than the median. Furthermore, presymptomatic carriers of pathogenic variants with rates of increase in soluble TREM2 above or below the median had opposite associations between Aβ42 in CSF and PiB-PET uptake when assessed longitudinally. Augmented annual rates of increase in soluble TREM2 in presymptomatic carriers of pathogenic variants correlated with decreased cortical shrinkage in the precuneus (r=0·46 [0·22]), p=0·040) and diminished cognitive decline (r=0·67 [0·22], p=0·0020). Interpretation: Our findings in autosomal dominant Alzheimer’s disease position the TREM2 response within the amyloid cascade immediately after the first pathological changes in Aβ aggregation and further support the role of TREM2 on Aβ plaque deposition and compaction. Furthermore, these findings underpin a beneficial effect of TREM2 on Aβ deposition, Aβ-dependent tau pathology, cortical shrinkage, and cognitive decline. Soluble TREM2 could, therefore, be a key marker for clinical trial design and interpretation. Efforts to develop TREM2-boosting therapies are ongoing. Funding: German Research Foundation, US National Institutes of Health. © 2022 Elsevier Ltd

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Long-Acting Recombinant Human Interleukin-7, NT-I7, Increases Cytotoxic CD8 T Cells and Enhances Survival in Mouse Glioma Models(2022) Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 28 (6), pp. 1229-1239. Cited 1 time.

Campian, J.L.a , Ghosh, S.b , Kapoor, V.b , Yan, R.a , Thotala, S.b , Jash, A.a , Hu, T.a c , Mahadevan, A.b , Rifai, K.b , Page, L.b , Lee, B.H.d , Ferrando-Martinez, S.d , Wolfarth, A.A.d , Yang, S.H.d , Hallahan, D.a e , Chheda, M.G.a c , Thotala, D.b e

AbstractPURPOSE: Patients with glioblastoma (GBM) are treated with radiotherapy (RT) and temozolomide (TMZ). These treatments may cause prolonged systemic lymphopenia, which itself is associated with poor outcomes. NT-I7 is a long-acting IL7 that expands CD4 and CD8 T-cell numbers in humans and mice. We tested whether NT-I7 prevents systemic lymphopenia and improves survival in mouse models of GBM. EXPERIMENTAL DESIGN: C57BL/6 mice bearing intracranial tumors (GL261 or CT2A) were treated with RT (1.8 Gy/day × 5 days), TMZ (33 mg/kg/day × 5 days), and/or NT-I7 (10 mg/kg on the final day of RT). We followed the mice for survival while serially analyzing levels of circulating T lymphocytes. We assessed regulatory T cells (Treg) and cytotoxic T lymphocytes in the tumor microenvironment, cervical lymph nodes, spleen, and thymus, and hematopoietic stem and progenitor cells in the bone marrow. RESULTS: GBM tumor-bearing mice treated with RT+NT-I7 increased T lymphocytes in the lymph nodes, thymus, and spleen, enhanced IFNγ production, and decreased Tregs in the tumor which was associated with a significant increase in survival. NT-I7 also enhanced central memory and effector memory CD8 T cells in lymphoid organs and tumor. Depleting CD8 T cells abrogated the effects of NT-I7. Furthermore, NT-I7 treatment decreased progenitor cells in the bone marrow. CONCLUSIONS: In orthotopic glioma-bearing mice, NT-I7 mitigates RT-related lymphopenia, increases cytotoxic CD8 T lymphocytes systemically and in the tumor, and improves survival. A phase I/II trial to evaluate NT-I7 in patients with high-grade gliomas is ongoing (NCT03687957). ©2022 American Association for Cancer Research.

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Mitochondrial Phenotypes in Genetically Diverse Neurodegenerative Diseases and Their Response to Mitofusin Activation(2022) Cells, 11 (6), art. no. 1053, . Cited 1 time.

Dang, X.a , Walton, E.K.a , Zablocka, B.b , Baloh, R.H.c , Shy, M.E.d , Dorn, G.W., IIa

