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769 results on '"Mane, Shrikant"'

1. Development, validation and application of single molecule molecular inversion probe based novel integrated genetic screening method for 29 common lysosomal storage disorders in India

Author

Sheth, Harsh, Nair, Aadhira, Bhavsar, Riddhi, Kamate, Mahesh, Gowda, Vykuntaraju K., Bavdekar, Ashish, Kadam, Sandeep, Nampoothiri, Sheela, Panigrahi, Inusha, Kaur, Anupriya, Shah, Siddharth, Mehta, Sanjeev, Jagadeesan, Sujatha, Suresh, Indrani, Kapoor, Seema, Bajaj, Shruti, Devi, Radha Rama, Prajapati, Ashka, Godbole, Koumudi, Patel, Harsh, Luhar, Zulfiqar, Shah, Raju C., Iyer, Anand, Bijarnia, Sunita, Puri, Ratna, Muranjan, Mamta, Shah, Ami, Magar, Suvarna, Gupta, Neerja, Tayade, Naresh, Gandhi, Ajit, Sowani, Ajit, Kale, Shrutikaa, Jalan, Anil, Solanki, Dhaval, Dalal, Ashwin, Mane, Shrikant, Prabha, C. Ratna, Sheth, Frenny, Joshi, Chaitanya G., Joshi, Madhvi, and Sheth, Jayesh

Published
2024
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2. Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations

Author

Zhao, Shujuan, Mekbib, Kedous Y., van der Ent, Martijn A., Allington, Garrett, Prendergast, Andrew, Chau, Jocelyn E., Smith, Hannah, Shohfi, John, Ocken, Jack, Duran, Daniel, Furey, Charuta G., Hao, Le Thi, Duy, Phan Q., Reeves, Benjamin C., Zhang, Junhui, Nelson-Williams, Carol, Chen, Di, Li, Boyang, Nottoli, Timothy, Bai, Suxia, Rolle, Myron, Zeng, Xue, Dong, Weilai, Fu, Po-Ying, Wang, Yung-Chun, Mane, Shrikant, Piwowarczyk, Paulina, Fehnel, Katie Pricola, See, Alfred Pokmeng, Iskandar, Bermans J., Aagaard-Kienitz, Beverly, Moyer, Quentin J., Dennis, Evan, Kiziltug, Emre, Kundishora, Adam J., DeSpenza, Jr., Tyrone, Greenberg, Ana B. W., Kidanemariam, Seblewengel M., Hale, Andrew T., Johnston, James M., Jackson, Eric M., Storm, Phillip B., Lang, Shih-Shan, Butler, William E., Carter, Bob S., Chapman, Paul, Stapleton, Christopher J., Patel, Aman B., Rodesch, Georges, Smajda, Stanislas, Berenstein, Alejandro, Barak, Tanyeri, Erson-Omay, E. Zeynep, Zhao, Hongyu, Moreno-De-Luca, Andres, Proctor, Mark R., Smith, Edward R., Orbach, Darren B., Alper, Seth L., Nicoli, Stefania, Boggon, Titus J., Lifton, Richard P., Gunel, Murat, King, Philip D., Jin, Sheng Chih, and Kahle, Kristopher T.

Published
2023
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4. Multiomic analyses implicate a neurodevelopmental program in the pathogenesis of cerebral arachnoid cysts

Author

Kundishora, Adam J., Allington, Garrett, McGee, Stephen, Mekbib, Kedous Y., Gainullin, Vladimir, Timberlake, Andrew T., Nelson-Williams, Carol, Kiziltug, Emre, Smith, Hannah, Ocken, Jack, Shohfi, John, Allocco, August, Duy, Phan Q., Elsamadicy, Aladine A., Dong, Weilai, Zhao, Shujuan, Wang, Yung-Chun, Qureshi, Hanya M., DiLuna, Michael L., Mane, Shrikant, Tikhonova, Irina R., Fu, Po-Ying, Castaldi, Christopher, López-Giráldez, Francesc, Knight, James R., Furey, Charuta G., Carter, Bob S., Haider, Shozeb, Moreno-De-Luca, Andres, Alper, Seth L., Gunel, Murat, Millan, Francisca, Lifton, Richard P., Torene, Rebecca I., Jin, Sheng Chih, and Kahle, Kristopher T.

