Search

Your search keyword '"Chung, Wendy"' showing total 3,903 results
Start Over Author "Chung, Wendy"
3,903 results on '"Chung, Wendy"'

1. Context-dependent roles of mitochondrial LONP1 in orchestrating the balance between airway progenitor versus progeny cells

Author

Xu, Le, Tan, Chunting, Barr, Justinn, Talaba, Nicole, Verheyden, Jamie, Chin, Ji Sun, Gaboyan, Samvel, Kasaraneni, Nikita, Elgamal, Ruth M, Gaulton, Kyle J, Lin, Grace, Afshar, Kamyar, Golts, Eugene, Meier, Angela, Alexander, Laura E Crotty, Borok, Zea, Shen, Yufeng, Chung, Wendy K, McCulley, David J, and Sun, Xin

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Chronic Obstructive Pulmonary Disease, Lung, Genetics, Stem Cell Research, Stem Cell Research - Nonembryonic - Non-Human, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Respiratory, ATF4, BOK, COPD, airway homeostasis, differentiated progeny cells, influenza infection, integrated stress response, lung epithelial cells, mitochondria, progenitor basal cells, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

While all eukaryotic cells are dependent on mitochondria for function, in a complex tissue, which cell type and which cell behavior are more sensitive to mitochondrial deficiency remain unpredictable. Here, we show that in the mouse airway, compromising mitochondrial function by inactivating mitochondrial protease gene Lonp1 led to reduced progenitor proliferation and differentiation during development, apoptosis of terminally differentiated ciliated cells and their replacement by basal progenitors and goblet cells during homeostasis, and failed airway progenitor migration into damaged alveoli following influenza infection. ATF4 and the integrated stress response (ISR) pathway are elevated and responsible for the airway phenotypes. Such context-dependent sensitivities are predicted by the selective expression of Bok, which is required for ISR activation. Reduced LONP1 expression is found in chronic obstructive pulmonary disease (COPD) airways with squamous metaplasia. These findings illustrate a cellular energy landscape whereby compromised mitochondrial function could favor the emergence of pathological cell types.

Published
2024

5. GestaltMML: Enhancing Rare Genetic Disease Diagnosis through Multimodal Machine Learning Combining Facial Images and Clinical Texts

Author

Wu, Da, Yang, Jingye, Liu, Cong, Hsieh, Tzung-Chien, Marchi, Elaine, Blair, Justin, Krawitz, Peter, Weng, Chunhua, Chung, Wendy, Lyon, Gholson J., Krantz, Ian D., Kalish, Jennifer M., and Wang, Kai

Subjects
Quantitative Biology - Quantitative Methods, Computer Science - Computer Vision and Pattern Recognition, Computer Science - Machine Learning, Computer Science - Multimedia, Quantitative Biology - Genomics
Abstract

Individuals with suspected rare genetic disorders often undergo multiple clinical evaluations, imaging studies, laboratory tests and genetic tests, to find a possible answer over a prolonged period of time. Addressing this "diagnostic odyssey" thus has substantial clinical, psychosocial, and economic benefits. Many rare genetic diseases have distinctive facial features, which can be used by artificial intelligence algorithms to facilitate clinical diagnosis, in prioritizing candidate diseases to be further examined by lab tests or genetic assays, or in helping the phenotype-driven reinterpretation of genome/exome sequencing data. Existing methods using frontal facial photos were built on conventional Convolutional Neural Networks (CNNs), rely exclusively on facial images, and cannot capture non-facial phenotypic traits and demographic information essential for guiding accurate diagnoses. Here we introduce GestaltMML, a multimodal machine learning (MML) approach solely based on the Transformer architecture. It integrates facial images, demographic information (age, sex, ethnicity), and clinical notes (optionally, a list of Human Phenotype Ontology terms) to improve prediction accuracy. Furthermore, we also evaluated GestaltMML on a diverse range of datasets, including 528 diseases from the GestaltMatcher Database, several in-house datasets of Beckwith-Wiedemann syndrome (BWS, over-growth syndrome with distinct facial features), Sotos syndrome (overgrowth syndrome with overlapping features with BWS), NAA10-related neurodevelopmental syndrome, Cornelia de Lange syndrome (multiple malformation syndrome), and KBG syndrome (multiple malformation syndrome). Our results suggest that GestaltMML effectively incorporates multiple modalities of data, greatly narrowing candidate genetic diagnoses of rare diseases and may facilitate the reinterpretation of genome/exome sequencing data., Comment: Significant revisions

Published
2023

6. Expanded phenotypic spectrum of neurodevelopmental and neurodegenerative disorder Bryant-Li-Bhoj syndrome with 38 additional individuals

Author

Layo-Carris, Dana E., Lubin, Emily E., Sangree, Annabel K., Clark, Kelly J., Durham, Emily L., Gonzalez, Elizabeth M., Smith, Sarina, Angireddy, Rajesh, Wang, Xiao Min, Weiss, Erin, Toutain, Annick, Mendoza-Londono, Roberto, Dupuis, Lucie, Damseh, Nadirah, Velasco, Danita, Valenzuela, Irene, Codina-Solà, Marta, Ziats, Catherine, Have, Jaclyn, Clarkson, Katie, Steel, Dora, Kurian, Manju, Barwick, Katy, Carrasco, Diana, Dagli, Aditi I., Nowaczyk, M. J. M., Hančárová, Miroslava, Bendová, Šárka, Prchalova, Darina, Sedláček, Zdeněk, Baxová, Alica, Nowak, Catherine Bearce, Douglas, Jessica, Chung, Wendy K., Longo, Nicola, Platzer, Konrad, Klöckner, Chiara, Averdunk, Luisa, Wieczorek, Dagmar, Krey, Ilona, Zweier, Christiane, Reis, Andre, Balci, Tugce, Simon, Marleen, Kroes, Hester Y., Wiesener, Antje, Vasileiou, Georgia, Marinakis, Nikolaos M., Veltra, Danai, Sofocleous, Christalena, Kosma, Konstantina, Traeger Synodinos, Joanne, Voudris, Konstantinos A., Vuillaume, Marie-Laure, Gueguen, Paul, Derive, Nicolas, Colin, Estelle, Battault, Clarisse, Au, Billie, Delatycki, Martin, Wallis, Mathew, Gallacher, Lyndon, Majdoub, Fatma, Smal, Noor, Weckhuysen, Sarah, Schoonjans, An-Sofie, Kooy, R. Frank, Meuwissen, Marije, Cocanougher, Benjamin T., Taylor, Kathryn, Pizoli, Carolyn E., McDonald, Marie T., James, Philip, Roeder, Elizabeth R., Littlejohn, Rebecca, Borja, Nicholas A., Thorson, Willa, King, Kristine, Stoeva, Radka, Suerink, Manon, Nibbeling, Esther, Baskin, Stephanie, L. E. Guyader, Gwenaël, Kaplan, Julie, Muss, Candace, Carere, Deanna Alexis, Bhoj, Elizabeth J. K., and Bryant, Laura M.

Published
2024
Full Text
View/download PDF

7. Rescuing lung development through embryonic inhibition of histone acetylation

Author

Stokes, Giangela, Li, Zhuowei, Talaba, Nicole, Genthe, William, Brix, Maria B, Pham, Betty, Wienhold, Mark D, Sandok, Gracia, Hernan, Rebecca, Wynn, Julia, Tang, Haiyang, Tabima, Diana M, Rodgers, Allison, Hacker, Timothy A, Chesler, Naomi C, Zhang, Pan, Murad, Rabi, Yuan, Jason X-J, Shen, Yufeng, Chung, Wendy K, and McCulley, David J

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Perinatal Period - Conditions Originating in Perinatal Period, Human Genome, Infant Mortality, Rare Diseases, Genetics, Orphan Drug, Pediatric, Digestive Diseases, Congenital Structural Anomalies, Lung, 2.1 Biological and endogenous factors, Aetiology, Respiratory, Good Health and Well Being, Animals, Humans, Mice, Hypertension, Pulmonary, Histones, Acetylation, Hernias, Diaphragmatic, Congenital, Biological Sciences, Medical and Health Sciences, Medical biotechnology, Biomedical engineering
Abstract

A major barrier to the impact of genomic diagnosis in patients with congenital malformations is the lack of understanding regarding how sequence variants contribute to disease pathogenesis and whether this information could be used to generate patient-specific therapies. Congenital diaphragmatic hernia (CDH) is among the most common and severe of all structural malformations; however, its underlying mechanisms are unclear. We identified loss-of-function sequence variants in the epigenomic regulator gene SIN3A in two patients with complex CDH. Tissue-specific deletion of Sin3a in mice resulted in defects in diaphragm development, lung hypoplasia, and pulmonary hypertension, the cardinal features of CDH and major causes of CDH-associated mortality. Loss of SIN3A in the lung mesenchyme resulted in reduced cellular differentiation, impaired cell proliferation, and increased DNA damage. Treatment of embryonic Sin3a mutant mice with anacardic acid, an inhibitor of histone acetyltransferase, reduced DNA damage, increased cell proliferation and differentiation, improved lung and pulmonary vascular development, and reduced pulmonary hypertension. These findings demonstrate that restoring the balance of histone acetylation can improve lung development in the Sin3a mouse model of CDH.

Published
2024

8. Evidence-based recruitment strategies for clinical research: Study personnels and research participants perceptions about successful methods of outreach for a U.S. Autism-Research Cohort.

Author

Goin-Kochel, Robin, Lozano, Ivana, Duhon, Gabrielle, Marzano, Gabriela, Daniels, Amy, Law, J, Diehl, Katharine, Green Snyder, LeeAnne, Feliciano, Pamela, and Chung, Wendy

Subjects
Research recruitment, autism, parent/caregiver, participant enrollment
Abstract

INTRODUCTION: Under enrollment of participants in clinical research is costly and delays study completion to impact public health. Given that research personnel make decisions about which strategies to pursue and participants are the recipients of these efforts, we surveyed research staff (n = 52) and participants (n = 4,144) affiliated with SPARK (Simons Foundation Powering Autism for Knowledge) - the largest study of autism in the U.S. - to understand their perceptions of effective recruitment strategies. METHODS: In Study 1, research personnel were asked to report recruitment strategies that they tried for SPARK and to indicate which ones they would and would not repeat/recommend. In Study 2, SPARK participants were asked to indicate all the ways they heard about the study prior to enrollment and which one was most influential in their decisions to enroll. RESULTS: Staff rated speaking with a SPARK-study-team member (36.5%), speaking with a medical provider (19.2%), word of mouth (11.5%), and a live TV news story (11.5%) as the most successful strategies. Participants most often heard about SPARK via social media (47.0%), speaking with a medical provider (23.1%), and an online search (20.1%). Research personnels and participants views on effective recruitment strategies often differed, with the exception of speaking with a medical provider. CONCLUSION: Results suggest that a combination of strategies is likely to be most effective in reaching diverse audiences. Findings have implications for the selection of strategies that meet a studys specific needs, as well as recruitment-strategy combinations that may enhance the influence of outreach efforts.