AbstractMitochondrial fusion is essential to mitochondrial fitness and cellular health. Neurons of patients with genetic neurodegenerative diseases often exhibit mitochondrial fragmentation, reflecting an imbalance in mitochondrial fusion and fission (mitochondrial dysdynamism). Charcot–Marie– Tooth (CMT) disease type 2A is the prototypical disorder of impaired mitochondrial fusion caused by mutations in the fusion protein mitofusin (MFN)2. Yet, cultured CMT2A patient fibroblast mitochondria are often reported as morphologically normal. Metabolic stress might evoke pathological mitochondrial phenotypes in cultured patient fibroblasts, providing a platform for the pre-clinical individualized evaluation of investigational therapeutics. Here, substitution of galactose for glucose in culture media was used to redirect CMT2A patient fibroblasts (MFN2 T105M, R274W, H361Y, R364W) from glycolytic metabolism to mitochondrial oxidative phosphorylation, which provoked characteristic mitochondrial fragmentation and depolarization and induced a distinct transcriptional signature. Pharmacological MFN activation of metabolically reprogrammed fibroblasts partially reversed the mitochondrial abnormalities in CMT2A and CMT1 and a subset of Parkinson’s and Alzheimer’s disease patients, implicating addressable mitochondrial dysdynamism in these illnesses. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

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Association of a Perioperative Multicomponent Fall Prevention Intervention With Falls and Quality of Life After Elective Inpatient Surgical Procedures(2022) JAMA network open, 5 (3), p. e221938. 

Fritz, B.A.a , King, C.R.a , Mehta, D.a , Somerville, E.b , Kronzer, A.a , Ben Abdallah, A.a , Wildes, T.a , Avidan, M.S.a , Lenze, E.J.c , Stark, S.b , ENGAGES Research Groupd

AbstractImportance: Falls after elective inpatient surgical procedures are common and have physical, emotional, and financial consequences. Close interactions between patients and health care teams before and after surgical procedures may offer opportunities to address modifiable risk factors associated with falls. Objective: To assess whether a multicomponent intervention that incorporates education, home medication review, and home safety assessment is associated with reductions in the incidence of falls after elective inpatient surgical procedures. Design, Setting, and Participants: This prospective propensity score-matched cohort study was a prespecified secondary analysis of data from the Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) randomized clinical trial, which was conducted at a single academic medical center between January 16, 2015, and May 7, 2018. Patients in the intervention group of the present study were enrolled in either arm of the ENGAGES clinical trial. Patients in the control group were selected from the Systematic Assessment and Targeted Improvement of Services Following Yearly Surgical Outcomes Surveys prospective observational cohort study, which created a registry of patient-reported postoperative outcomes at the same single center. The propensity score-matched cohort in the present study included 1396 patients (698 pairs) selected from a pool of 2013 eligible patients. All patients underwent elective surgical procedures with general anesthesia and had a hospital stay of 2 or more days. Data were analyzed from January 2, 2020, to January 11, 2022. Interventions: The multicomponent safety intervention (offered to all patients in the ENGAGES clinical trial) included patient education on fall prevention techniques, home medication review by a geriatric psychiatrist (with communication of recommended changes to the surgeon), a self-administered home safety assessment, and targeted occupational therapy home visits with home hazard removal (offered to patients with a preoperative history of falls). Main Outcomes and Measures: The primary outcome was patient-reported falls within 1 year after an elective inpatient surgical procedure. The secondary outcome was quality of life 1 year after an elective surgical procedure, which was measured using the physical and mental composite summary scores on the Veterans RAND 12-item health survey (score range, 0-100 points, with 0 indicating lowest quality of life and 100 indicating highest quality of life). Results: Among 1396 patients, the median age was 69 years (IQR, 64-75 years), and 739 patients (52.9%) were male. With regard to race, 5 patients (0.4%) were Asian, 97 (6.9%) were Black or African American, 2 (0.1%) were Native Hawaiian or Pacific Islander, 1237 (88.6%) were White, 3 (0.2%) were of other race, and 52 (3.7%) were of unknown race; with regard to ethnicity, 12 patients (0.9%) were Hispanic or Latino, 1335 (95.6%) were non-Hispanic or non-Latino, and 49 (3.5%) were of unknown ethnicity. Adherence to individual intervention components was modest (from 22.9% for completion of the self-administered home safety assessment to 28.2% for implementation of the geriatric psychiatrist’s recommended medication changes). Falls within 1 year after surgical procedures were reported by 228 of 698 patients (32.7%) in the intervention group and 225 of 698 patients (32.2%) in the control group. No significant difference was found in falls between the 2 groups (standardized risk difference, 0.4%; 95% CI, -4.5% to 5.3%). After adjusting for preoperative quality of life, patients in the intervention group had higher physical composite summary scores (3.8 points; 95% CI, 2.4-5.1 points) and higher mental composite summary scores (5.7 points; 95% CI, 4.7-6.7 points) at 1 year compared with patients in the control group. Conclusions and Relevance: In this cohort study, a multicomponent safety intervention was not associated with reductions in falls within the first year after an elective surgical procedure; however, an increase in quality of life at 1 year was observed. These results suggest a need for other interventions, such as those designed to increase adherence, to lower the incidence of falls after surgical procedures.