Published
2023
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5. Diagnostic Utility of Exome Sequencing Among Israeli Children With Kidney Failure

Author

Ben-Moshe, Yishay, Shlomovitz, Omer, Atias-Varon, Danit, Haskin, Orly, Ben-Shalom, Efrat, Shasha Lavsky, Hadas, Volovelsky, Oded, Mane, Shrikant, Ben-Ruby, Dror, Chowers, Guy, Skorecki, Karl, Borovitz, Yael, Kagan, Maayan, Mor, Nofar, Khavkin, Yulia, Tzvi-Behr, Shimrit, Pollack, Shirley, Toder, Moran Plonsky, Geylis, Michael, Schnapp, Aviad, Becker-Cohen, Rachel, Weissman, Irith, Schreiber, Ruth, Davidovits, Miriam, Frishberg, Yaacov, Magen, Daniella, Barel, Ortal, and Vivante, Asaf

Published
2023
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6. De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis.

Author

Weng, Patricia, Majmundar, Amar, Khan, Kamal, Lim, Tze, Shril, Shirlee, Jin, Gina, Musgrove, John, Wang, Minxian, Ahram, Dina, Aggarwal, Vimla, Bier, Louise, Heinzen, Erin, Onuchic-Whitford, Ana, Mann, Nina, Buerger, Florian, Schneider, Ronen, Deutsch, Konstantin, Kitzler, Thomas, Klämbt, Verena, Kolb, Amy, Mao, Youying, Moufawad El Achkar, Christelle, Mitrotti, Adele, Martino, Jeremiah, Beck, Bodo, Altmüller, Janine, Benz, Marcus, Yano, Shoji, Mikati, Mohamad, Gunduz, Talha, Cope, Heidi, Shashi, Vandana, Trachtman, Howard, Bodria, Monica, Caridi, Gianluca, Pisani, Isabella, Fiaccadori, Enrico, AbuMaziad, Asmaa, Martinez-Agosto, Julian, Yadin, Ora, Zuckerman, Jonathan, Kim, Arang, John-Kroegel, Ulrike, Tyndall, Amanda, Parboosingh, Jillian, Innes, A, Bierzynska, Agnieszka, Koziell, Ania, Muorah, Mordi, Saleem, Moin, Hoefele, Julia, Riedhammer, Korbinian, Gharavi, Ali, Jobanputra, Vaidehi, Pierce-Hoffman, Emma, Seaby, Eleanor, ODonnell-Luria, Anne, Rehm, Heidi, Mane, Shrikant, DAgati, Vivette, Pollak, Martin, Ghiggeri, Gian, Lifton, Richard, Goldstein, David, Davis, Erica, Hildebrandt, Friedhelm, and Sanna-Cherchi, Simone

Subjects
FSGS, SRNS, TRIM8, epilepsy, genomics, monogenic, nuclear body, Adult, Animals, Carrier Proteins, Cell Line, Child, Child, Preschool, Codon, Nonsense, Developmental Disabilities, Epilepsy, Female, Glomerulosclerosis, Focal Segmental, Humans, Intranuclear Space, Kidney, Male, Mice, Mutation, Nephrotic Syndrome, Nerve Tissue Proteins, Phenotype, Podocytes, Exome Sequencing
Abstract

Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28 × 10-11). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10-15). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease.

Published
2021

7. Copy Number Variation Analysis Facilitates Identification of Genetic Causation in Patients with Congenital Anomalies of the Kidney and Urinary Tract

Author

Wu, Chen-Han Wilfred, Lim, Tze Y., Wang, Chunyan, Seltzsam, Steve, Zheng, Bixia, Schierbaum, Luca, Schneider, Sophia, Mann, Nina, Connaughton, Dervla M., Nakayama, Makiko, van der Ven, Amelie T., Dai, Rufeng, Kolvenbach, Caroline M., Kause, Franziska, Ottlewski, Isabel, Stajic, Natasa, Soliman, Neveen A., Kari, Jameela A., El Desoky, Sherif, Fathy, Hanan M., Milosevic, Danko, Turudic, Daniel, Al Saffar, Muna, Awad, Hazem S., Eid, Loai A., Ramanathan, Aravind, Senguttuvan, Prabha, Mane, Shrikant M., Lee, Richard S., Bauer, Stuart B., Lu, Weining, Hilger, Alina C., Tasic, Velibor, Shril, Shirlee, Sanna-Cherchi, Simone, and Hildebrandt, Friedhelm

Published
2022
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8. Rare Single Nucleotide and Copy Number Variants and the Etiology of Congenital Obstructive Uropathy: Implications for Genetic Diagnosis

