المؤلفون: Mavura, Yusuph, Sahin-Hodoglugil, Nuriye, Hodoglugil, Ugur, Kvale, Mark, Martin, Pierre-Marie, Van Ziffle, Jessica, Devine, W Patrick, Ackerman, Sara L, Koenig, Barbara A, Kwok, Pui-Yan, Norton, Mary E, Slavotinek, Anne, Risch, Neil

المصدر: npj Genomic Medicine. 9(1)

مصطلحات موضوعية: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Clinical Research, Pediatric, Medical biotechnology

الوصف: It has been suggested that diagnostic yield (DY) from Exome Sequencing (ES) may be lower among patients with non-European ancestries than those with European ancestry. We examined the association of DY with estimated continental/subcontinental genetic ancestry in a racially/ethnically diverse pediatric and prenatal clinical cohort. Cases (N = 845) with suspected genetic disorders underwent ES for diagnosis. Continental/subcontinental genetic ancestry proportions were estimated from the ES data. We compared the distribution of genetic ancestries in positive, negative, and inconclusive cases by Kolmogorov-Smirnov tests and linear associations of ancestry with DY by Cochran-Armitage trend tests. We observed no reduction in overall DY associated with any genetic ancestry (African, Native American, East Asian, European, Middle Eastern, South Asian). However, we observed a relative increase in proportion of autosomal recessive homozygous inheritance versus other inheritance patterns associated with Middle Eastern and South Asian ancestry, due to consanguinity. In this empirical study of ES for undiagnosed pediatric and prenatal genetic conditions, genetic ancestry was not associated with the likelihood of a positive diagnosis, supporting the equitable use of ES in diagnosis of previously undiagnosed but potentially Mendelian disorders across all ancestral populations.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/5js1c05xTest

المؤلفون: Williams, Erik A, Ravindranathan, Ajay, Gupta, Rohit, Stevers, Nicholas O, Suwala, Abigail K, Hong, Chibo, Kim, Somang, Yuan, Jimmy Bo, Wu, Jasper, Barreto, Jairo, Lucas, Calixto-Hope G, Chan, Emily, Pekmezci, Melike, LeBoit, Philip E, Mully, Thaddeus, Perry, Arie, Bollen, Andrew, Van Ziffle, Jessica, Devine, W Patrick, Reddy, Alyssa T, Gupta, Nalin, Basnet, Kristen M, Macaulay, Robert JB, Malafronte, Patrick, Lee, Han, Yong, William H, Williams, Kevin Jon, Juratli, Tareq A, Mata, Douglas A, Huang, Richard SP, Hiemenz, Matthew C, Pavlick, Dean C, Frampton, Garrett M, Janovitz, Tyler, Ross, Jeffrey S, Chang, Susan M, Berger, Mitchel S, Jacques, Line, Song, Jun S, Costello, Joseph F, Solomon, David A

المصدر: Neuro-Oncology. 25(12)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Pediatric, Cancer, Human Genome, Neurosciences, Biotechnology, Genetics, Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Humans, INDEL Mutation, Transcriptional Activation, Neurilemmoma, Neuroma, Acoustic, Mutation, Nerve Sheath Neoplasms, SOXE Transcription Factors, myelination, PMP2, Schwann cell, schwannoma, SOX10, Oncology and Carcinogenesis, Oncology & Carcinogenesis, Oncology and carcinogenesis