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Partial Ablation of Postsynaptic Dopamine D2 Receptors in the Central Nucleus of the Amygdala Increases Risk Avoidance in Exploratory Tasks(2022) eNeuro, 9 (2), art. no. ENEURO.0528-21.2022, . 

Casey, E.a d , Avale, M.E.a b , Kravitz, A.c d e , Rubinstein, M.a b

Abstract
The central nucleus of the amygdala (CeA) is involved in the expression of fear and has been implicated in several anxiety disorders. This structure is densely innervated by DAergic projections that impinge on amygdalar neurons expressing various dopamine (DA) receptor subtypes, including D2 receptors (D2Rs). Although various pharmacological approaches have assessed the role of D2Rs in the CeA, the actual participation of postsynaptic D2Rs in the CeA to defensive behaviors remains unclear. Here, we investigated the distribution of D2Rs in the CeA and their role in modifying neuronal activity and fear related behaviors in mice. First, using the mouse reporter strain D2R-EGFP, we verified that D2Rs are present both in neurons of the CeA and in A10 dorsocaudal (A10dc) DAergic neurons that innervate the CeA. Moreover, we showed that pharmacological stimulation of D2Rs increases the activity of protein kinase C (PKC)δ cells present in the CeA, a type of neuron previously associated with reduced defensive behaviors. Finally, using a molecular genetics approach that discriminates postsynaptic D2Rs from presynaptic D2 autoreceptors, we demonstrated that mice carrying targeted deletions of postsynaptic D2Rs in the CeA display increased risk avoidance in exploratory tasks. Together, our results indicate that postsynaptic D2Rs in the CeA attenuate behavioral reactions to potential environmental threats. © 2022 Casey et al.

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Cerebrospinal fluid regulates skull bone marrow niches via direct access through dural channels(2022) Nature Neuroscience, . 

Mazzitelli, J.A.abcd , Smyth, L.C.D.ab , Cross, K.A.be , Dykstra, T.ab , Sun, J.c , Du, S.abf , Mamuladze, T.abf , Smirnov, I.ab , Rustenhoven, J.abg , Kipnis, J.abcde

Abstract
It remains unclear how immune cells from skull bone marrow niches are recruited to the meninges. Here we report that cerebrospinal fluid (CSF) accesses skull bone marrow via dura–skull channels, and CSF proteins signal onto diverse cell types within the niches. After spinal cord injury, CSF-borne cues promote myelopoiesis and egress of myeloid cells into meninges. This reveals a mechanism of CNS-to-bone-marrow communication via CSF that regulates CNS immune responses. © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

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Reproducible brain-wide association studies require thousands of individuals(2022) Nature, . 

Marek, S.a , Tervo-Clemmens, B.bc , Calabro, F.J.de , Montez, D.F.f , Kay, B.P.f , Hatoum, A.S.a , Donohue, M.R.a , Foran, W.d , Miller, R.L.af , Hendrickson, T.J.g , Malone, S.M.h , Kandala, S.a , Feczko, E.ij , Miranda-Dominguez, O.ij , Graham, A.M.k , Earl, E.A.ik , Perrone, A.J.ik , Cordova, M.k , Doyle, O.k , Moore, L.A.k , Conan, G.M.ik , Uriarte, J.k , Snider, K.k , Lynch, B.J.il , Wilgenbusch, J.C.il , Pengo, T.g , Tam, A.mnop , Chen, J.mnop , Newbold, D.J.f , Zheng, A.f , Seider, N.A.f , Van, A.N.fq , Metoki, A.f , Chauvin, R.J.f , Laumann, T.O.a , Greene, D.J.r , Petersen, S.E.fqstu , Garavan, H.v , Thompson, W.K.w , Nichols, T.E.x , Yeo, B.T.T.mnopyz , Barch, D.M.au , Luna, B.cd , Fair, D.A.ijaa , Dosenbach, N.U.F.fqsabac

