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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. 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
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6. 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

11. 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

12. 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

13. 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
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16. 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

17. 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
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18. 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
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21. 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
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22. 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

23. 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

24. 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

25. 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

26. 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
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27. 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
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28. 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
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29. 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
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30. 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
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32. 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

33. 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
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34. 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
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35. 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
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37. 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
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38. 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
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39. 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
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41. Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants

Author

Li, Shuai, Silvestri, Valentina, Leslie, Goska, Rebbeck, Timothy R, Neuhausen, Susan L, Hopper, John L, Nielsen, Henriette Roed, Lee, Andrew, Yang, Xin, McGuffog, Lesley, Parsons, Michael T, Andrulis, Irene L, Arnold, Norbert, Belotti, Muriel, Borg, Åke, Buecher, Bruno, Buys, Saundra S, Caputo, Sandrine M, Chung, Wendy K, Colas, Chrystelle, Colonna, Sarah V, Cook, Jackie, Daly, Mary B, de la Hoya, Miguel, de Pauw, Antoine, Delhomelle, Hélène, Eason, Jacqueline, Engel, Christoph, Evans, D Gareth, Faust, Ulrike, Fehm, Tanja N, Fostira, Florentia, Fountzilas, George, Frone, Megan, Garcia-Barberan, Vanesa, Garre, Pilar, Gauthier-Villars, Marion, Gehrig, Andrea, Glendon, Gord, Goldgar, David E, Golmard, Lisa, Greene, Mark H, Hahnen, Eric, Hamann, Ute, Hanson, Helen, Hassan, Tiara, Hentschel, Julia, Horvath, Judit, Izatt, Louise, Janavicius, Ramunas, Jiao, Yue, John, Esther M, Karlan, Beth Y, Kim, Sung-Won, Konstantopoulou, Irene, Kwong, Ava, Laugé, Anthony, Lee, Jong Won, Lesueur, Fabienne, Mebirouk, Noura, Meindl, Alfons, Mouret-Fourme, Emmanuelle, Musgrave, Hannah, Yie, Joanne Ngeow Yuen, Niederacher, Dieter, Park, Sue K, Pedersen, Inge Sokilde, Ramser, Juliane, Ramus, Susan J, Rantala, Johanna, Rashid, Muhammad U, Reichl, Florian, Ritter, Julia, Rump, Andreas, Santamariña, Marta, Saule, Claire, Schmidt, Gunnar, Schmutzler, Rita K, Senter, Leigha, Shariff, Saba, Singer, Christian F, Southey, Melissa C, Stoppa-Lyonnet, Dominique, Sutter, Christian, Tan, Yen, Teo, Soo Hwang, Terry, Mary Beth, Thomassen, Mads, Tischkowitz, Marc, Toland, Amanda E, Torres, Diana, Vega, Ana, Wagner, Sebastian A, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Weber, Bernhard HF, Yannoukakos, Drakoulis, Spurdle, Amanda B, Easton, Douglas F, and Chenevix-Trench, Georgia

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Prostate Cancer, Women's Health, Digestive Diseases, Breast Cancer, Ovarian Cancer, Pancreatic Cancer, Prevention, Cancer, Urologic Diseases, Rare Diseases, 2.1 Biological and endogenous factors, BRCA1 Protein, BRCA2 Protein, Breast Neoplasms, Breast Neoplasms, Male, Female, Genetic Predisposition to Disease, Heterozygote, Humans, Infant, Newborn, Male, Mutation, Ovarian Neoplasms, Pancreatic Neoplasms, Risk, Clinical Sciences, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

PurposeTo provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) in BRCA1 and BRCA2 for effective cancer risk management.MethodsWe used data from 3,184 BRCA1 and 2,157 BRCA2 families in the Consortium of Investigators of Modifiers of BRCA1/2 to estimate age-specific relative (RR) and absolute risks for 22 first primary cancer types adjusting for family ascertainment.ResultsBRCA1 PVs were associated with risks of male breast (RR = 4.30; 95% CI, 1.09 to 16.96), pancreatic (RR = 2.36; 95% CI, 1.51 to 3.68), and stomach (RR = 2.17; 95% CI, 1.25 to 3.77) cancers. Associations with colorectal and gallbladder cancers were also suggested. BRCA2 PVs were associated with risks of male breast (RR = 44.0; 95% CI, 21.3 to 90.9), stomach (RR = 3.69; 95% CI, 2.40 to 5.67), pancreatic (RR = 3.34; 95% CI, 2.21 to 5.06), and prostate (RR = 2.22; 95% CI, 1.63 to 3.03) cancers. The stomach cancer RR was higher for females than males (6.89 v 2.76; P = .04). The absolute risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers.ConclusionIn addition to female breast and ovarian cancers, BRCA1 and BRCA2 PVs are associated with increased risks of male breast, pancreatic, stomach, and prostate (only BRCA2 PVs) cancers, but not with the risks of other previously suggested cancers. The estimated age-specific risks will refine cancer risk management in men and women with BRCA1/2 PVs.