Published
2024

9. Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel

Author

Levi, Hagai, Carmi, Shai, Rosset, Saharon, Yerushalmi, Rinat, Zick, Aviad, Yablonski-Peretz, Tamar, Consortium, The BCAC, Wang, Qin, Bolla, Manjeet K, Dennis, Joe, Michailidou, Kyriaki, Lush, Michael, Ahearn, Thomas, Andrulis, Irene L, Anton-Culver, Hoda, Antoniou, Antonis C, Arndt, Volker, Augustinsson, Annelie, Auvinen, Päivi, Freeman, Laura Beane, Beckmann, Matthias, Behrens, Sabine, Bermisheva, Marina, Bodelon, Clara, Bogdanova, Natalia V, Bojesen, Stig E, Brenner, Hermann, Byers, Helen, Camp, Nicola, Castelao, Jose, Chang-Claude, Jenny, Chirlaque, María-Dolores, Chung, Wendy, Clarke, Christine, Collaborators, NBCS, Collee, Margriet J, Colonna, Sarah, Consortium, CTS, Couch, Fergus, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary, Devilee, Peter, Dork, Thilo, Dossus, Laure, Eccles, Diana M, Eliassen, A Heather, Eriksson, Mikael, Evans, Gareth, Fasching, Peter, Fletcher, Olivia, Flyger, Henrik, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, García-Closas, Montserrat, Garcia-Saenz, Jose Angel, Genkinger, Jeanine, Giles, Graham G, Goldberg, Mark, Guénel, Pascal, Hall, Per, Hamann, Ute, He, Wei, Hillemanns, Peter, Hollestelle, Antoinette, Hoppe, Reiner, Hopper, John, Investigators, ABCTB, Jakovchevska, Simona, Jakubowska, Anna, Jernström, Helena, John, Esther, Johnson, Nichola, Jones, Michael, Vijai, Joseph, Kaaks, Rudolf, Khusnutdinova, Elza, Kitahara, Cari, Koutros, Stella, Kristensen, Vessela, Kurian, Allison W, Lacey, James, Lambrechts, Diether, Le Marchand, Loic, Lejbkowicz, Flavio, Lindblom, Annika, Loibl, Sibylle, Lori, Adriana, Lubinski, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Mavroudis, Dimitrios, Menon, Usha, Mulligan, AnnaMarie, Murphy, Rachel, Nevelsteen, Ines, Newman, William G, and Obi, Nadia

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Breast Cancer, Prevention, Cancer, Humans, Female, Breast Neoplasms, Genome-Wide Association Study, Jews, Israel, Genetic Predisposition to Disease, Risk Factors, Multifactorial Inheritance, Transcription Factors, Genomics, Polymorphism, Genetic, BCAC Consortium, NBCS Collaborators, CTS Consortium, ABCTB Investigators, Polymorphism, Genetic, Medical and Health Sciences, Genetics & Heredity, Clinical sciences
Abstract

BackgroundPolygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women.MethodsWe generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel.ResultsIn the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28).ConclusionsExtant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.

Published
2023

10. Association of genetic and sulcal traits with executive function in congenital heart disease.

Author

Maleyeff, Lara, Newburger, Jane, Wypij, David, Thomas, Nina, Anagnoustou, Evdokia, Brueckner, Martina, Chung, Wendy, Cleveland, John, Cunningham, Sean, Gelb, Bruce, Goldmuntz, Elizabeth, Huang, Hao, King, Eileen, McQuillen, Patrick, Miller, Thomas, Norris-Brilliant, Ami, Porter, George, Roberts, Amy, Grant, P, Im, Kiho, Morton, Sarah, and Hagler, Donald

Abstract

OBJECTIVE: Persons with congenital heart disease (CHD) are at increased risk of neurodevelopmental disabilities, including impairments to executive function. Sulcal pattern features correlate with executive function in adolescents with single-ventricle heart disease and tetralogy of Fallot. However, the interaction of sulcal pattern features with genetic and participant factors in predicting executive dysfunction is unknown. METHODS: We studied sulcal pattern features, participant factors, and genetic risk for executive function impairment in a cohort with multiple CHD types using stepwise linear regression and machine learning. RESULTS: Genetic factors, including predicted damaging de novo or rare inherited variants in neurodevelopmental disabilities risk genes, apolipoprotein E genotype, and principal components of sulcal pattern features were associated with executive function measures after adjusting for age at testing, sex, mothers education, and biventricular versus single-ventricle CHD in a linear regression model. Using regression trees and bootstrap validation, younger participant age and larger alterations in sulcal pattern features were consistently identified as important predictors of decreased cognitive flexibility with left hemisphere graph topology often selected as the most important predictor. Inclusion of both sulcal pattern and genetic factors improved model fit compared to either alone. INTERPRETATION: We conclude that sulcal measures remain important predictors of cognitive flexibility, and the model predicting executive outcomes is improved by inclusion of potential genetic sources of neurodevelopmental risk. If confirmed, measures of sulcal patterning may serve as early imaging biomarkers to identify those at heightened risk for future neurodevelopmental disabilities.

Published
2023

11. PLS3 missense variants affecting the actin-binding domains cause X-linked congenital diaphragmatic hernia and body-wall defects.

Author

Petit, Florence, Longoni, Mauro, Wells, Julie, Maser, Richard, Bogenschutz, Eric, Dysart, Matthew, Contreras, Hannah, Frénois, Frederic, Pober, Barbara, Clark, Robin, Giampietro, Philip, Ropers, Hilger, Hu, Hao, Loscertales, Maria, Wagner, Richard, Ai, Xingbin, Brand, Harrison, Jourdain, Anne-Sophie, Delrue, Marie-Ange, Gilbert-Dussardier, Brigitte, Devisme, Louise, Keren, Boris, McCulley, David, Qiao, Lu, Hernan, Rebecca, Wynn, Julia, Scott, Tiana, Calame, Daniel, Coban-Akdemir, Zeynep, Hernandez, Patricia, Hernandez-Garcia, Andres, Yonath, Hagith, Lupski, James, Shen, Yufeng, Chung, Wendy, Scott, Daryl, Bult, Carol, Donahoe, Patricia, and High, Frances

Subjects
PLS3, plastin, X-linked, abdominal hernia, actin-binding protein, congenital diaphragmatic hernia, fimbrin, omphalocele, umbilical hernia, Adult, Humans, Male, Animals, Mice, Hernias, Diaphragmatic, Congenital, Actins, Mutation, Missense, Osteoporosis
Abstract

Congenital diaphragmatic hernia (CDH) is a relatively common and genetically heterogeneous structural birth defect associated with high mortality and morbidity. We describe eight unrelated families with an X-linked condition characterized by diaphragm defects, variable anterior body-wall anomalies, and/or facial dysmorphism. Using linkage analysis and exome or genome sequencing, we found that missense variants in plastin 3 (PLS3), a gene encoding an actin bundling protein, co-segregate with disease in all families. Loss-of-function variants in PLS3 have been previously associated with X-linked osteoporosis (MIM: 300910), so we used in silico protein modeling and a mouse model to address these seemingly disparate clinical phenotypes. The missense variants in individuals with CDH are located within the actin-binding domains of the protein but are not predicted to affect protein structure, whereas the variants in individuals with osteoporosis are predicted to result in loss of function. A mouse knockin model of a variant identified in one of the CDH-affected families, c.1497G>C (p.Trp499Cys), shows partial perinatal lethality and recapitulates the key findings of the human phenotype, including diaphragm and abdominal-wall defects. Both the mouse model and one adult human male with a CDH-associated PLS3 variant were observed to have increased rather than decreased bone mineral density. Together, these clinical and functional data in humans and mice reveal that specific missense variants affecting the actin-binding domains of PLS3 might have a gain-of-function effect and cause a Mendelian congenital disorder.

Published
2023

12. ARF1-related disorder: phenotypic and molecular spectrum.

Author

de Sainte Agathe, Jean-Madeleine, Pode-Shakked, Ben, Naudion, Sophie, Michaud, Vincent, Arveiler, Benoit, Fergelot, Patricia, Delmas, Jean, Keren, Boris, Poirsier, Céline, Alkuraya, Fowzan, Tabarki, Brahim, Bend, Eric, Davis, Kellie, Bebin, Martina, Thompson, Michelle, Bryant, Emily, Wagner, Matias, Hannibal, Iris, Lenberg, Jerica, Krenn, Martin, Wigby, Kristen, Friedman, Jennifer, Iascone, Maria, Cereda, Anna, Miao, Térence, LeGuern, Eric, Sherr, Elliott, Caluseriu, Oana, Tidwell, Timothy, Bayrak-Toydemir, Pinar, Hagedorn, Caroline, Brugger, Melanie, Vill, Katharina, Morneau-Jacob, Francois-Dominique, Chung, Wendy, Weaver, Kathryn, Owens, Joshua, Husami, Ammar, Chaudhari, Bimal, Stone, Brandon, Burns, Katie, Li, Rachel, de Lange, Iris, Biehler, Margaux, Ginglinger, Emmanuelle, Gérard, Bénédicte, Stottmann, Rolf, Trimouille, Aurélien, and Argilli, Emanuela

Subjects
epilepsy, human genetics, sequence analysis, DNA, Humans, Brain, Genotype, Intellectual Disability, Microcephaly, Periventricular Nodular Heterotopia, Phenotype, Seizures
Abstract

PURPOSE: ARF1 was previously implicated in periventricular nodular heterotopia (PVNH) in only five individuals and systematic clinical characterisation was not available. The aim of this study is to provide a comprehensive description of the phenotypic and genotypic spectrum of ARF1-related neurodevelopmental disorder. METHODS: We collected detailed phenotypes of an international cohort of individuals (n=17) with ARF1 variants assembled through the GeneMatcher platform. Missense variants were structurally modelled, and the impact of several were functionally validated. RESULTS: De novo variants (10 missense, 1 frameshift, 1 splice altering resulting in 9 residues insertion) in ARF1 were identified among 17 unrelated individuals. Detailed phenotypes included intellectual disability (ID), microcephaly, seizures and PVNH. No specific facial characteristics were consistent across all cases, however microretrognathia was common. Various hearing and visual defects were recurrent, and interestingly, some inflammatory features were reported. MRI of the brain frequently showed abnormalities consistent with a neuronal migration disorder. CONCLUSION: We confirm the role of ARF1 in an autosomal dominant syndrome with a phenotypic spectrum including severe ID, microcephaly, seizures and PVNH due to impaired neuronal migration.