Author

Ahram, Dina F., Lim, Tze Y., Ke, Juntao, Jin, Gina, Verbitsky, Miguel, Bodria, Monica, Kil, Byum Hee, Chatterjee, Debanjana, Piva, Stacy E., Marasa, Maddalena, Zhang, Jun Y., Cocchi, Enrico, Caridi, Gianluca, Gucev, Zoran, Lozanovski, Vladimir J., Pisani, Isabella, Izzi, Claudia, Savoldi, Gianfranco, Gnutti, Barbara, Capone, Valentina P., Morello, William, Guarino, Stefano, Esposito, Pasquale, Lambert, Sarah, Radhakrishnan, Jai, Appel, Gerald B., Uy, Natalie S., Rao, Maya K., Canetta, Pietro A., Bomback, Andrew S., Nestor, Jordan G., Hays, Thomas, Cohen, David J., Finale, Carolina, Wijk, Joanna A.E. van, La Scola, Claudio, Baraldi, Olga, Tondolo, Francesco, Di Renzo, Dacia, Jamry-Dziurla, Anna, Pezzutto, Alessandro, Manca, Valeria, Mitrotti, Adele, Santoro, Domenico, Conti, Giovanni, Martino, Marida, Giordano, Mario, Gesualdo, Loreto, Zibar, Lada, Masnata, Giuseppe, Bonomini, Mario, Alberti, Daniele, La Manna, Gaetano, Caliskan, Yasar, Ranghino, Andrea, Marzuillo, Pierluigi, Kiryluk, Krzysztof, Krzemień, Grażyna, Miklaszewska, Monika, Lin, Fangming, Montini, Giovanni, Scolari, Francesco, Fiaccadori, Enrico, Arapović, Adela, Saraga, Marijan, McKiernan, James, Alam, Shumyle, Zaniew, Marcin, Szczepańska, Maria, Szmigielska, Agnieszka, Sikora, Przemysław, Drożdż, Dorota, Mizerska-Wasiak, Malgorzata, Mane, Shrikant, Lifton, Richard P., Tasic, Velibor, Latos-Bielenska, Anna, Gharavi, Ali G., Ghiggeri, Gian Marco, Materna-Kiryluk, Anna, Westland, Rik, and Sanna-Cherchi, Simone

Published
2023
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9. Comparative transmissibility of SARS-CoV-2 variants Delta and Alpha in New England, USA

Author

Altajar, Ahmad, DeJesus, Alexandra, Brito, Anderson, Watkins, Anne E., Muyombwe, Anthony, Blumenstiel, Brendan S., Neal, Caleb, Kalinich, Chaney C., Liu, Chen, Loreth, Christine, Castaldi, Christopher, Pearson, Claire, Bernard, Clare, Nolet, Corey M., Ferguson, David, Buzby, Erika, Laszlo, Eva, Reagan, Faye L., Vicente, Gina, Rooke, Heather M., Munger, Heidi, Johnson, Hillary, Tikhonova, Irina R., Ott, Isabel M., Razeq, Jafar, Meldrim, James C., Brown, Jessica, Wang, Jianhui, Vostok, Johanna, Beauchamp, John P., Grimsby, Jonna L., Hall, Joshua, Messer, Katelyn S., Larkin, Katie L., Vernest, Kyle, Madoff, Lawrence C., Green, Lisa M., Webber, Lori, Gagne, Luc, Ulcena, Maesha A., Ray, Marianne C., Fisher, Marissa E., Barter, Mary, Lee, Matthew D., DeFelice, Matthew T., Cipicchio, Michelle C., Smith, Natasha L., Lennon, Niall J., Fitzgerald, Nicholas A., Kerantzas, Nicholas, Hui, Pei, Harrington, Rachel, Downing, Randy, Haye, Rashida, Lynch, Ryan, Anderson, Scott E., Hennigan, Scott, English, Sean, Cofsky, Seana, Clancy, Selina, Mane, Shrikant, Ash, Stephanie, Baez, Stephanie, Fleming, Steve, Murphy, Steven, Chaluvadi, Sushma, Alpert, Tara, Rivard, Trevor, Schulz, Wade, Mandese, Zoe M., Earnest, Rebecca, Uddin, Rockib, Matluk, Nicholas, Renzette, Nicholas, Turbett, Sarah E., Siddle, Katherine J., Adams, Gordon, Tomkins-Tinch, Christopher H., Petrone, Mary E., Rothman, Jessica E., Breban, Mallery I., Koch, Robert Tobias, Billig, Kendall, Fauver, Joseph R., Vogels, Chantal B.F., Bilguvar, Kaya, De Kumar, Bony, Landry, Marie L., Peaper, David R., Kelly, Kevin, Omerza, Greg, Grieser, Heather, Meak, Sim, Martha, John, Dewey, Hannah B., Kales, Susan, Berenzy, Daniel, Carpenter-Azevedo, Kristin, King, Ewa, Huard, Richard C., Novitsky, Vlad, Howison, Mark, Darpolor, Josephine, Manne, Akarsh, Kantor, Rami, Smole, Sandra C., Brown, Catherine M., Fink, Timelia, Lang, Andrew S., Gallagher, Glen R., Pitzer, Virginia E., Sabeti, Pardis C., Gabriel, Stacey, MacInnis, Bronwyn L., Tewhey, Ryan, Adams, Mark D., Park, Daniel J., Lemieux, Jacob E., and Grubaugh, Nathan D.