الوصف: BackgroundSchwannomas are common peripheral nerve sheath tumors that can cause severe morbidity given their stereotypic intracranial and paraspinal locations. Similar to many solid tumors, schwannomas and other nerve sheath tumors are primarily thought to arise due to aberrant hyperactivation of the RAS growth factor signaling pathway. Here, we sought to further define the molecular pathogenesis of schwannomas.MethodsWe performed comprehensive genomic profiling on a cohort of 96 human schwannomas, as well as DNA methylation profiling on a subset. Functional studies including RNA sequencing, chromatin immunoprecipitation-DNA sequencing, electrophoretic mobility shift assay, and luciferase reporter assays were performed in a fetal glial cell model following transduction with wildtype and tumor-derived mutant isoforms of SOX10.ResultsWe identified that nearly one-third of sporadic schwannomas lack alterations in known nerve sheath tumor genes and instead harbor novel recurrent in-frame insertion/deletion mutations in SOX10, which encodes a transcription factor responsible for controlling Schwann cell differentiation and myelination. SOX10 indel mutations were highly enriched in schwannomas arising from nonvestibular cranial nerves (eg facial, trigeminal, vagus) and were absent from vestibular nerve schwannomas driven by NF2 mutation. Functional studies revealed these SOX10 indel mutations have retained DNA binding capacity but impaired transactivation of glial differentiation and myelination gene programs.ConclusionsWe thus speculate that SOX10 indel mutations drive a unique subtype of schwannomas by impeding proper differentiation of immature Schwann cells.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/6zq333xtTest

المؤلفون: Slavotinek, Anne, Rego, Shannon, Sahin-Hodoglugil, Nuriye, Kvale, Mark, Lianoglou, Billie, Yip, Tiffany, Hoban, Hannah, Outram, Simon, Anguiano, Beatrice, Chen, Flavia, Michelson, Jeremy, Cilio, Roberta M, Curry, Cynthia, Gallagher, Renata C, Gardner, Marisa, Kuperman, Rachel, Mendelsohn, Bryce, Sherr, Elliott, Shieh, Joseph, Strober, Jonathan, Tam, Allison, Tenney, Jessica, Weiss, William, Whittle, Amy, Chin, Garrett, Faubel, Amanda, Prasad, Hannah, Mavura, Yusuph, Van Ziffle, Jessica, Devine, W Patrick, Hodoglugil, Ugur, Martin, Pierre-Marie, Sparks, Teresa N, Koenig, Barbara, Ackerman, Sara, Risch, Neil, Kwok, Pui-Yan, Norton, Mary E

المصدر: npj Genomic Medicine. 8(1)

مصطلحات موضوعية: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Clinical Research, Perinatal Period - Conditions Originating in Perinatal Period, Human Genome, Pediatric, Medical biotechnology

الوصف: The diagnostic yield of exome sequencing (ES) has primarily been evaluated in individuals of European ancestry, with less focus on underrepresented minority (URM) and underserved (US) patients. We evaluated the diagnostic yield of ES in a cohort of predominantly US and URM pediatric and prenatal patients suspected to have a genetic disorder. Eligible pediatric patients had multiple congenital anomalies and/or neurocognitive disabilities and prenatal patients had one or more structural anomalies, disorders of fetal growth, or fetal effusions. URM and US patients were prioritized for enrollment and underwent ES at a single academic center. We identified definitive positive or probable positive results in 201/845 (23.8%) patients, with a significantly higher diagnostic rate in pediatric (26.7%) compared to prenatal patients (19.0%) (P = 0.01). For both pediatric and prenatal patients, the diagnostic yield and frequency of inconclusive findings did not differ significantly between URM and non-URM patients or between patients with US status and those without US status. Our results demonstrate a similar diagnostic yield of ES between prenatal and pediatric URM/US patients and non-URM/US patients for positive and inconclusive results. These data support the use of ES to identify clinically relevant variants in patients from diverse populations.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/2gp2s68bTest

المؤلفون: Kathiriya, Irfan S., Dominguez, Martin H., Rao, Kavitha S., Muncie-Vasic, Jonathon M., Devine, W. Patrick, Hu, Kevin M., Hota, Swetansu K., Garay, Bayardo I., Quintero, Diego, Goyal, Piyush, Matthews, Megan N., Thomas, Reuben, Sukonnik, Tatyana, Miguel-Perez, Dario, Winchester, Sarah, Brower, Emily F., Forjaz, André, Wu, Pei-Hsun, Wirtz, Denis, Kiemen, Ashley L., Bruneau, Benoit G.