Published
2023

16. Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer‐specific survival

Author

Morra, Anna, Schreurs, Maartje AC, Andrulis, Irene L, Anton‐Culver, Hoda, Augustinsson, Annelie, Beckmann, Matthias W, Behrens, Sabine, Bojesen, Stig E, Bolla, Manjeet K, Brauch, Hiltrud, Broeks, Annegien, Buys, Saundra S, Camp, Nicola J, Castelao, Jose E, Cessna, Melissa H, Chang‐Claude, Jenny, Chung, Wendy K, Sahlberg, Kristine K, Børresen‐Dale, Anne‐Lise, Gram, Inger Torhild, Olsen, Karina Standahl, Engebråten, Olav, Naume, Bjørn, Geisler, Jürgen, OSBREAC, Alnæs, Grethe I Grenaker, Colonna, Sarah V, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Dennis, Joe, Devilee, Peter, Dörk, Thilo, Dunning, Alison M, Dwek, Miriam, Easton, Douglas F, Eccles, Diana M, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Fehm, Tanja N, Figueroa, Jonine D, Flyger, Henrik, Gabrielson, Marike, Gago‐Dominguez, Manuela, García‐Closas, Montserrat, García‐Sáenz, José A, Genkinger, Jeanine, Grassmann, Felix, Gündert, Melanie, Hahnen, Eric, Haiman, Christopher A, Hamann, Ute, Harrington, Patricia A, Hartikainen, Jaana M, Hoppe, Reiner, Hopper, John L, Houlston, Richard S, Howell, Anthony, Clarke, Christine, Marsh, Deborah, Scott, Rodney, Baxter, Robert, Yip, Desmond, Carpenter, Jane, Davis, Alison, Pathmanathan, Nirmala, Simpson, Peter, Graham, J Dinny, Sachchithananthan, Mythily, Amor, David, Andrews, Lesley, Antill, Yoland, Balleine, Rosemary, Beesley, Jonathan, Bennett, Ian, Bogwitz, Michael, Botes, Leon, Brennan, Meagan, Brown, Melissa, Buckley, Michael, Burke, Jo, Butow, Phyllis, Caldon, Liz, Campbell, Ian, Cao, Michelle, Chakrabarti, Anannya, Chauhan, Deepa, Chauhan, Manisha, Chenevix‐Trench, Georgia, Christian, Alice, Cohen, Paul, Colley, Alison, Crook, Ashley, Cui, James, Courtney, Eliza, Cummings, Margaret, and Dawson, Sarah‐Jane

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Women's Health, Breast Cancer, Clinical Research, Prevention, Cancer, Female, Humans, Breast Neoplasms, Checkpoint Kinase 2, Genetic Predisposition to Disease, Germ-Line Mutation, Heterozygote, Proportional Hazards Models, CHEK2 c.1100delC germline genetic variant, contralateral breast cancer risk, radiotherapy, survival, systemic treatment, NBCS Collaborators, ABCTB Investigators, kConFab Investigators, Biochemistry and Cell Biology, Oncology and carcinogenesis
Abstract

BackgroundBreast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers.AimTo assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS.MethodsAnalyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death.ResultsThere was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55-0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09-1.56)].ConclusionSystemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk.

Published
2023

17. Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2

Author

O’Mahony, Denise G, Ramus, Susan J, Southey, Melissa C, Meagher, Nicola S, Hadjisavvas, Andreas, John, Esther M, Hamann, Ute, Imyanitov, Evgeny N, Andrulis, Irene L, Sharma, Priyanka, Daly, Mary B, Hake, Christopher R, Weitzel, Jeffrey N, Jakubowska, Anna, Godwin, Andrew K, Arason, Adalgeir, Bane, Anita, Simard, Jacques, Soucy, Penny, Caligo, Maria A, Mai, Phuong L, Claes, Kathleen BM, Teixeira, Manuel R, Chung, Wendy K, Lazaro, Conxi, Hulick, Peter J, Toland, Amanda E, Pedersen, Inge Sokilde, Neuhausen, Susan L, Vega, Ana, de la Hoya, Miguel, Nevanlinna, Heli, Dhawan, Mallika, Zampiga, Valentina, Danesi, Rita, Varesco, Liliana, Gismondi, Viviana, Vellone, Valerio Gaetano, James, Paul A, Janavicius, Ramunas, Nikitina-Zake, Liene, Nielsen, Finn Cilius, van Overeem Hansen, Thomas, Pejovic, Tanja, Borg, Ake, Rantala, Johanna, Offit, Kenneth, Montagna, Marco, Nathanson, Katherine L, Domchek, Susan M, Osorio, Ana, García, María J, Karlan, Beth Y, De Fazio, Anna, Bowtell, David, McGuffog, Lesley, Leslie, Goska, Parsons, Michael T, Dörk, Thilo, Speith, Lisa-Marie, dos Santos, Elizabeth Santana, da Costa, Alexandre André BA, Radice, Paolo, Peterlongo, Paolo, Papi, Laura, Engel, Christoph, Hahnen, Eric, Schmutzler, Rita K, Wappenschmidt, Barbara, Easton, Douglas F, Tischkowitz, Marc, Singer, Christian F, Tan, Yen Yen, Whittemore, Alice S, Sieh, Weiva, Brenton, James D, Yannoukakos, Drakoulis, Fostira, Florentia, Konstantopoulou, Irene, Soukupova, Jana, Vocka, Michal, Chenevix-Trench, Georgia, Pharoah, Paul DP, Antoniou, Antonis C, Goldgar, David E, Spurdle, Amanda B, and Michailidou, Kyriaki

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Cancer, Breast Cancer, Genetics, Ovarian Cancer, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Humans, Female, Virulence, BRCA1 Protein, BRCA2 Protein, Ovarian Neoplasms, Genetic Predisposition to Disease, Breast Neoplasms, HEBON Investigators, GEMO Study Collaborators, AOCS Group, CZECANCA Consortium, Consortium of Investigators of Modifiers of BRCA1/2, Evidence-based Network for the Interpretation of Germline Mutant Alleles Consortium, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundThe distribution of ovarian tumour characteristics differs between germline BRCA1 and BRCA2 pathogenic variant carriers and non-carriers. In this study, we assessed the utility of ovarian tumour characteristics as predictors of BRCA1 and BRCA2 variant pathogenicity, for application using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) variant classification system.MethodsData for 10,373 ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies. Likelihood ratios (LR) were calculated for the association of ovarian cancer histology and other characteristics, with BRCA1 and BRCA2 variant pathogenicity. Estimates were aligned to ACMG/AMP code strengths (supporting, moderate, strong).ResultsNo histological subtype provided informative ACMG/AMP evidence in favour of BRCA1 and BRCA2 variant pathogenicity. Evidence against variant pathogenicity was estimated for the mucinous and clear cell histologies (supporting) and borderline cases (moderate). Refined associations are provided according to tumour grade, invasion and age at diagnosis.ConclusionsWe provide detailed estimates for predicting BRCA1 and BRCA2 variant pathogenicity based on ovarian tumour characteristics. This evidence can be combined with other variant information under the ACMG/AMP classification system, to improve classification and carrier clinical management.

Published
2023

18. Oligogenic Architecture of Rare Noncoding Variants Distinguishes 4 Congenital Heart Disease Phenotypes.

Author

Yu, Mengyao, Aguirre, Matthew, Jia, Meiwen, Gjoni, Ketrin, Cordova-Palomera, Aldo, Munger, Chad, Amgalan, Dulguun, Rosa Ma, X, Pereira, Alexandre, Tcheandjieu, Catherine, Seidman, Christine, Seidman, Jonathan, Tristani-Firouzi, Martin, Chung, Wendy, Goldmuntz, Elizabeth, Loos, Ruth, Chami, Nathalie, Cordell, Heather, Dreßen, Martina, Mueller-Myhsok, Bertram, Lahm, Harald, Krane, Markus, Engreitz, Jesse, Gagliano Taliun, Sarah, Gelb, Bruce, Priest, James, Pollard, Katherine, and Srivastava, Deepak

Subjects
alleles, chromatin, live birth, phenotype, prevalence, Humans, Heart Defects, Congenital, Phenotype, Gene Frequency, Whole Genome Sequencing, Chromatin, Adaptor Proteins, Signal Transducing
Abstract

BACKGROUND: Congenital heart disease (CHD) is highly heritable, but the power to identify inherited risk has been limited to analyses of common variants in small cohorts. METHODS: We performed reimputation of 4 CHD cohorts (n=55 342) to the TOPMed reference panel (freeze 5), permitting meta-analysis of 14 784 017 variants including 6 035 962 rare variants of high imputation quality as validated by whole genome sequencing. RESULTS: Meta-analysis identified 16 novel loci, including 12 rare variants, which displayed moderate or large effect sizes (median odds ratio, 3.02) for 4 separate CHD categories. Analyses of chromatin structure link 13 of the genome-wide significant loci to key genes in cardiac development; rs373447426 (minor allele frequency, 0.003 [odds ratio, 3.37 for Conotruncal heart disease]; P=1.49×10-8) is predicted to disrupt chromatin structure for 2 nearby genes BDH1 and DLG1 involved in Conotruncal development. A lead variant rs189203952 (minor allele frequency, 0.01 [odds ratio, 2.4 for left ventricular outflow tract obstruction]; P=1.46×10-8) is predicted to disrupt the binding sites of 4 transcription factors known to participate in cardiac development in the promoter of SPAG9. A tissue-specific model of chromatin conformation suggests that common variant rs78256848 (minor allele frequency, 0.11 [odds ratio, 1.4 for Conotruncal heart disease]; P=2.6×10-8) physically interacts with NCAM1 (PFDR=1.86×10-27), a neural adhesion molecule acting in cardiac development. Importantly, while each individual malformation displayed substantial heritability (observed h2 ranging from 0.26 for complex malformations to 0.37 for left ventricular outflow tract obstructive disease) the risk for different CHD malformations appeared to be separate, without genetic correlation measured by linkage disequilibrium score regression or regional colocalization. CONCLUSIONS: We describe a set of rare noncoding variants conferring significant risk for individual heart malformations which are linked to genes governing cardiac development. These results illustrate that the oligogenic basis of CHD and significant heritability may be linked to rare variants outside protein-coding regions conferring substantial risk for individual categories of cardiac malformation.

Published
2023

19. Contribution of Previously Unrecognized RNA Splice-Altering Variants to Congenital Heart Disease.

Author

Jang, Min, Patel, Parth, Pereira, Alexandre, Willcox, Jon, Haghighi, Alireza, Tai, Angela, Ito, Kaoru, Morton, Sarah, Gorham, Joshua, McKean, David, DePalma, Steven, Bernstein, Daniel, Brueckner, Martina, Chung, Wendy, Giardini, Alessandro, Goldmuntz, Elizabeth, Kaltman, Jonathan, Kim, Richard, Newburger, Jane, Shen, Yufeng, Tristani-Firouzi, Martin, Gelb, Bruce, Porter, George, Seidman, Christine, Seidman, Jonathan, and Srivastava, Deepak

Subjects
RNA splicing, algorithms, alleles, child, humans, Child, Humans, RNA, Heart Defects, Congenital, Mutation, RNA Splicing, Gene Frequency, RNA Splicing Factors, Repressor Proteins
Abstract

BACKGROUND: Known genetic causes of congenital heart disease (CHD) explain

Published
2023

20. Engineered cardiac tissue model of restrictive cardiomyopathy for drug discovery.

Author

Wang, Bryan, Nash, Trevor, Zhang, Xiaokan, Rao, Jenny, Abriola, Laura, Kim, Youngbin, Zakharov, Sergey, Kim, Michael, Luo, Lori, Morsink, Margaretha, Lock, Roberta, Fleischer, Sharon, Tamargo, Manuel, Bohnen, Michael, Welch, Carrie, Chung, Wendy, Marx, Steven, Surovtseva, Yulia, Vunjak-Novakovic, Gordana, Fine, Barry, and Liu, Bohao

Subjects
FLNC, high throughput drug screen, induced pluripotent stem cell, restrictive cardiomyopathy, tissue engineering, Humans, Cardiomyopathy, Restrictive, Tissue Engineering, Myocytes, Cardiac, Myocardium, Drug Discovery
Abstract

Restrictive cardiomyopathy (RCM) is defined as increased myocardial stiffness and impaired diastolic relaxation leading to elevated ventricular filling pressures. Human variants in filamin C (FLNC) are linked to a variety of cardiomyopathies, and in this study, we investigate an in-frame deletion (c.7416_7418delGAA, p.Glu2472_Asn2473delinAsp) in a patient with RCM. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) with this variant display impaired relaxation and reduced calcium kinetics in 2D culture when compared with a CRISPR-Cas9-corrected isogenic control line. Similarly, mutant engineered cardiac tissues (ECTs) demonstrate increased passive tension and impaired relaxation velocity compared with isogenic controls. High-throughput small-molecule screening identifies phosphodiesterase 3 (PDE3) inhibition by trequinsin as a potential therapy to improve cardiomyocyte relaxation in this genotype. Together, these data demonstrate an engineered cardiac tissue model of RCM and establish the translational potential of this precision medicine approach to identify therapeutics targeting myocardial relaxation.