Published
2022
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10. Combining genomic and epidemiological data to compare the transmissibility of SARS-CoV-2 variants Alpha and Iota

Author

Petrone, Mary E., Rothman, Jessica E., Breban, Mallery I., Ott, Isabel M., Russell, Alexis, Lasek-Nesselquist, Erica, Badr, Hamada, Kelly, Kevin, Omerza, Greg, Renzette, Nicholas, Watkins, Anne E., Kalinich, Chaney C., Alpert, Tara, Brito, Anderson F., Earnest, Rebecca, Tikhonova, Irina R., Castaldi, Christopher, Kelly, John P., Shudt, Matthew, Plitnick, Jonathan, Schneider, Erasmus, Murphy, Steven, Neal, Caleb, Laszlo, Eva, Altajar, Ahmad, Pearson, Claire, Muyombwe, Anthony, Downing, Randy, Razeq, Jafar, Niccolai, Linda, Wilson, Madeline S., Anderson, Margaret L., Wang, Jianhui, Liu, Chen, Hui, Pei, Mane, Shrikant, Taylor, Bradford P., Hanage, William P., Landry, Marie L., Peaper, David R., Bilguvar, Kaya, Fauver, Joseph R., Vogels, Chantal B. F., Gardner, Lauren M., Pitzer, Virginia E., St. George, Kirsten, Adams, Mark D., and Grubaugh, Nathan D.

Published
2022
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11. Improved Survival With Adjuvant Cyclooxygenase 2 Inhibition in PIK3CA -Activated Stage III Colon Cancer: CALGB/SWOG 80702 (Alliance).

Author

Nowak, Jonathan A., Twombly, Tyler, Ma, Chao, Shi, Qian, Haruki, Koichiro, Fujiyoshi, Kenji, Väyrynen, Juha, Zhao, Melissa, Knight, James, Mane, Shrikant, Shergill, Ardaman, Kumar, Pankaj, Couture, Felix, Kuebler, Philip, Krishnamurthi, Smitha, Tan, Benjamin, Philip, Philip, O'Reilly, Eileen M., Shields, Anthony F., and Ogino, Shuji

Published
2024
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12. Molecular and cellular reorganization of neural circuits in the human lineage

Author

Sousa, André MM, Zhu, Ying, Raghanti, Mary Ann, Kitchen, Robert R, Onorati, Marco, Tebbenkamp, Andrew TN, Stutz, Bernardo, Meyer, Kyle A, Li, Mingfeng, Kawasawa, Yuka Imamura, Liu, Fuchen, Perez, Raquel Garcia, Mele, Marta, Carvalho, Tiago, Skarica, Mario, Gulden, Forrest O, Pletikos, Mihovil, Shibata, Akemi, Stephenson, Alexa R, Edler, Melissa K, Ely, John J, Elsworth, John D, Horvath, Tamas L, Hof, Patrick R, Hyde, Thomas M, Kleinman, Joel E, Weinberger, Daniel R, Reimers, Mark, Lifton, Richard P, Mane, Shrikant M, Noonan, James P, State, Matthew W, Lein, Ed S, Knowles, James A, Marques-Bonet, Tomas, Sherwood, Chet C, Gerstein, Mark B, and Sestan, Nenad