المساهمون: Pediatrics, School of Medicine

المصدر: PMC

مصطلحات موضوعية: Interventricular septum (IVS), Congenital heart defect (CHD), Cardiac birth defects

الوصف: Failure of septation of the interventricular septum (IVS) is the most common congenital heart defect (CHD), but mechanisms for patterning the IVS are largely unknown. We show that a Tbx5+/Mef2cAHF+ progenitor lineage forms a compartment boundary bisecting the IVS. This coordinated population originates at a first- and second heart field interface, subsequently forming a morphogenetic nexus. Ablation of Tbx5+/Mef2cAHF+ progenitors cause IVS disorganization, right ventricular hypoplasia and mixing of IVS lineages. Reduced dosage of the CHD transcription factor TBX5 disrupts boundary position and integrity, resulting in ventricular septation defects (VSDs) and patterning defects, including Slit2 and Ntn1 misexpression. Reducing NTN1 dosage partly rescues cardiac defects in Tbx5 mutant embryos. Loss of Slit2 or Ntn1 causes VSDs and perturbed septal lineage distributions. Thus, we identify essential cues that direct progenitors to pattern a compartment boundary for proper cardiac septation, revealing new mechanisms for cardiac birth defects.

وصف الملف: application/pdf

العلاقة: Kathiriya IS, Dominguez MH, Rao KS, et al. A disrupted compartment boundary underlies abnormal cardiac patterning and congenital heart defects. Preprint. bioRxiv. 2024;2024.02.05.578995. Published 2024 Mar 4. doi:10.1101/2024.02.05.578995; https://hdl.handle.net/1805/41591Test

الإتاحة: https://doi.org/10.1101/2024.02.05.578995Test
https://hdl.handle.net/1805/41591Test

المؤلفون: Norton, Mary E, Ziffle, Jessica Van, Lianoglou, Billie R, Hodoglugil, Ugur, Devine, W Patrick, Sparks, Teresa N

المصدر: American Journal of Obstetrics and Gynecology. 226(1)

مصطلحات موضوعية: Genetics, Clinical Research, Pediatric, Human Genome, Biotechnology, Genetic Testing, Rare Diseases, Aetiology, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, 2.1 Biological and endogenous factors, Good Health and Well Being, Adult, Cohort Studies, Female, Gestational Age, High-Throughput Nucleotide Sequencing, Humans, Hydrops Fetalis, Predictive Value of Tests, Pregnancy, Prenatal Diagnosis, Exome Sequencing, exome sequencing, nonimmune hydrops, RASopathy, targeted gene panels, Paediatrics and Reproductive Medicine, Obstetrics & Reproductive Medicine