Published
2023

21. Selection, optimization and validation of ten chronic disease polygenic risk scores for clinical implementation in diverse US populations

Author

Lennon, Niall J., Kottyan, Leah C., Kachulis, Christopher, Abul-Husn, Noura S., Arias, Josh, Belbin, Gillian, Below, Jennifer E., Berndt, Sonja I., Chung, Wendy K., Cimino, James J., Clayton, Ellen Wright, Connolly, John J., Crosslin, David R., Dikilitas, Ozan, Velez Edwards, Digna R., Feng, QiPing, Fisher, Marissa, Freimuth, Robert R., Ge, Tian, Glessner, Joseph T., Gordon, Adam S., Patterson, Candace, Hakonarson, Hakon, Harden, Maegan, Harr, Margaret, Hirschhorn, Joel N., Hoggart, Clive, Hsu, Li, Irvin, Marguerite R., Jarvik, Gail P., Karlson, Elizabeth W., Khan, Atlas, Khera, Amit, Kiryluk, Krzysztof, Kullo, Iftikhar, Larkin, Katie, Limdi, Nita, Linder, Jodell E., Loos, Ruth J. F., Luo, Yuan, Malolepsza, Edyta, Manolio, Teri A., Martin, Lisa J., McCarthy, Li, McNally, Elizabeth M., Meigs, James B., Mersha, Tesfaye B., Mosley, Jonathan D., Musick, Anjene, Namjou, Bahram, Pai, Nihal, Pesce, Lorenzo L., Peters, Ulrike, Peterson, Josh F., Prows, Cynthia A., Puckelwartz, Megan J., Rehm, Heidi L., Roden, Dan M., Rosenthal, Elisabeth A., Rowley, Robb, Sawicki, Konrad Teodor, Schaid, Daniel J., Smit, Roelof A. J., Smith, Johanna L., Smoller, Jordan W., Thomas, Minta, Tiwari, Hemant, Toledo, Diana M., Vaitinadin, Nataraja Sarma, Veenstra, David, Walunas, Theresa L., Wang, Zhe, Wei, Wei-Qi, Weng, Chunhua, Wiesner, Georgia L., Yin, Xianyong, and Kenny, Eimear E.

Published
2024
Full Text
View/download PDF

24. Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry

Author

Mueller, Stefanie H, Lai, Alvina G, Valkovskaya, Maria, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Lush, Michael, Abu-Ful, Zomoruda, Ahearn, Thomas U, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Augustinsson, Annelie, Baert, Thais, Freeman, Laura E Beane, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Bonanni, Bernardo, Brenner, Hermann, Brucker, Sara Y, Buys, Saundra S, Castelao, Jose E, Chan, Tsun L, Chang-Claude, Jenny, Chanock, Stephen J, Choi, Ji-Yeob, Chung, Wendy K, Colonna, Sarah V, Cornelissen, Sten, Couch, Fergus J, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dörk, Thilo, Dossus, Laure, Dwek, Miriam, Eccles, Diana M, Ekici, Arif B, Eliassen, A Heather, Engel, Christoph, Evans, D Gareth, Fasching, Peter A, Fletcher, Olivia, Flyger, Henrik, Gago-Dominguez, Manuela, Gao, Yu-Tang, García-Closas, Montserrat, García-Sáenz, José A, Genkinger, Jeanine, Gentry-Maharaj, Aleksandra, Grassmann, Felix, Guénel, Pascal, Gündert, Melanie, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Harkness, Elaine F, Harrington, Patricia A, Hartikainen, Jaana M, Hartman, Mikael, Hein, Alexander, Ho, Weang-Kee, Hooning, Maartje J, Hoppe, Reiner, Hopper, John L, Houlston, Richard S, Howell, Anthony, Hunter, David J, Huo, Dezheng, Ito, Hidemi, Iwasaki, Motoki, Jakubowska, Anna, Janni, Wolfgang, John, Esther M, Jones, Michael E, Jung, Audrey, Kaaks, Rudolf, Kang, Daehee, Khusnutdinova, Elza K, Kim, Sung-Won, Kitahara, Cari M, Koutros, Stella, Kraft, Peter, Kristensen, Vessela N, Kubelka-Sabit, Katerina, Kurian, Allison W, Kwong, Ava, Lacey, James V, Lambrechts, Diether, and Le Marchand, Loic

Subjects
Breast Cancer, Genetics, Clinical Research, Cancer, Aetiology, 2.1 Biological and endogenous factors, Humans, Female, Breast Neoplasms, Genetic Predisposition to Disease, Black People, Genetic Testing, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Formins, Breast cancer susceptibility, Diverse ancestry, Rare variants, Gene regulation, Genome-wide association study, NBCS Collaborators, CTS Consortium, ABCTB Investigators, Clinical Sciences
Abstract

BackgroundLow-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes.MethodsWe evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry.ResultsIn European ancestry samples, 14 genes were significantly associated (q

Published
2023

25. Frameshift variants in C10orf71 cause dilated cardiomyopathy in human, mouse, and organoid models

Author

Li, Yang, Ma, Ke, Dong, Zhujun, Gao, Shijuan, Zhang, Jing, Huang, Shan, Yang, Jie, Fang, Guangming, Li, Yujie, Li, Xiaowei, Welch, Carrie, Griffin, Emily L., Ramaswamy, Prema, Valivullah, Zaheer, Liu, Xiuying, Dong, Jianzeng, Wang, Dao Wen, Du, Jie, Chung, Wendy K., and Li, Yulin

Subjects
Heart diseases -- Models -- Causes of -- Genetic aspects, Organs, Culture of -- Research, Cardiovascular research, Genetic variation -- Research, Mice -- Research, Cardiomyopathy -- Models -- Causes of -- Genetic aspects, Health care industry
Abstract

Research advances over the past 30 years have confirmed a critical role for genetics in the etiology of dilated cardiomyopathies (DCMs). However, full knowledge of the genetic architecture of DCM remains incomplete. We identified candidate DCM causal gene, C10orf71, in a large family with 8 patients with DCM by whole-exome sequencing. Four loss-of-function variants of C10orf71 were subsequently identified in an additional group of492 patients with sporadic DCM from 2 independent cohorts. C10orf71 was found to be an intrinsically disordered protein specifically expressed in cardiomyocytes. C10orf71-KO mice had abnormal heart morphogenesis during embryonic development and cardiac dysfunction as adults with altered expression and splicing of contractile cardiac genes. C10orf71-null cardiomyocytes exhibited impaired contractile function with unaffected sarcomere structure. Cardiomyocytes and heart organoids derived from human induced pluripotent stem cells with C10orf71 frameshift variants also had contractile defects with normal electrophysiological activity. A rescue study using a cardiac myosin activator, omecamtiv mecarbil, restored contractile function in C10orf71-KO mice. These data support C10orf71 as a causal gene for DCM by contributing to the contractile function of cardiomyocytes. Mutation-specific pathophysiology may suggest therapeutic targets and more individualized therapy., Introduction Cardiomyopathies are a heterogeneous group of cardiac disorders with primary abnormalities in the structure and function of the heart (1). These disorders are commonly divided into primary--including hypertrophic, dilated, [...]

Published
2024
Full Text
View/download PDF

26. List of Contributors

Author

Agrawal, Pankaj B., primary, Akhtar, Yasmin, additional, Alallah, Jubara, additional, Alhassen, Ziad, additional, Altit, Gabriel, additional, AlZubaidi, Abbas, additional, Amlani, Lahin M., additional, Antelo, Martin, additional, Athalye-Jape, Gayatri, additional, Badarch, Jargalsaikhan, additional, Baer, Gerri, additional, Bagga, Nitasha, additional, Bahr, Timothy M., additional, Bar-Cohen, Yaniv, additional, M. Barr, Stephanie, additional, Bauer, Andrew J., additional, Bearer, Cynthia F., additional, Beckman, Ross M., additional, Beltempo, Marc, additional, Bembea, Melania M., additional, Berlin, Sheila, additional, Berry, Shandeigh N., additional, Bhandari, Vineet, additional, Bhatia, Shaifali, additional, Bhombal, Shazia, additional, Bigelow, Elaine O., additional, Blevins, Carley, additional, Boppana, Suresh, additional, Boss, Renee, additional, Brooks, Sandra, additional, Buonocore, Giuseppe, additional, Burnsed, Jennifer, additional, Calabria, Andrew C., additional, Carrasco, Melisa, additional, Carter, Brian S., additional, Chandrasekharan, Praveen, additional, Chavez-Valdez, Raul, additional, Choleva, Lauryn, additional, Christensen, Robert D., additional, Chung, Wendy K., additional, Coggins, Sarah A., additional, Cooke, David W., additional, Cummings, Laura, additional, Currie, Erin R., additional, Davidson, Joanne O., additional, Davis, Jonathan M., additional, Day-Richardson, Colby L., additional, De Leon, Diva D., additional, Dedhia, Kavita, additional, Dendi, Alvaro, additional, Deshpande, Anita, additional, Dionne, Janis M., additional, Donda, Keyur, additional, Donohue, Lee, additional, Doyle, Jefferson J., additional, Dulkerian, Susan J., additional, Dumpa, Vikramaditya, additional, Duncan, Andrea F., additional, Dunham, Alexandra M., additional, Ecret, DiAnn, additional, Ellis, Kelstan, additional, El-Metwally, Dina, additional, Etchill, Eric W., additional, Ethawi, Yahya, additional, Everett, Allen D., additional, Fabres, Jorge, additional, Felling, Ryan J., additional, Fenton, Tanis R., additional, Flannery, Dustin D., additional, Flynn, Joseph T., additional, Fredenburg, Michaelene, additional, Fuqua, John, additional, Garcia, Alejandro V., additional, Garzon, Steven, additional, Gauda, Estelle B., additional, Thompson, Marisa Gilstrop, additional, Goldenberg, Barton, additional, Salazar, Andres J. Gonzalez, additional, Goodwin, Julie E., additional, Goudy, Steven L., additional, Graham, Ernest, additional, Grauerholz, Kathryn, additional, Groves, Mari L., additional, Guillot, Mireille, additional, Gunn, Alistair J., additional, Gupta, Arjun, additional, Hackam, David J., additional, Hidalgo, Joaquin, additional, Honcharuk, Erin, additional, Htun, Zeyar, additional, Hudak, Mark L., additional, Driscoll, Colleen A. Hughes, additional, Huisman, Thierry A.G.M., additional, Jabroun, Mireille, additional, Jackson, Eric M., additional, Jain, Naveen, additional, Jain, Rajesh, additional, Jelin, Angie, additional, Jelin, Eric, additional, Juul, Sandra E., additional, Kaufman, David A., additional, BMBS, Alison Kent,, additional, Khuder, Sundos, additional, Kovler, Mark L., additional, Kraus, Courtney L., additional, Krishnamurthy, Ganga, additional, Kukora, Stephanie K., additional, Kumar, Ashok, additional, Kunisaki, Shaun M., additional, Kuper-Sassé, Margaret, additional, Kwiatkowski, David M., additional, Lakshminrusimha, Satyan, additional, Laventhal, Naomi T., additional, Lawrence, Shelley M., additional, Lee-Winn, Angela E., additional, Leuthner, Steven, additional, Lewallen, Laura, additional, Lewis, Tamorah R., additional, Liken, Hillary B., additional, Liubšys, Arūnas, additional, Lui, Kei, additional, Maheshwari, Akhil, additional, Maitre, Nathalie L., additional, Makker, Kartikeya, additional, Mammen, Cherry, additional, J. Martin, Richard, additional, Mattos Castellano, María, additional, Maxwell, Jessie R., additional, McFarlane, Renske, additional, McLemore, Gabrielle, additional, McNelis, Kera M., additional, McPherson, Christopher, additional, Mietzsch, Ulrike, additional, Milante, Rachel R., additional, Miller, Jena L., additional, Mukhopadhyay, Sagori, additional, Mynak, Mimi L., additional, Nasr, Isam W., additional, Natarajan, Niranjana, additional, Navaneethan, Hema, additional, Nees, Shannon N., additional, Nguyen, Mai, additional, Noori, Shahab, additional, Odackal, Namrita J., additional, Ohls, Robin K., additional, Ostrander, Betsy E., additional, Pammi, Mohan, additional, Parimi, Prabhu S., additional, Park, Albert, additional, Patil, Monika S., additional, Pereira, Elaine M., additional, Premkumar, Muralidhar H., additional, Price-Douglas, Webra, additional, Puopolo, Karen M., additional, Rabe, Heike, additional, M. Rahman, Mohammad, additional, Reber, Kristina, additional, Kallem, Venkat Reddy, additional, Repka, Michael X., additional, Rhee, Daniel S., additional, Ringle, Megan L., additional, Rohrer, Allison, additional, Romero, Christopher J., additional, Ryan, Marisa A., additional, Sampah, Maame E.S., additional, Sanchez-Valle, Amarilis, additional, Sant’Anna, Guilherme M., additional, Saugstad, Ola D., additional, RobertH., Anne and, additional, Schacht, John P., additional, Schelonka, Robert L., additional, Schofield, Erin E., additional, Selewski, David T., additional, Shah, Prakesh S., additional, Shih, Jessica G., additional, Sibinga, Erica M.S., additional, Sigal, Winnie, additional, Sims, Brian, additional, Singh, Rachana, additional, Singh, Srijan, additional, Snyder, Donna, additional, Sobrero, Helena, additional, Sponseller, Paul D., additional, Stafstrom, Carl E., additional, Steflik, Heidi J., additional, Sun, Lisa R., additional, Sundararajan, Sripriya, additional, Taylor, Sarah N., additional, Terrin, Norma, additional, Thacker, Prolima G., additional, Thébaud, Bernard, additional, Toms, Rune, additional, Torres, Benjamin A., additional, Tunkel, David E., additional, Umandap, Christine H., additional, Chaves, Diana Vargas, additional, Vento, Maximo, additional, Walsh, Jonathan, additional, Walter, Jolan, additional, Weaver, Meaghann S., additional, Weimer, Kristin, additional, Weller, Jennine, additional, Winter, Lindy W., additional, Wu, Tai-Wei, additional, and Yau, Mabel, additional