Published
2022

42. Neither cardiac mitochondrial DNA variation nor copy number contribute to congenital heart disease risk

Author

Willcox, Jon AL, Geiger, Joshua T, Morton, Sarah U, McKean, David, Quiat, Daniel, Gorham, Joshua M, Tai, Angela C, DePalma, Steven, Bernstein, Daniel, Brueckner, Martina, Chung, Wendy K, Giardini, Alessandro, Goldmuntz, Elizabeth, Kaltman, Jonathan R, Kim, Richard, Newburger, Jane W, Shen, Yufeng, Srivastava, Deepak, Tristani-Firouzi, Martin, Gelb, Bruce, Porter, George A, Seidman, JG, and Seidman, Christine E

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Genetics, Congenital Structural Anomalies, Cardiovascular, Heart Disease, Clinical Research, Pediatric, Aetiology, 2.1 Biological and endogenous factors, DNA Copy Number Variations, DNA, Mitochondrial, Heart Defects, Congenital, Humans, Mitochondria, Mutation, congenital heart disease, genome sequencing, mitochondrial copy number, mitochondrial genome, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

The well-established manifestation of mitochondrial mutations in functional cardiac disease (e.g., mitochondrial cardiomyopathy) prompted the hypothesis that mitochondrial DNA (mtDNA) sequence and/or copy number (mtDNAcn) variation contribute to cardiac defects in congenital heart disease (CHD). MtDNAcns were calculated and rare, non-synonymous mtDNA mutations were identified in 1,837 CHD-affected proband-parent trios, 116 CHD-affected singletons, and 114 paired cardiovascular tissue/blood samples. The variant allele fraction (VAF) of heteroplasmic variants in mitochondrial RNA from 257 CHD cardiovascular tissue samples was also calculated. On average, mtDNA from blood had 0.14 rare variants and 52.9 mtDNA copies per nuclear genome per proband. No variation with parental age at proband birth or CHD-affected proband age was seen. mtDNAcns in valve/vessel tissue (320 ± 70) were lower than in atrial tissue (1,080 ± 320, p = 6.8E-21), which were lower than in ventricle tissue (1,340 ± 280, p = 1.4E-4). The frequency of rare variants in CHD-affected individual DNA was indistinguishable from the frequency in an unaffected cohort, and proband mtDNAcns did not vary from those of CHD cohort parents. In both the CHD and the comparison cohorts, mtDNAcns were significantly correlated between mother-child, father-child, and mother-father. mtDNAcns among people with European (mean = 52.0), African (53.0), and Asian haplogroups (53.5) were calculated and were significantly different for European and Asian haplogroups (p = 2.6E-3). Variant heteroplasmic fraction (HF) in blood correlated well with paired cardiovascular tissue HF (r = 0.975) and RNA VAF (r = 0.953), which suggests blood HF is a reasonable proxy for HF in heart tissue. We conclude that mtDNA mutations and mtDNAcns are unlikely to contribute significantly to CHD risk.