الوصف: BackgroundNext-generation sequencing is increasingly used in prenatal diagnosis. Targeted gene panels and exome sequencing are both available, but the comparative diagnostic yields of these approaches are not known.ObjectiveWe compared the diagnostic yield of exome sequencing with the simulated application of commercial targeted gene panels in a large cohort of fetuses with nonimmune hydrops fetalis.Study designThis was a secondary analysis of a cohort study of exome sequencing for nonimmune hydrops fetalis, in which recruitment, exome sequencing, and phenotype-driven variant analysis were completed in 127 pregnancies with features of nonimmune hydrops fetalis. An Internet search was performed to identify commercial laboratories that offer targeted gene panels for the prenatal evaluation of nonimmune hydrops fetalis or for specific disorders associated with nonimmune hydrops fetalis using the terms "non-immune hydrops fetalis," "fetal non-immune hydrops," "hydrops," "cystic hygroma," "lysosomal storage disease," "metabolic disorder," "inborn error of metabolism," "RASopathy," and "Noonan." Our primary outcome was the proportion of all genetic variants identified through exome sequencing that would have been identified if a targeted gene panel had instead been used. The secondary outcomes were the proportion of genetic variants that would have been identified by type of targeted gene panel (general nonimmune hydrops fetalis, RASopathy, or metabolic) and the percent of variants of uncertain significance that would have been identified on the panels, assuming 100% analytical sensitivity and specificity of panels for variants in the included genes.ResultsExome sequencing identified a pathogenic or likely pathogenic variant in 37 of 127 cases (29%) in a total of 29 genes. A variant of uncertain significance, strongly suspected to be associated with the phenotype, was identified in another 12 cases (9%). We identified 7 laboratories that offer 10 relevant targeted gene panels; 6 are described as RASopathy panels, 3 as nonimmune hydrops fetalis panels, and 1 as a metabolic panel. The median number of genes included on each of these panels is 22, ranging from 11 to 148. Had a nonimmune hydrops fetalis targeted gene panel been used instead of exome sequencing, 13 to 15 of the 29 genes (45%-52%) identified in our nonimmune hydrops fetalis cohort would have been sequenced, and 19 to 24 of the pathogenic variants (51%-62%) would have been detected. The yield was predicted to be the lowest with the metabolic panel (11%) and the highest with the largest nonimmune hydrops fetalis panel (62%). The largest nonimmune hydrops fetalis targeted gene panel would have had a diagnostic yield of 18% compared with 29% with exome sequencing. The exome sequencing platform used provided 30× or more coverage for all of the exons on the commercial targeted gene panels, supporting our assumption of 100% analytical sensitivity for exome sequencing.ConclusionThe broader coverage of exome sequencing for genetically heterogeneous disorders, such as nonimmune hydrops fetalis, made it a superior alternative to targeted gene panel testing.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/1qf7b9phTest

المؤلفون: Kathiriya, Irfan S, Rao, Kavitha S, Iacono, Giovanni, Devine, W Patrick, Blair, Andrew P, Hota, Swetansu K, Lai, Michael H, Garay, Bayardo I, Thomas, Reuben, Gong, Henry Z, Wasson, Lauren K, Goyal, Piyush, Sukonnik, Tatyana, Hu, Kevin M, Akgun, Gunes A, Bernard, Laure D, Akerberg, Brynn N, Gu, Fei, Li, Kai, Speir, Matthew L, Haeussler, Maximilian, Pu, William T, Stuart, Joshua M, Seidman, Christine E, Seidman, JG, Heyn, Holger, Bruneau, Benoit G

المصدر: Developmental cell. 56(3)

مصطلحات موضوعية: Heart Ventricles, Myocytes, Cardiac, Animals, Humans, Mice, Heart Defects, Congenital, T-Box Domain Proteins, Cell Differentiation, Transcription, Genetic, Body Patterning, Gene Dosage, Mutation, Models, Biological, Gene Regulatory Networks, Haploinsufficiency, MEF2 Transcription Factors, cardiomyocyte differentiation, congenital heart disease, disease modeling, gene dosage, gene regulation, gene regulatory networks, haploinsufficiency, human induced pluripotent stem cells, single cell transcriptomics, transcription factor, Heart Disease - Coronary Heart Disease, Cardiovascular, Genetics, Human Genome, Stem Cell Research, Heart Disease, Congenital Structural Anomalies, Pediatric, 1.1 Normal biological development and functioning, Aetiology, 2.1 Biological and endogenous factors, Underpinning research, Biological Sciences, Medical and Health Sciences, Developmental Biology

الوصف: Haploinsufficiency of transcriptional regulators causes human congenital heart disease (CHD); however, the underlying CHD gene regulatory network (GRN) imbalances are unknown. Here, we define transcriptional consequences of reduced dosage of the CHD transcription factor, TBX5, in individual cells during cardiomyocyte differentiation from human induced pluripotent stem cells (iPSCs). We discovered highly sensitive dysregulation of TBX5-dependent pathways-including lineage decisions and genes associated with heart development, cardiomyocyte function, and CHD genetics-in discrete subpopulations of cardiomyocytes. Spatial transcriptomic mapping revealed chamber-restricted expression for many TBX5-sensitive transcripts. GRN analysis indicated that cardiac network stability, including vulnerable CHD-linked nodes, is sensitive to TBX5 dosage. A GRN-predicted genetic interaction between Tbx5 and Mef2c, manifesting as ventricular septation defects, was validated in mice. These results demonstrate exquisite and diverse sensitivity to TBX5 dosage in heterogeneous subsets of iPSC-derived cardiomyocytes and predicts candidate GRNs for human CHDs, with implications for quantitative transcriptional regulation in disease.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/0ws080ncTest