Published
2024
Full Text
View/download PDF

29. Correction: Expanded phenotypic spectrum of neurodevelopmental and neurodegenerative disorder Bryant-Li-Bhoj syndrome with 38 additional individuals

Author

Layo-Carris, Dana E., Lubin, Emily E., Sangree, Annabel K., Clark, Kelly J., Durham, Emily L., Gonzalez, Elizabeth M., Smith, Sarina, Angireddy, Rajesh, Wang, Xiao Min, Weiss, Erin, Toutain, Annick, Mendoza-Londono, Roberto, Dupuis, Lucie, Damseh, Nadirah, Velasco, Danita, Valenzuela, Irene, Codina-Solà, Marta, Ziats, Catherine, Have, Jaclyn, Clarkson, Katie, Steel, Dora, Kurian, Manju, Barwick, Katy, Carrasco, Diana, Dagli, Aditi I., Nowaczyk, M. J. M., Hančárová, Miroslava, Bendová, Šárka, Prchalova, Darina, Sedláček, Zdeněk, Baxová, Alica, Nowak, Catherine Bearce, Douglas, Jessica, Chung, Wendy K., Longo, Nicola, Platzer, Konrad, Klöckner, Chiara, Averdunk, Luisa, Wieczorek, Dagmar, Krey, Ilona, Zweier, Christiane, Reis, Andre, Balci, Tugce, Simon, Marleen, Kroes, Hester Y., Wiesener, Antje, Vasileiou, Georgia, Marinakis, Nikolaos M., Veltra, Danai, Sofocleous, Christalena, Kosma, Konstantina, Synodinos, Joanne Traeger, Voudris, Konstantinos A., Vuillaume, Marie-Laure, Gueguen, Paul, Derive, Nicolas, Colin, Estelle, Battault, Clarisse, Au, Billie, Delatycki, Martin, Wallis, Mathew, Gallacher, Lyndon, Majdoub, Fatma, Smal, Noor, Weckhuysen, Sarah, Schoonjans, An-Sofie, Kooy, R. Frank, Meuwissen, Marije, Cocanougher, Benjamin T., Taylor, Kathryn, Pizoli, Carolyn E., McDonald, Marie T., James, Philip, Roeder, Elizabeth R., Littlejohn, Rebecca, Borja, Nicholas A., Thorson, Willa, King, Kristine, Stoeva, Radka, Suerink, Manon, Nibbeling, Esther, Baskin, Stephanie, Guyader, Gwenaël L. E., Kaplan, Julie, Muss, Candace, Carere, Deanna Alexis, Bhoj, Elizabeth J. K., and Bryant, Laura M.

Published
2024
Full Text
View/download PDF

30. Integrated gene analyses of de novo variants from 46,612 trios with autism and developmental disorders

Author

Wang, Tianyun, Kim, Chang N, Bakken, Trygve E, Gillentine, Madelyn A, Henning, Barbara, Mao, Yafei, Gilissen, Christian, Consortium, The SPARK, Nowakowski, Tomasz J, Eichler, Evan E, Acampado, John, Ace, Andrea J, Amatya, Alpha, Astrovskaya, Irina, Bashar, Asif, Brooks, Elizabeth, Butler, Martin E, Cartner, Lindsey A, Chin, Wubin, Chung, Wendy K, Daniels, Amy M, Feliciano, Pamela, Fleisch, Chris, Ganesan, Jensen, William, Lash, Alex E, Marini, Richard, Myers, Vincent J, O'Connor, Eirene, Rigby, Chris, Robertson, Beverly E, Shah, Neelay, Shah, Swapnil, Singer, Emily, Snyder, LeeAnne G, Stephens, Alexandra N, Tjernagel, Jennifer, Vernoia, Brianna M, Volfovsky, Natalia, White, Loran Casey, Hsieh, Alexander, Shen, Yufeng, Zhou, Xueya, Turner, Tychele N, Bahl, Ethan, Thomas, Taylor R, Brueggeman, Leo, Koomar, Tanner, Michaelson, Jacob J, O'Roak, Brian J, Barnard, Rebecca A, Gibbs, Richard A, Muzny, Donna, Sabo, Aniko, Ahmed, Kelli L Baalman, Siegel, Matthew, Abbeduto, Leonard, Amaral, David G, Hilscher, Brittani A, Li, Deana, Smith, Kaitlin, Thompson, Samantha, Albright, Charles, Butter, Eric M, Eldred, Sara, Hanna, Nathan, Jones, Mark, Coury, Daniel Lee, Scherr, Jessica, Pifher, Taylor, Roby, Erin, Dennis, Brandy, Higgins, Lorrin, Brown, Melissa, Alessandri, Michael, Gutierrez, Anibal, Hale, Melissa N, Herbert, Lynette M, Schneider, Hoa Lam, David, Giancarla, Annett, Robert D, Sarver, Dustin E, Arriaga, Ivette, Camba, Alexies, Gulsrud, Amanda C, Haley, Monica, McCracken, James T, Sandhu, Sophia, Tafolla, Maira, Yang, Wha S, Carpenter, Laura A, Bradley, Catherine C, Gwynette, Frampton, Manning, Patricia, Shaffer, Rebecca, Thomas, Carrie, Bernier, Raphael A, Fox, Emily A, and Gerdts, Jennifer A

Subjects
Biological Sciences, Genetics, Mental Health, Intellectual and Developmental Disabilities (IDD), Biotechnology, Pediatric, Autism, Brain Disorders, Mental health, Child, Male, Female, Humans, Autistic Disorder, Autism Spectrum Disorder, Developmental Disabilities, Genetic Predisposition to Disease, Exome, Histone Deacetylases, Repressor Proteins, Carrier Proteins, de novo variants, neurodevelopmental disorder, protein-protein interaction, single-nuclei transcriptome, SPARK Consortium, protein–protein interaction
Abstract

Most genetic studies consider autism spectrum disorder (ASD) and developmental disorder (DD) separately despite overwhelming comorbidity and shared genetic etiology. Here, we analyzed de novo variants (DNVs) from 15,560 ASD (6,557 from SPARK) and 31,052 DD trios independently and also combined as broader neurodevelopmental disorders (NDDs) using three models. We identify 615 NDD candidate genes (false discovery rate [FDR] < 0.05) supported by ≥1 models, including 138 reaching Bonferroni exome-wide significance (P < 3.64e-7) in all models. The genes group into five functional networks associating with different brain developmental lineages based on single-cell nuclei transcriptomic data. We find no evidence for ASD-specific genes in contrast to 18 genes significantly enriched for DD. There are 53 genes that show mutational bias, including enrichments for missense (n = 41) or truncating (n = 12) DNVs. We also find 10 genes with evidence of male- or female-bias enrichment, including 4 X chromosome genes with significant female burden (DDX3X, MECP2, WDR45, and HDAC8). This large-scale integrative analysis identifies candidates and functional subsets of NDD genes.

Published
2022

31. Body mass index rebound and pubertal timing in girls with and without a family history of breast cancer: the LEGACY girls study.

Author

Houghton, Lauren C, Wei, Ying, Wang, Tianying, Goldberg, Mandy, Paniagua-Avila, Alejandra, Sweeden, Rachel L, Bradbury, Angela, Daly, Mary, Schwartz, Lisa A, Keegan, Theresa, John, Esther M, Knight, Julia A, Andrulis, Irene L, Buys, Saundra S, Frost, Caren J, O'Toole, Karen, White, Melissa L, Chung, Wendy K, and Terry, Mary Beth

Subjects
Breast Cancer, Prevention, Contraception/Reproduction, Obesity, Pediatric, Cancer, Clinical Research, Body Mass Index, Breast, Breast Neoplasms, Child, Child, Preschool, Female, Humans, Menarche, Puberty, Growth, puberty, BMI, adiposity rebound, Statistics, Public Health and Health Services, Epidemiology
Abstract

BackgroundHeavier body mass index (BMI) is the most established predictor of earlier age at puberty. However, it is unknown whether the timing of the childhood switch to heavier BMI (age at BMI rebound) also matters for puberty.MethodsIn the LEGACY Girls Study (n = 1040), a longitudinal cohort enriched with girls with a family history of breast cancer, we collected paediatric growth chart data from 852 girls and assessed pubertal development every 6 months. Using constrained splines, we interpolated individual growth curves and then predicted BMI at ages 2, 4, 6, 8 and 9 years for 591 girls. We defined age at BMI rebound as the age at the lowest BMI between ages 2 and 8 years and assessed its association with onset of thelarche, pubarche and menarche using Weibull survival models.ResultsThe median age at BMI rebound was 5.3 years (interquartile range: 3.6-6.7 years). A 1-year increase in age at BMI rebound was associated with delayed thelarche (HR = 0.90; 95% CI = 0.83-0.97) and menarche (HR = 0.86; 95% CI = 0.79-0.94). The magnitude of these associations remained after adjusting for weight between birth and 2 years, was stronger after adjusting for BMI at age 9, and was stronger in a subset of girls with clinically assessed breast development.ConclusionsEarlier BMI rebound is associated with earlier pubertal timing. Our observation that BMI rebound may be a driver of pubertal timing in girls with and without a family history of breast cancer provides insight into how growth and pubertal timing are associated with breast cancer risk.