Abstract
Magnetic resonance imaging (MRI) has transformed our understanding of the human brain through well-replicated mapping of abilities to specific structures (for example, lesion studies) and functions1–3 (for example, task functional MRI (fMRI)). Mental health research and care have yet to realize similar advances from MRI. A primary challenge has been replicating associations between inter-individual differences in brain structure or function and complex cognitive or mental health phenotypes (brain-wide association studies (BWAS)). Such BWAS have typically relied on sample sizes appropriate for classical brain mapping4 (the median neuroimaging study sample size is about 25), but potentially too small for capturing reproducible brain–behavioural phenotype associations5,6. Here we used three of the largest neuroimaging datasets currently available—with a total sample size of around 50,000 individuals—to quantify BWAS effect sizes and reproducibility as a function of sample size. BWAS associations were smaller than previously thought, resulting in statistically underpowered studies, inflated effect sizes and replication failures at typical sample sizes. As sample sizes grew into the thousands, replication rates began to improve and effect size inflation decreased. More robust BWAS effects were detected for functional MRI (versus structural), cognitive tests (versus mental health questionnaires) and multivariate methods (versus univariate). Smaller than expected brain–phenotype associations and variability across population subsamples can explain widespread BWAS replication failures. In contrast to non-BWAS approaches with larger effects (for example, lesions, interventions and within-person), BWAS reproducibility requires samples with thousands of individuals. © 2022, The Author(s), under exclusive licence to Springer Nature Limited.

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Therapeutic Targets for Alzheimer’s Disease: Amyloid Vs. Non-Amyloid. Where Does Consensus Lie Today? An CTAD Task Force Report(2022) Journal of Prevention of Alzheimer’s Disease, . 

Gauthier, S.a , Boxer, A.b , Knopman, D.c , Sims, J.d , Doody, R.e , Aisen, P.f , Iwatsubo, T.g , Bateman, R.h , Vellas, B.i

AbstractThere was consensus that both amyloid and tau pathologies should be targeted in Alzheimer’s disease, as well as additional pathophysiological mechanisms such as neuroinflammation. The selection of one or both of these targets may depend upon a personalized approach that takes into account the genetic and acquired factors that cause AD in any given person as well as their stage of disease as reflected in a biomarker profile. The validation of this therapeutic approach will be made possible by new methodologies for subdividing into predominant pathology, by efficient methods for identifying people in the earliest stages of disease, and by combination studies. © 2022, The Author(s).

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Gärtner, J.a , Hauser, S.L.b , Bar-Or, A.c , Montalban, X.d , Cohen, J.A.e , Cross, A.H.f , Deiva, K.g , Ganjgahi, H.hl , Häring, D.A.i , Li, B.j , Pingili, R.j , Ramanathan, K.i , Su, W.j , Willi, R.i , Kieseier, B.i , Kappos, L.k
Abstract

Background: In the phase III ASCLEPIOS I and II trials, participants with relapsing multiple sclerosis receiving ofatumumab had significantly better clinical and magnetic resonance imaging (MRI) outcomes than those receiving teriflunomide. Objectives: To assess the efficacy and safety of ofatumumab versus teriflunomide in recently diagnosed, treatment-naive (RDTN) participants from ASCLEPIOS. Methods: Participants were randomized to receive ofatumumab (20 mg subcutaneously every 4 weeks) or teriflunomide (14 mg orally once daily) for up to 30 months. Endpoints analysed post hoc in the protocol-defined RDTN population included annualized relapse rate (ARR), confirmed disability worsening (CDW), progression independent of relapse activity (PIRA) and adverse events. Results: Data were analysed from 615 RDTN participants (ofatumumab: n = 314; teriflunomide: n = 301). Compared with teriflunomide, ofatumumab reduced ARR by 50% (rate ratio (95% confidence interval (CI)): 0.50 (0.33, 0.74); p < 0.001), and delayed 6-month CDW by 46% (hazard ratio (HR; 95% CI): 0.54 (0.30, 0.98); p = 0.044) and 6-month PIRA by 56% (HR: 0.44 (0.20, 1.00); p = 0.049). Safety findings were manageable and consistent with those of the overall ASCLEPIOS population. Conclusion: The favourable benefit–risk profile of ofatumumab versus teriflunomide supports its consideration as a first-line therapy in RDTN patients. ASCLEPIOS I and II are registered at ClinicalTrials.gov (NCT02792218 and NCT02792231). © The Author(s), 2022.

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Analysis workflow to assess de novo genetic variants from human whole-exome sequencing(2021) STAR protocols, 2 (1), p. 100383. 

Diab, N.S.a , King, S.b c , Dong, W.a d , Allington, G.a , Sheth, A.e , Peters, S.T.b , Kahle, K.T.e f g , Jin, S.C.b

Abstract
Here, we present a protocol to analyze de novo genetic variants derived from the whole-exome sequencing (WES) of proband-parent trios. We provide stepwise instructions for using existing pipelines to call de novo mutations (DNMs) and determine whether the observed number of such mutations is enriched relative to the expected number. This protocol may be extended to any human disease trio-based cohort. Cohort size is a limiting determinant to the discovery of high-confidence pathogenic DNMs. For complete details on the use and execution of this protocol, please refer to Dong et al. (2020). © 2021 The Author(s).

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