Published
2022

43. Correction: Polygenic risk modeling for prediction of epithelial ovarian cancer risk

Author

Dareng, Eileen O, Tyrer, Jonathan P, Barnes, Daniel R, Jones, Michelle R, Yang, Xin, Aben, Katja KH, Adank, Muriel A, Agata, Simona, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Aravantinos, Gerasimos, Arun, Banu K, Augustinsson, Annelie, Balmaña, Judith, Bandera, Elisa V, Barkardottir, Rosa B, Barrowdale, Daniel, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q, Bjorge, Line, Black, Amanda, Bogdanova, Natalia V, Bonanni, Bernardo, Borg, Ake, Brenton, James D, Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S, Cai, Hui, Caligo, Maria A, Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J, Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K, Claes, Kathleen BM, Colonna, Sarah, Cook, Linda S, Couch, Fergus J, Daly, Mary B, Dao, Fanny, Davies, Eleanor, de la Hoya, Miguel, de Putter, Robin, Dennis, Joe, DePersia, Allison, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer A, Domchek, Susan M, Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Eccles, Diana M, Eliassen, Heather A, Engel, Christoph, Evans, Gareth D, Fasching, Peter A, Flanagan, James M, Fortner, Renée T, Machackova, Eva, Friedman, Eitan, Ganz, Patricia A, Garber, Judy, Gensini, Francesca, Giles, Graham G, Glendon, Gord, Godwin, Andrew K, Goodman, Marc T, Greene, Mark H, Gronwald, Jacek, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hamann, Ute, Hansen, Thomas VO, Harris, Holly R, Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle AT, Høgdall, Estrid, Høgdall, Claus K, Hopper, John L, Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J, Huntsman, David G, Imyanitov, Evgeny N, Isaacs, Claudine, Jakubowska, Anna, James, Paul A, and Janavicius, Ramunas

Subjects
GEMO Study Collaborators, GC-HBOC Study Collaborators, EMBRACE Collaborators, OPAL Study Group, AOCS Group, KConFab Investigators, HEBON Investigators, OCAC Consortium, CIMBA Consortium, Genetics, Clinical Sciences, Genetics & Heredity
Published
2022

44. Polygenic risk modeling for prediction of epithelial ovarian cancer risk

Author

Dareng, Eileen O, Tyrer, Jonathan P, Barnes, Daniel R, Jones, Michelle R, Yang, Xin, Aben, Katja KH, Adank, Muriel A, Agata, Simona, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Aravantinos, Gerasimos, Arun, Banu K, Augustinsson, Annelie, Balmaña, Judith, Bandera, Elisa V, Barkardottir, Rosa B, Barrowdale, Daniel, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q, Bjorge, Line, Black, Amanda, Bogdanova, Natalia V, Bonanni, Bernardo, Borg, Ake, Brenton, James D, Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S, Cai, Hui, Caligo, Maria A, Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J, Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K, Claes, Kathleen BM, Colonna, Sarah, Cook, Linda S, Couch, Fergus J, Daly, Mary B, Dao, Fanny, Davies, Eleanor, de la Hoya, Miguel, de Putter, Robin, Dennis, Joe, DePersia, Allison, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer A, Domchek, Susan M, Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Eccles, Diana M, Eliassen, Heather A, Engel, Christoph, Evans, Gareth D, Fasching, Peter A, Flanagan, James M, Fortner, Renée T, Machackova, Eva, Friedman, Eitan, Ganz, Patricia A, Garber, Judy, Gensini, Francesca, Giles, Graham G, Glendon, Gord, Godwin, Andrew K, Goodman, Marc T, Greene, Mark H, Gronwald, Jacek, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hamann, Ute, Hansen, Thomas VO, Harris, Holly R, Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle AT, Høgdall, Estrid, Høgdall, Claus K, Hopper, John L, Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J, Huntsman, David G, Imyanitov, Evgeny N, Isaacs, Claudine, Jakubowska, Anna, James, Paul A, and Janavicius, Ramunas

Subjects
Prevention, Cancer, Ovarian Cancer, Rare Diseases, Good Health and Well Being, Bayes Theorem, Breast Neoplasms, Carcinoma, Ovarian Epithelial, Female, Genetic Predisposition to Disease, Humans, Male, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Prospective Studies, Risk Factors, GEMO Study Collaborators, GC-HBOC Study Collaborators, EMBRACE Collaborators, OPAL Study Group, AOCS Group, KConFab Investigators, HEBON Investigators, OCAC Consortium, CIMBA Consortium, Genetics, Clinical Sciences, Genetics & Heredity
Abstract

Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.

Published
2022

45. Phenotypic effects of genetic variants associated with autism

Author

Rolland, Thomas, Cliquet, Freddy, Anney, Richard J. L., Moreau, Clara, Traut, Nicolas, Mathieu, Alexandre, Huguet, Guillaume, Duan, Jinjie, Warrier, Varun, Portalier, Swan, Dry, Louise, Leblond, Claire S., Douard, Elise, Amsellem, Frédérique, Malesys, Simon, Maruani, Anna, Toro, Roberto, Børglum, Anders D., Grove, Jakob, Baron-Cohen, Simon, Packer, Alan, Chung, Wendy K., Jacquemont, Sébastien, Delorme, Richard, and Bourgeron, Thomas