Published
2022

32. Identifying phenotypic expansions for congenital diaphragmatic hernia plus (CDH+) using DECIPHER data.

Author

Hardcastle, Amy, Berry, Aliska, Campbell, Ian, Zhao, Xiaonan, Liu, Pengfei, Gerard, Amanda, Rosenfeld, Jill, Sisoudiya, Saumya, Hernandez-Garcia, Andres, Loddo, Sara, Di Tommaso, Silvia, Novelli, Antonio, Dentici, Maria, Capolino, Rossella, Digilio, Maria, Graziani, Ludovico, Rustad, Cecilie, Neas, Katherine, Ferrero, Giovanni, Brusco, Alfredo, Di Gregorio, Eleonora, Wellesley, Diana, Beneteau, Claire, Joubert, Madeleine, Van Den Bogaert, Kris, Boogaerts, Anneleen, McMullan, Dominic, Dean, John, Giuffrida, Maria, Bernardini, Laura, Varghese, Vinod, Shannon, Nora, Harrison, Rachel, Lam, Wayne, McKee, Shane, Turnpenny, Peter, Cole, Trevor, Morton, Jenny, Eason, Jacqueline, Hall, Rebecca, Wright, Michael, Horridge, Karen, Shaw, Chad, Chung, Wendy, Scott, Daryl, and Jones, Marilyn

Subjects
CREBBP, DECIPHER database, SMARCA4, UBA2, USP9X, congenital diaphragmatic hernia, Animals, DNA Copy Number Variations, Diaphragm, Hernias, Diaphragmatic, Congenital, Mice
Abstract

Congenital diaphragmatic hernia (CDH) can occur in isolation or in conjunction with other birth defects (CDH+). A molecular etiology can only be identified in a subset of CDH cases. This is due, in part, to an incomplete understanding of the genes that contribute to diaphragm development. Here, we used clinical and molecular data from 36 individuals with CDH+ who are cataloged in the DECIPHER database to identify genes that may play a role in diaphragm development and to discover new phenotypic expansions. Among this group, we identified individuals who carried putatively deleterious sequence or copy number variants affecting CREBBP, SMARCA4, UBA2, and USP9X. The role of these genes in diaphragm development was supported by their expression in the developing mouse diaphragm, their similarity to known CDH genes using data from a previously published and validated machine learning algorithm, and/or the presence of CDH in other individuals with their associated genetic disorders. Our results demonstrate how data from DECIPHER, and other public databases, can be used to identify new phenotypic expansions and suggest that CREBBP, SMARCA4, UBA2, and USP9X play a role in diaphragm development.

Published
2022

33. Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers

Author

Hakkaart, Christopher, Pearson, John F, Marquart, Louise, Dennis, Joe, Wiggins, George AR, Barnes, Daniel R, Robinson, Bridget A, Mace, Peter D, Aittomäki, Kristiina, Andrulis, Irene L, Arun, Banu K, Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B, Belhadj, Sami, Berger, Lieke, Blok, Marinus J, Boonen, Susanne E, Borde, Julika, Bradbury, Angela R, Brunet, Joan, Buys, Saundra S, Caligo, Maria A, Campbell, Ian, Chung, Wendy K, Claes, Kathleen BM, Collonge-Rame, Marie-Agnès, Cook, Jackie, Cosgrove, Casey, Couch, Fergus J, Daly, Mary B, Dandiker, Sita, Davidson, Rosemarie, de la Hoya, Miguel, de Putter, Robin, Delnatte, Capucine, Dhawan, Mallika, Diez, Orland, Ding, Yuan Chun, Domchek, Susan M, Donaldson, Alan, Eason, Jacqueline, Easton, Douglas F, Ehrencrona, Hans, Engel, Christoph, Evans, D Gareth, Faust, Ulrike, Feliubadaló, Lidia, Fostira, Florentia, Friedman, Eitan, Frone, Megan, Frost, Debra, Garber, Judy, Gayther, Simon A, Gehrig, Andrea, Gesta, Paul, Godwin, Andrew K, Goldgar, David E, Greene, Mark H, Hahnen, Eric, Hake, Christopher R, Hamann, Ute, Hansen, Thomas VO, Hauke, Jan, Hentschel, Julia, Herold, Natalie, Honisch, Ellen, Hulick, Peter J, Imyanitov, Evgeny N, Isaacs, Claudine, Izatt, Louise, Izquierdo, Angel, Jakubowska, Anna, James, Paul A, Janavicius, Ramunas, John, Esther M, Joseph, Vijai, Karlan, Beth Y, Kemp, Zoe, Kirk, Judy, Konstantopoulou, Irene, Koudijs, Marco, Kwong, Ava, Laitman, Yael, Lalloo, Fiona, Lasset, Christine, Lautrup, Charlotte, Lazaro, Conxi, Legrand, Clémentine, Leslie, Goska, Lesueur, Fabienne, Mai, Phuong L, Manoukian, Siranoush, Mari, Véronique, Martens, John WM, McGuffog, Lesley, Mebirouk, Noura, Meindl, Alfons, Miller, Austin, and Montagna, Marco

Subjects
Human Genome, Prevention, Breast Cancer, Cancer, Genetics, Aetiology, 2.1 Biological and endogenous factors, BRCA1 Protein, BRCA2 Protein, Breast Neoplasms, DNA Copy Number Variations, Female, Genetic Predisposition to Disease, Heterozygote, Humans, RNA, Messenger, GEMO Study Collaborators, EMBRACE Collaborators, SWE-BRCA Investigators, kConFab Investigators, HEBON Investigators
Abstract

The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.

Published
2022

34. Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes

Author

Zhou, Xueya, Feliciano, Pamela, Shu, Chang, Wang, Tianyun, Astrovskaya, Irina, Hall, Jacob B, Obiajulu, Joseph U, Wright, Jessica R, Murali, Shwetha C, Xu, Simon Xuming, Brueggeman, Leo, Thomas, Taylor R, Marchenko, Olena, Fleisch, Christopher, Barns, Sarah D, Snyder, LeeAnne Green, Han, Bing, Chang, Timothy S, Turner, Tychele N, Harvey, William T, Nishida, Andrew, O’Roak, Brian J, Geschwind, Daniel H, Michaelson, Jacob J, Volfovsky, Natalia, Eichler, Evan E, Shen, Yufeng, and Chung, Wendy K

Subjects
Pediatric Research Initiative, Genetics, Intellectual and Developmental Disabilities (IDD), Autism, Clinical Research, Genetic Testing, Pediatric, Mental Health, Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Autism Spectrum Disorder, Autistic Disorder, Exome, Forkhead Transcription Factors, Genetic Predisposition to Disease, Humans, Mutation, Repressor Proteins, Exome Sequencing, SPARK Consortium, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

To capture the full spectrum of genetic risk for autism, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 autism cases, including 35,130 new cases recruited online by SPARK. We identified 60 genes with exome-wide significance (P

Published
2022

35. Common variants increase risk for congenital diaphragmatic hernia within the context of de novo variants

Author

Qiao, Lu, Welch, Carrie L., Hernan, Rebecca, Wynn, Julia, Krishnan, Usha S., Zalieckas, Jill M., Buchmiller, Terry, Khlevner, Julie, De, Aliva, Farkouh-Karoleski, Christiana, Wagner, Amy J., Heydweiller, Andreas, Mueller, Andreas C., de Klein, Annelies, Warner, Brad W., Maj, Carlo, Chung, Dai, McCulley, David J., Schindel, David, Potoka, Douglas, Fialkowski, Elizabeth, Schulz, Felicitas, Kipfmuller, Florian, Lim, Foong-Yen, Magielsen, Frank, Mychaliska, George B., Aspelund, Gudrun, Reutter, Heiko Martin, Needelman, Howard, Schnater, J. Marco, Fisher, Jason C., Azarow, Kenneth, Elfiky, Mahmoud, Nöthen, Markus M., Danko, Melissa E., Li, Mindy, Kosiński, Przemyslaw, Wijnen, Rene M.H., Cusick, Robert A., Soffer, Samuel Z., Cochius-Den Otter, Suzan C.M., Schaible, Thomas, Crombleholme, Timothy, Duron, Vincent P., Donahoe, Patricia K., Sun, Xin, High, Frances A., Bendixen, Charlotte, Brosens, Erwin, Shen, Yufeng, and Chung, Wendy K.