المؤلفون: Afshar, Armin R, Pekmezci, Melike, Bloomer, Michele M, Cadenas, Nicola J, Stevers, Meredith, Banerjee, Anuradha, Roy, Ritu, Olshen, Adam B, Van Ziffle, Jessica, Onodera, Courtney, Devine, W Patrick, Grenert, James P, Bastian, Boris C, Solomon, David A, Damato, Bertil E

المصدر: Ophthalmology. 127(6)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Neurosciences, Rare Diseases, Genetics, Clinical Research, Pediatric, Pediatric Cancer, Pediatric Research Initiative, Child, Child, Preschool, Cohort Studies, DNA Mutational Analysis, DNA, Neoplasm, Eye Enucleation, Female, Gene Silencing, Germ-Line Mutation, High-Throughput Nucleotide Sequencing, Humans, Infant, Male, Paraffin Embedding, Retinal Neoplasms, Retinoblastoma, Retinoblastoma Binding Proteins, Tissue Fixation, Ubiquitin-Protein Ligases, Clinical Sciences, Opthalmology and Optometry, Public Health and Health Services, Ophthalmology & Optometry, Ophthalmology and optometry

الوصف: PurposeTo determine the usefulness of a comprehensive, targeted-capture next-generation sequencing (NGS) assay for the clinical management of children undergoing enucleation for retinoblastoma.DesignCohort study.ParticipantsThirty-two children with retinoblastoma.MethodsWe performed targeted NGS using the UCSF500 Cancer Panel (University of California, San Francisco, San Francisco, CA) on formalin-fixed, paraffin-embedded tumor tissue along with constitutional DNA isolated from peripheral blood, buccal swab, or uninvolved optic nerve. Peripheral blood samples were also sent to a commercial laboratory for germline RB1 mutation testing.Main outcome measuresPresence or absence of germline RB1 mutation or deletion, tumor genetic profile, and association of genetic alterations with clinicopathologic features.ResultsGermline mutation or deletion of the RB1 gene was identified in all children with bilateral retinoblastoma (n = 12), and these NGS results were 100% concordant with commercial germline RB1 mutation analysis. In tumor tissue tested with NGS, biallelic inactivation of RB1 was identified in 28 tumors and focal MYCN amplification was identified in 4 tumors (2 with wild-type RB1 and 2 with biallelic RB1 inactivation). Additional likely pathogenic alterations beyond RB1 were identified in 13 tumors (41%), several of which have not been reported previously in retinoblastoma. These included focal amplifications of MDM4 and RAF1, as well as damaging mutations involving BCOR, ARID1A, MGA, FAT1, and ATRX. The presence of additional likely pathogenetic mutations beyond RB1 inactivation was associated with aggressive histopathologic features, including higher histologic grade and anaplasia, and also with both unilateral and sporadic disease.ConclusionsComprehensive NGS analysis reliably detects relevant mutations, amplifications, and chromosomal copy number changes in retinoblastoma. The presence of genetic alterations beyond RB1 inactivation correlates with aggressive histopathologic features.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/69x937mnTest

المؤلفون: Pfeil, Jacob, Sanders, Lauren M, Anastopoulos, Ioannis, Lyle, A Geoffrey, Weinstein, Alana S, Xue, Yuanqing, Blair, Andrew, Beale, Holly C, Lee, Alex, Leung, Stanley G, Dinh, Phuong T, Shah, Avanthi Tayi, Breese, Marcus R, Devine, W Patrick, Bjork, Isabel, Salama, Sofie R, Sweet-Cordero, E Alejandro, Haussler, David, Vaske, Olena Morozova