Published
2023
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48. De novo variants in FRYL are associated with developmental delay, intellectual disability, and dysmorphic features

Author

Burrage, Lindsay C., Heaney, Jason D., Kim, Seon-Young, Lanza, Denise G., Liu, Zhandong, Mao, Dongxue, Milosavljevic, Aleksander, Nagamani, Sandesh C.S., Posey, Jennifer E., Ramamurthy, Uma, Ramanathan, Vivek, Rogers, Jeffrey, Rosenfeld, Jill A., Roth, Matthew, Zahedi Darshoori, Ramin, Pan, Xueyang, Tao, Alice M., Lu, Shenzhao, Ma, Mengqi, Hannan, Shabab B., Slaugh, Rachel, Drewes Williams, Sarah, O'Grady, Lauren, Kanca, Oguz, Person, Richard, Carter, Melissa T., Platzer, Konrad, Schnabel, Franziska, Abou Jamra, Rami, Roberts, Amy E., Newburger, Jane W., Revah-Politi, Anya, Granadillo, Jorge L., Stegmann, Alexander P.A., Sinnema, Margje, Accogli, Andrea, Salpietro, Vincenzo, Capra, Valeria, Ghaloul-Gonzalez, Lina, Brueckner, Martina, Simon, Marleen E.H., Sweetser, David A., Glinton, Kevin E., Kirk, Susan E., Wangler, Michael F., Yamamoto, Shinya, Chung, Wendy K., and Bellen, Hugo J.

Published
2024
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49. Biallelic variants in SLC4A10 encoding a sodium-dependent bicarbonate transporter lead to a neurodevelopmental disorder

Author

Maroofian, Reza, Zamani, Mina, Kaiyrzhanov, Rauan, Liebmann, Lutz, Karimiani, Ehsan Ghayoor, Vona, Barbara, Huebner, Antje K., Calame, Daniel G., Misra, Vinod K., Sadeghian, Saeid, Azizimalamiri, Reza, Mohammadi, Mohammad Hasan, Zeighami, Jawaher, Heydaran, Sogand, Toosi, Mehran Beiraghi, Akhondian, Javad, Babaei, Meisam, Hashemi, Narges, Schnur, Rhonda E., Suri, Mohnish, Setzke, Jonas, Wagner, Matias, Brunet, Theresa, Grochowski, Christopher M., Emrick, Lisa, Chung, Wendy K., Hellmich, Ute A., Schmidts, Miriam, Lupski, James R., Galehdari, Hamid, Severino, Mariasavina, Houlden, Henry, and Hübner, Christian A.

Published
2024
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50. Genetics dictating therapeutic decisions in pediatric pulmonary hypertension? A case report suggesting we are getting closer.

Author

Stevens, Leah, Colglazier, Elizabeth, Parker, Claire, Amin, Elena K, Nawaytou, Hythem, Teitel, David, Reddy, Vadiyala M, Welch, Carrie L, Chung, Wendy K, and Fineman, Jeffrey R

Subjects
ATP13A3, Potts shunt, pulmonary vascular disease, Pediatric, Rare Diseases, Genetics, Clinical Research, Orphan Drug, Lung, 2.1 Biological and endogenous factors, Cardiovascular, Cardiorespiratory Medicine and Haematology
Abstract

Despite therapeutic advances over the past decades, pulmonary arterial hypertension (PAH) and related pulmonary vascular diseases continue to cause significant morbidity and mortality in neonates, infants, and children. Unfortunately, an adequate understanding of underlying biology is lacking. There has been a growing interest in the role that genetic factors influence pulmonary vascular disease, with the hope that genetic information may aid in identifying disease etiologies, guide therapeutic decisions, and ultimately identify novel therapeutic targets. In fact, current data suggest that genetic factors contribute to ~42% of pediatric-onset PH compared to ~12.5% of adult-onset PAH. We report a case in which the knowledge that biallelic ATP13A3 mutations are associated with malignant progression of PAH in young childhood, led us to alter our traditional treatment plan for a 21-month-old PAH patient. In this case, we elected to perform a historically high-risk Potts shunt before expected rapid deterioration. Short-term follow-up is encouraging, and the patient remains the only known surviving pediatric PAH patient with an associated biallelic ATP13A3 mutation in the literature. We speculate that an increased use of comprehensive genetic testing can aid in identifying the underlying pathobiology and the expected natural history, and guide treatment plans among PAH patients.

Published
2022

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