Published
2024
Full Text
View/download PDF

36. Return of genetic research results in 21,532 individuals with autism

Author

Aarrestad, Alexandria, Abbeduto, Leonard, Aberbach, Gabriella, Aberle, Shelley, Adegbite, Adediwura, Adeniji, Debbie, Aguilar, Maria, Ahlers, Kaitlyn, Albright, Charles, Alessandri, Michael, Algaze, Zach, Alkazi, Jasem, Amador, Raquel, Amaral, David, Amon, Logan, Amundsen, Leonor, Andrus, Alicia, Anglo, Claudine, Annett, Robert, Arar, Adam, Arnold, Jonathan, Arriaga, Ivette, Arzate, Eduardo, Ashley, Raven, Aslamy, Leilemah, Baalman, Kelli, Baer, Melissa, Bahi, Ethan, Bailey, Joshua, Baldlock, Zachary, Banks, Grabrielle, Baraghoshi, Gabriele, Bardett, Nicole, Barrett, Mallory, Bartholomew, Yan, Bates, Heidi, Beard, Katie, Becerra, Juana, Beckwith, Malia, Beechan, Paige, Beeson, Landon, Beeson, Josh, Bell, Brandi, Belli, Monica, Bentley, Dawn, Berger, Natalie, Berman, Anna, Bernier, Raphael, Berry-Kravis, Elizabeth, Berwanger, Mary, Birdwell, Shelby, Blank, Elizabeth, Bond, Rebecca, Booker, Stephanie, Bordofsky, Aniela, Bower, Erin, Bowers, Lukas, Bradley, Catherine, Brayer, Heather, Brewster, Stephanie, Brown, Hallie, Brown, Alison, Brown, Melissa, Buck, Catherine, Buescher, Cate, Bullon, Kayleigh, Buraima, Joy, Butter, Eric, Caamano, Amalia, Cacciato, Nicole, CaI, Wenteng, Calderon, Norma, Callahan, Kristen, Camba, Alexies, Campo-Soria, Claudia, Caprara, Giuliana, Carbone, Paul, Carpenter, Laura, Carpenter, Sarah, Casseus, Myriam, Casten, Lucas, Catherine, Sullivan, Chappo, Ashley, Chavez, Kimberly, Cheathem-Johnson, Randi, Chen, Tia, Chintalapalli, Sharmista, Cho, Daniel, Choi, Y.B., Clark, Nia, Clark, Renee, Coffman, Marika, Coleman, Laura, Coleman, Kendra, Collins, Alister, Columbi, Costanza, Comitre, Joaquin, Constant, Stephanie, Contra, Arin, Conyers, Sarah, Cooper, Lindsey, Cooper, Cameron, Coppola, Leigh, Corlett, Allison, Corrales, Lady, Correa, Dahriana, Cottrell, Hannah, Coughlin, Michelle, Courchesne, Eric, Coury, Dan, Crocetti, Deana, Croson, Carrie, Crowell, Judith, Cubells, Joseph, Cunningham, Sean, Currin, Mary, Cutri, Michele, D'Ambrosi, Sophia, David, Giancarla, Davis, Ayana, Davis, Sabrina, Decius, Nickelle, Delaporte, Jennifer, DeMarco, Lindsey, Dennis, Brandy, Deronda, Alyssa, Dhawan, Esha, Dichter, Gabriel, Doan, Ryan, Dominick, Kelli, Ortega, Leonardo Dominquez, Doyle, Erin, Drayton, Andrea, DuBois, Megan, Dudley, Johnny, Duhon, Gabrielle, Duncan, Grabrielle, Duncan, Amie, Dunlevy, Megan, Dyer, Meaghan, Earl, Rachel, Edmonson, Catherine, Eldred, Sara, Elliott, Nelita, Emery, Brooke, Enright, Barbara, Erb, Sarah, Erickson, Craig, Esler, Amy, Estevez, Liza, Fanta, Anne, Fassler, Carrie, Fatemi, Ali, Fazal, Faris, Featherston, Marilyn, Ferguson, Jonathan, Fish, Angela, Fitzgerald, Kate, Flores, Kathleen, Fombonne, Eric, Foster, Margaret, Fowler, Tiffany, Fox, Emma, Fox, Emily, Francis, Sunday, Frayne, Margot, Froman, Sierra, Fuller, Laura, Galbraith, Virginia, Gallimore, Dakota, Gambrell, Ariana, Gazestani, Vahid, Geisheker, Madeleine R., Gerdts, Jennifer, Geschwind, Daniel, Ghaziuddin, Mohammad, Ghina, Haidar, Given, Erin, Goetz, Mykayla, Gong, Jared, Gonring, Kelsey, Gonzalez, Natalia, Gonzalez, Antonio, Goodwill, Ellie, Gordon, Rachel, Graham, Carter, Gray, Catherine, Grimes, Ellen, Griswold, Anthony, Gu, Pan, Guilfoyle, Janna, Gulsrud, Amanda, Gunderson, Jaclyn, Gunter, Chris, Gupta, Sanya, Gupta, Abha, Gutierrez, Anibal, Gwynette, Frampton, Haidar, Ghina, Hale, Melissa, Haley, Monica, Hall, Lauren K., Hamer, Kira, Hamilton, Piper, Hanna, Nathan, Hardan, Antonio, Harkins, Christina, Harrell, Eldric, Harris, Jill, Harris, Nina, Hayes, Caitlin, Hayse, Braden, Heckers, Teryn, Heerwagen, Kathryn, Hennelly, Daniela, Herbert, Lynette, Hermle, Luke, Hernandez, Briana, Herrera, Clara, Hess, Amy, Heyman, Michelle, Higgins, Lorrin, Phillips, Brittani Hilscher, Hirst, Kathy, Ho, Theodore, Hoffman, Emily, Hojlo, Margaret, Honaker, Makayla, Hong, Michael, Hooks, Gregory, Horner, Susannah, Horton, Danielle, Hounchell, Melanie, Howes, Dain, Huang-Storm, Lark, Hunter, Samantha, Hutter, Hanna, Hyde, Emily, Ibanez, Teresa, Ingram, Kelly, Istephanous, Dalia, Jacob, Suma, Jarratt, Andrea, Jelinek, Anna, Johnson, Mary, Jones, Mya, Jones, Garland, Jones, Mark, Jorgenson, Alissa, Judge, Jessyca, Kalb, Luther, Kalmus, Taylor, Kang, Sungeun, Kangas, Elizabeth, Kanne, Stephen, Kaplan, Hannah, Khan, Sara, Kim, Sophy, Kim, Annes, Kitaygordsky, Alex, Klaiman, Cheryl, Klever, Adam, Koene, Hope, Koomar, Tanner, Koza, Melinda, Kramer, Sydney, Krushena, Meghan, Kurtz-Nelson, Eva, Lamarche, Elena, Lampert, Erica, Lamy, Martine, Landa, Rebecca, Lebron-Cruz, Alexa, Lechniak, Holly, Lee, Soo, Leight, Bruce, Lerner, Matthew, Lesher, Laurie, Lewis, Courtney, Li, Hai, Li, Deana, Libove, Robin, Lillie, Natasha, Limon, Danica, Limpoco, Desi, Lin, Melody, Littlefield, Sandy, Lobisi, Brandon, Locarno, Laura, Long, Nancy, Long, Bailey, Long, Kennadie, Lopez, Marilyn, Lovering, Taylor, Lozano, Ivana, Lucio, Daniella, Luo, Addie, Luu, My-Linh, Lyon, Audrey, Ma, Julia, Madi, Natalie, Malloch, Lacy, Mankaryous, Reanna, Manning, Patricia, Mantey, Alvin, Marini, Richard, Marsden, Alexandra, Marwali, Clarissa, Marzano, Gabriela, Mason, Andrew, Mastel, Sarah, Mathai, Sheena, Matthews, Emily, Matusoff, Emma, Maxim, Clara, McCarthy, Caitlin, McClellen, Lynn, Mccoy, Nicole, McCullough, Kaylen, McDonald, Brooke, McGalliard, Julie, McIntyre, Anne-Marie, McKenna, Brooke, McKenzie, Alexander, McTaggart, Megan, Meinen, Hannah, Melnyk, Sophia, Miceli, Alexandra, Michaels, Sarah, Michaelson, Jacob, Milan, Estefania, Miller, Melissa, Milliken, Anna, Minton, Kyla, Mitchell, Terry, Gunn, Amanda Moffitt, Mohiuddin, Sarah, Money, Gina, Montezuma, Jessie, Mooney, Lindsey, Moore, Margo, Morales-Lara, Amy, Morgan, Kelly, Morotti, Hadley, Morrier, Michael, Munoz, Maria, Lavanderos, Ambar Munoz, Murali, Shwetha, Murillo, Karla, Murray, Kailey, Myhre, Erin, Neely, Jason, Neuhaus, Emily, Newman, Olivia, Nguyen, Richard, Nguyen, Victoria, Nichols, Evelyn, Nicholson, Amy, Niederhauser, Melanie, Norris, Megan, Norton, Shai, Nowell, Kerri, O’Brien, Kaela, O’Meara, Mitchell, O’Neil, Molly, O'Roak, Brian, Ocampo, Edith, Ochoa-Lubinoff, Cesar, Oft, Anna, Orobio, Jessica, Ortiz, Crissy, Ousley, Opal, Oyeyemi, Motunrayo, Pacheco, Lillian, Palacios, Valeria, Palmer, Samiza, Palmeri, Isabella, Pama, Katrina, Pandey, Juhi, Paolicelli, Anna Marie, Parker, Jaylaan, Patterson, Morgan, Pawlowski, Katherine, Pedapati, Ernest, Pepper, Michah, Perrin, Jeremy, Peura, Christine, Phillips, Diamond, Pierce, Karen, Piven, Joseph, Plate, Juhi, Polanco, Jose, Pott-Schmidt, Natalie, Pramparo, Tiziano, Pratt, Taleen, Prock, Lisa, White, Stormi Pulver, Qi, Hongjian, Qiu, Shanping, Queen, Eva, Questel, Marcia, Quinones, Ashley, Rambeck, Desiree, Randall, Shelley, Ranganathan, Vaikunt, Raymond, Laurie, Rayos, Madelyn, Real, Kelly, Rhea, Anna, Rice, Catherine, Richardson, Harper, Riffle, Stacy, Robertson, Tracy, Roby, Erin, Rocha, Ana, Roche, Casey, Rodriguez, Nicki, Rodriguez, Bianca, Roeder, Katherine, Rojas, Daniela, Rosewater, Jacob, Rosselott, Hilary, Runyan, Payton, Russo, Nicole, Rutter, Tara, Ruzzo, Elizabeth, Sahin, Mustafa, Salem, Fatima, Sanchez, Rebecca, Sanders, Muave, Sanderson, Tayler, Sandhu, Sophie, Sanford, Katelyn, Santangelo, Susan, Santulli, Madeline, Sarver, Dustin, Savage, Madeline, Scherr, Jessica, Schneider, Hoa, Schools, Hayley, Schoonover, Gregory, Schultz, Robert, Sebolt, Cheyanne, Shaffer, Rebecca, Shameen, Sana, Sherard, Curry, Shikov, Roman, Shillington, Amelle, Shir, Mojeeb, Shocklee, Amanda, Shrier, Clara, Shulman, Lisa, Siegel, Matt, Simon, Andrea, Simon, Laura, Singh, Arushi, Singh, Vini, Smalley, Devin, Smith, Kaitlin, Smith, Chris, Smith, Ashlyn, Soorya, Latha, Soscia, Julia, Soucy, Aubrie, Stchur, Laura, Steele, Morgan, Srishyla, Diksha, Stamps, Danielle, Sussman, Nicole, Swanson, Amy, Sweeney, Megan, Sziklay, Anthony, Tafolla, Maira, Taiba, Jabeen, Takahashi, Nicole, Terroso, Sydney, Strathearn, Camilla, Thomas, Taylor, Thompson, Samantha, Touchette, Ellyn, Townsend, Laina, Trog, Madison, Tsai, Katherine, Tseng, Angela, Tshering, Paullani, Tso, Ivy, Valicenti-Mcdermott, Maria, VanMetre, Bonnie, VanWade, Candace, Turecki, Samuel, Vargo, Kerrigan, Vattuone, Cristiana, Veenstra-Vanderweele, Jeremy, Vehorn, Alison, Benitez Velazquez, Alan Jesus, Verdi, Mary, Villalobos, Michele, Vrittamani, Lakshmi, Wainer, Allison, Wallace, Jermel, Walston, Corrie, Wang, Jiayaho, Ward, Audrey, Warren, Zachary, Washington, Katherine, Westerkamp, Grace, White, Sabrina, Wink, Logan, Winoto, Fiona, Winters, Sarah, Wodka, Ericka, Xavier, Samantha, Xu, Sidi, Yang, Yi, Yang, WhaJames, Yang, Amy, Yinger, Meredith, Yu, Timothy, Zaro, Christopher, Zha, Cindy, Zhang, Haicang, Zhao, Haoquan, Zick, Allyson, Salmon, Lauren Ziegelmayer, Wright, Jessica R., Astrovskaya, Irina, Barns, Sarah D., Goler, Alexandra, Zhou, Xueya, Shu, Chang, Snyder, LeeAnne Green, Han, Bing, Shen, Yufeng, Volfovsky, Natalia, Hall, Jacob B., Feliciano, Pamela, and Chung, Wendy K.