المصدر: PLoS computational biology. 16(4)

مصطلحات موضوعية: Humans, Neoplasms, Neuroblastoma, Cluster Analysis, Models, Statistical, Gene Expression Profiling, Computational Biology, Gene Expression Regulation, Neoplastic, Child, Tumor Microenvironment, Transcriptome, Biomarkers, Tumor, Precision Medicine, Models, Statistical, Gene Expression Regulation, Neoplastic, Biomarkers, Tumor, Bioinformatics, Mathematical Sciences, Biological Sciences, Information and Computing Sciences

الوصف: Precision oncology has primarily relied on coding mutations as biomarkers of response to therapies. While transcriptome analysis can provide valuable information, incorporation into workflows has been difficult. For example, the relative rather than absolute gene expression level needs to be considered, requiring differential expression analysis across samples. However, expression programs related to the cell-of-origin and tumor microenvironment effects confound the search for cancer-specific expression changes. To address these challenges, we developed an unsupervised clustering approach for discovering differential pathway expression within cancer cohorts using gene expression measurements. The hydra approach uses a Dirichlet process mixture model to automatically detect multimodally distributed genes and expression signatures without the need for matched normal tissue. We demonstrate that the hydra approach is more sensitive than widely-used gene set enrichment approaches for detecting multimodal expression signatures. Application of the hydra analysis framework to small blue round cell tumors (including rhabdomyosarcoma, synovial sarcoma, neuroblastoma, Ewing sarcoma, and osteosarcoma) identified expression signatures associated with changes in the tumor microenvironment. The hydra approach also identified an association between ATRX deletions and elevated immune marker expression in high-risk neuroblastoma. Notably, hydra analysis of all small blue round cell tumors revealed similar subtypes, characterized by changes to infiltrating immune and stromal expression signatures.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/4fp081x6Test

المؤلفون: Slavotinek, Anne, Rego, Shannon, Sahin-Hodoglugil, Nuriye, Kvale, Mark, Lianoglou, Billie, Yip, Tiffany, Hoban, Hannah, Outram, Simon, Anguiano, Beatrice, Chen, Flavia, Michelson, Jeremy, Cilio, Roberta M., Curry, Cynthia, Gallagher, Renata C., Gardner, Marisa, Kuperman, Rachel, Mendelsohn, Bryce, Sherr, Elliott, Shieh, Joseph, Strober, Jonathan, Tam, Allison, Tenney, Jessica, Weiss, William, Whittle, Amy, Chin, Garrett, Faubel, Amanda, Prasad, Hannah, Mavura, Yusuph, Van Ziffle, Jessica, Devine, W. Patrick, Hodoglugil, Ugur, Martin, Pierre-Marie, Sparks, Teresa N., Koenig, Barbara, Ackerman, Sara, Risch, Neil, Kwok, Pui-Yan, Norton, Mary E.

المصدر: npj Genomic Medicine ; volume 8, issue 1 ; ISSN 2056-7944

مصطلحات موضوعية: Genetics (clinical), Genetics, Molecular Biology

الإتاحة: https://doi.org/10.1038/s41525-023-00382-9Test
https://www.nature.com/articles/s41525-023-00382-9.pdfTest
https://www.nature.com/articles/s41525-023-00382-9Test

المؤلفون: Sparks, Teresa, Lianoglou, Billie, Sahin-Holodlugil, Nuriye, Kvale, Mark, Van Ziffle, Jessica, Devine, W. Patrick, Hodoglugil, Ugur, Martin, Pierre-Marie, Koenig, Barbara, Kwok, Pui-Yan, Ackerman, Sara, Slavotinek, Anne, Risch, Neil, Norton, Mary

المصدر: Genetics in Medicine Open ; volume 1, issue 1, page 100648 ; ISSN 2949-7744

الإتاحة: https://doi.org/10.1016/j.gimo.2023.100648Test
https://api.elsevier.com/content/article/PII:S2949774423006489?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S2949774423006489?httpAccept=text/plainTest