Published
2024
Full Text
View/download PDF

37. Clinical and neuroradiological spectrum of biallelic variants in NOTCH3

Author

Iruzubieta, Pablo, Alves, César Augusto Pinheiro Ferreira, Al Shamsi, Aisha M., ElGhazali, Gehad, Zaki, Maha S., Pinelli, Lorenzo, Lopergolo, Diego, Cho, Bernard P.H., Jolly, Amy A., Al Futaisi, Amna, Al-Amrani, Fatema, Galli, Jessica, Fazzi, Elisa, Vulin, Katarina, Barajas-Olmos, Francisco, Hengel, Holger, Aljamal, Bayan Mohammed, Nasr, Vahideh, Assarzadegan, Farhad, Ragno, Michele, Trojano, Luigi, Ojeda, Naomi Meave, Çakar, Arman, Bianchi, Silvia, Pescini, Francesca, Poggesi, Anna, Al Tenalji, Amal, Aziz, Majid, Mohammad, Rahema, Chedrawi, Aziza, De Stefano, Nicola, Zifarelli, Giovanni, Schöls, Ludger, Haack, Tobias B., Rebelo, Adriana, Zuchner, Stephan, Koc, Filiz, Griffiths, Lyn R., Orozco, Lorena, Helmes, Karla García, Babaei, Meisam, Bauer, Peter, Chan Jeong, Won, Karimiani, Ehsan Ghayoor, Schmidts, Miriam, Gleeson, Joseph G., Chung, Wendy K., Alkuraya, Fowzan Sami, Shalbafan, Bita, Markus, Hugh S., Houlden, Henry, and Maroofian, Reza

Published
2024
Full Text
View/download PDF

38. Pediatric cardiomyopathy illustrates the importance of reinterpreting the significance of genetic variants

Author

Lee, Teresa M., Miller, Erin, Sridhar, Arthi, Fan, Xiao, Dexheimer, Phillip J., Bansal, Neha, Godown, Justin, Hsu, Daphne T., Kantor, Paul, Kirmani, Sonya, Lal, Ashwin K., Rossano, Joseph W., Towbin, Jeffrey A., Webber, Steven A., Shi, Ling, Hamza, Taye H., Aronow, Bruce J., Bhatnaghar, Surbhi, Martin, Lisa J., Schubert, Jeffrey, Ware, Stephanie M., Chung, Wendy K., Wilkinson, James D., and Lipshultz, Steven E.

Published
2024
Full Text
View/download PDF

39. Heterozygous rare variants in NR2F2 cause a recognizable multiple congenital anomaly syndrome with developmental delays

Author

Ganapathi, Mythily, Matsuoka, Leticia S., March, Michael, Li, Dong, Brokamp, Elly, Benito-Sanz, Sara, White, Susan M., Lachlan, Katherine, Ahimaz, Priyanka, Sewda, Anshuman, Bastarache, Lisa, Thomas-Wilson, Amanda, Stoler, Joan M., Bramswig, Nuria C., Baptista, Julia, Stals, Karen, Demurger, Florence, Cogne, Benjamin, Isidor, Bertrand, Bedeschi, Maria Francesca, Peron, Angela, Amiel, Jeanne, Zackai, Elaine, Schacht, John P., Iglesias, Alejandro D., Morton, Jenny, Schmetz, Ariane, Seidel, Verónica, Lucia, Stephanie, Baskin, Stephanie M., Thiffault, Isabelle, Cogan, Joy D., Gordon, Christopher T., Chung, Wendy K., Bowdin, Sarah, and Bhoj, Elizabeth

Published
2023
Full Text
View/download PDF

41. Newborn screening for neurodevelopmental diseases: Are we there yet?

Author

Chung, Wendy K, Berg, Jonathan S, Botkin, Jeffrey R, Brenner, Steven E, Brosco, Jeffrey P, Brothers, Kyle B, Currier, Robert J, Gaviglio, Amy, Kowtoniuk, Walter E, Olson, Colleen, Lloyd‐Puryear, Michele, Saarinen, Annamarie, Sahin, Mustafa, Shen, Yufeng, Sherr, Elliott H, Watson, Michael S, and Hu, Zhanzhi

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Clinical Research, Brain Disorders, Infant Mortality, Prevention, Intellectual and Developmental Disabilities (IDD), Pediatric Research Initiative, Perinatal Period - Conditions Originating in Perinatal Period, Pediatric, Reproductive health and childbirth, Good Health and Well Being, Infant, Infant, Newborn, Humans, Neonatal Screening, Pilot Projects, Neurodevelopmental Disorders, Parents, Clinical Sciences, Genetics & Heredity, Clinical sciences
Abstract

In the US, newborn screening (NBS) is a unique health program that supports health equity and screens virtually every baby after birth, and has brought timely treatments to babies since the 1960's. With the decreasing cost of sequencing and the improving methods to interpret genetic data, there is an opportunity to add DNA sequencing as a screening method to facilitate the identification of babies with treatable conditions that cannot be identified in any other scalable way, including highly penetrant genetic neurodevelopmental disorders (NDD). However, the lack of effective dietary or drug-based treatments has made it nearly impossible to consider NDDs in the current NBS framework, yet it is anticipated that any treatment will be maximally effective if started early. Hence there is a critical need for large scale pilot studies to assess if and how NDDs can be effectively screened at birth, if parents desire that information, and what impact early diagnosis may have. Here we attempt to provide an overview of the recent advances in NDD treatments, explore the possible framework of setting up a pilot study to genetically screen for NDDs, highlight key technical, practical, and ethical considerations and challenges, and examine the policy and health system implications.

Published
2022

42. Identifying novel data-driven subgroups in congenital heart disease using multi-modal measures of brain structure

Author

Vandewouw, Marlee M., Norris-Brilliant, Ami, Rahman, Anum, Assimopoulos, Stephania, Morton, Sarah U., Kushki, Azadeh, Cunningham, Sean, King, Eileen, Goldmuntz, Elizabeth, Miller, Thomas A., Thomas, Nina H., Adams, Heather R., Cleveland, John, Cnota, James F., Ellen Grant, P, Goldberg, Caren S., Huang, Hao, Li, Jennifer S., McQuillen, Patrick, Porter, George A., Roberts, Amy E., Russell, Mark W., Seidman, Christine E., Tivarus, Madalina E., Chung, Wendy K., Hagler, Donald J., Newburger, Jane W., Panigrahy, Ashok, Lerch, Jason P, Gelb, Bruce D., and Anagnostou, Evdokia

Published
2024
Full Text
View/download PDF

43. Pathogenic PHIP Variants are Variably Associated With CAKUT

Author

de Fallois, Jonathan, Sieckmann, Tobias, Schönauer, Ria, Petzold, Friederike, Münch, Johannes, Pauly, Melissa, Vasileiou, Georgia, Findeisen, Christin, Kampmeier, Antje, Kuechler, Alma, Reis, André, Decker, Eva, Bergmann, Carsten, Platzer, Konrad, Tasic, Velibor, Kirschner, Karin Michaela, Shril, Shirlee, Hildebrandt, Friedhelm, Chung, Wendy K., and Halbritter, Jan

Published
2024
Full Text
View/download PDF

44. Heterogeneity of comprehensive clinical phenotype and longitudinal adaptive function and correlation with computational predictions of severity of missense genotypes in KIF1A-associated neurological disorder

Author

Sudnawa, Khemika K., Li, Wenxing, Calamia, Sean, Kanner, Cara H., Bain, Jennifer M., Abdelhakim, Aliaa H., Geltzeiler, Alexa, Mebane, Caroline M., Provenzano, Frank A., Sands, Tristan T., Fee, Robert J., Montes, Jacqueline, Shen, Yufeng, and Chung, Wendy K.

Published
2024
Full Text
View/download PDF

46. Homozygous missense variants in YKT6 result in loss of function and are associated with developmental delay, with or without severe infantile liver disease and risk for hepatocellular carcinoma

Author

Ma, Mengqi, Ganapathi, Mythily, Zheng, Yiming, Tan, Kai-Li, Kanca, Oguz, Bove, Kevin E., Quintanilla, Norma, Sag, Sebnem O., Temel, Sehime G., LeDuc, Charles A., McPartland, Amanda J., Pereira, Elaine M., Shen, Yufeng, Hagen, Jacob, Thomas, Christie P., Nguyen Galván, Nhu Thao, Pan, Xueyang, Lu, Shenzhao, Rosenfeld, Jill A., Calame, Daniel G., Wangler, Michael F., Lupski, James R., Pehlivan, Davut, Hertel, Paula M., Chung, Wendy K., and Bellen, Hugo J.

Published
2024
Full Text
View/download PDF

48. Strong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease

Author

Gupta, Yask, Friedman, David J., McNulty, Michelle T., Khan, Atlas, Lane, Brandon, Wang, Chen, Ke, Juntao, Jin, Gina, Wooden, Benjamin, Knob, Andrea L., Lim, Tze Y., Appel, Gerald B., Huggins, Kinsie, Liu, Lili, Mitrotti, Adele, Stangl, Megan C., Bomback, Andrew, Westland, Rik, Bodria, Monica, Marasa, Maddalena, Shang, Ning, Cohen, David J., Crew, Russell J., Morello, William, Canetta, Pietro, Radhakrishnan, Jai, Martino, Jeremiah, Liu, Qingxue, Chung, Wendy K., Espinoza, Angelica, Luo, Yuan, Wei, Wei-Qi, Feng, Qiping, Weng, Chunhua, Fang, Yilu, Kullo, Iftikhar J., Naderian, Mohammadreza, Limdi, Nita, Irvin, Marguerite R., Tiwari, Hemant, Mohan, Sumit, Rao, Maya, Dube, Geoffrey K., Chaudhary, Ninad S., Gutiérrez, Orlando M., Judd, Suzanne E., Cushman, Mary, Lange, Leslie A., Lange, Ethan M., Bivona, Daniel L., Verbitsky, Miguel, Winkler, Cheryl A., Kopp, Jeffrey B., Santoriello, Dominick, Batal, Ibrahim, Pinheiro, Sérgio Veloso Brant, Oliveira, Eduardo Araújo, Simoes e Silva, Ana Cristina, Pisani, Isabella, Fiaccadori, Enrico, Lin, Fangming, Gesualdo, Loreto, Amoroso, Antonio, Ghiggeri, Gian Marco, D’Agati, Vivette D., Magistroni, Riccardo, Kenny, Eimear E., Loos, Ruth J. F., Montini, Giovanni, Hildebrandt, Friedhelm, Paul, Dirk S., Petrovski, Slavé, Goldstein, David B., Kretzler, Matthias, Gbadegesin, Rasheed, Gharavi, Ali G., Kiryluk, Krzysztof, Sampson, Matthew G., Pollak, Martin R., and Sanna-Cherchi, Simone

Published
2023
Full Text
View/download PDF

49. Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity

Author

Lin, Sheng-Jia, Vona, Barbara, Lau, Tracy, Huang, Kevin, Zaki, Maha S., Aldeen, Huda Shujaa, Karimiani, Ehsan Ghayoor, Rocca, Clarissa, Noureldeen, Mahmoud M., Saad, Ahmed K., Petree, Cassidy, Bartolomaeus, Tobias, Abou Jamra, Rami, Zifarelli, Giovanni, Gotkhindikar, Aditi, Wentzensen, Ingrid M., Liao, Mingjuan, Cork, Emalyn Elise, Varshney, Pratishtha, Hashemi, Narges, Mohammadi, Mohammad Hasan, Rad, Aboulfazl, Neira, Juanita, Toosi, Mehran Beiraghi, Knopp, Cordula, Kurth, Ingo, Challman, Thomas D., Smith, Rebecca, Abdalla, Asmahan, Haaf, Thomas, Suri, Mohnish, Joshi, Manali, Chung, Wendy K., Moreno-De-Luca, Andres, Houlden, Henry, Maroofian, Reza, and Varshney, Gaurav K.

Published
2023
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results