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Neurosciences, Brain Disorders, 1.1 Normal biological development and functioning, Underpinning research, Neurological, Animals, Gene Expression Profiling, Humans, Interneurons, Macaca, Neocortex, Neural Pathways, Pan troglodytes, Phylogeny, Species Specificity, Transcriptome, General Science & Technology
Abstract

To better understand the molecular and cellular differences in brain organization between human and nonhuman primates, we performed transcriptome sequencing of 16 regions of adult human, chimpanzee, and macaque brains. Integration with human single-cell transcriptomic data revealed global, regional, and cell-type-specific species expression differences in genes representing distinct functional categories. We validated and further characterized the human specificity of genes enriched in distinct cell types through histological and functional analyses, including rare subpallial-derived interneurons expressing dopamine biosynthesis genes enriched in the human striatum and absent in the nonhuman African ape neocortex. Our integrated analysis of the generated data revealed diverse molecular and cellular features of the phylogenetic reorganization of the human brain across multiple levels, with relevance for brain function and disease.

Published
2017

13. Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands

Author

Jin, Sheng Chih, Homsy, Jason, Zaidi, Samir, Lu, Qiongshi, Morton, Sarah, DePalma, Steven R, Zeng, Xue, Qi, Hongjian, Chang, Weni, Sierant, Michael C, Hung, Wei-Chien, Haider, Shozeb, Zhang, Junhui, Knight, James, Bjornson, Robert D, Castaldi, Christopher, Tikhonoa, Irina R, Bilguvar, Kaya, Mane, Shrikant M, Sanders, Stephan J, Mital, Seema, Russell, Mark W, Gaynor, J William, Deanfield, John, Giardini, Alessandro, Porter, George A, Srivastava, Deepak, Lo, Cecelia W, Shen, Yufeng, Watkins, W Scott, Yandell, Mark, Yost, H Joseph, Tristani-Firouzi, Martin, Newburger, Jane W, Roberts, Amy E, Kim, Richard, Zhao, Hongyu, Kaltman, Jonathan R, Goldmuntz, Elizabeth, Chung, Wendy K, Seidman, Jonathan G, Gelb, Bruce D, Seidman, Christine E, Lifton, Richard P, and Brueckner, Martina

Subjects
Biological Sciences, Genetics, Cardiovascular, Pediatric, Congenital Structural Anomalies, Brain Disorders, Heart Disease, Heart Disease - Coronary Heart Disease, 2.1 Biological and endogenous factors, Aetiology, Adult, Autistic Disorder, Cardiac Myosins, Case-Control Studies, Child, Exome, Female, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Growth Differentiation Factor 1, Heart Defects, Congenital, Heterozygote, High-Throughput Nucleotide Sequencing, Homozygote, Humans, Male, Mutation, Myosin Heavy Chains, Pedigree, Risk, Vascular Endothelial Growth Factor Receptor-3, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Here, exome sequencing of a single cohort of 2,871 CHD probands, including 2,645 parent-offspring trios, implicated rare inherited mutations in 1.8%, including a recessive founder mutation in GDF1 accounting for ∼5% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for ∼11% of Shone complex, and dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot. De novo mutations (DNMs) accounted for 8% of cases, including ∼3% of isolated CHD patients and ∼28% with both neurodevelopmental and extra-cardiac congenital anomalies. Seven genes surpassed thresholds for genome-wide significance, and 12 genes not previously implicated in CHD had >70% probability of being disease related. DNMs in ∼440 genes were inferred to contribute to CHD. Striking overlap between genes with damaging DNMs in probands with CHD and autism was also found.

Published
2017

14. Expanding the spectrum of novel candidate genes using trio exome sequencing and identification of monogenic cause in 27.5% of 320 families with steroid-resistant nephrotic syndrome

Author

Schneider, Ronen, primary, Shril, Shirlee, additional, Buerger, Florian, additional, Deutsch, Konstantin, additional, Yousef, Kirollos, additional, Frank, Camille N., additional, Onuchic-Whitford, Ana C., additional, Kitzler, Thomas M., additional, Mao, Youying, additional, Klämbt, Verena, additional, Zahoor, Muhammad Y., additional, Lemberg, Katharina, additional, Majmundar, Amar J., additional, Mansour, Bshara, additional, Saida, Ken, additional, Seltzsam, Steve, additional, Kolvenbach, Caroline M., additional, Merz, Lea Maria, additional, Mertens, Nils D., additional, Hermle, Tobias, additional, Mann, Nina, additional, Pantel, Dalia, additional, Halawi, Abdul A., additional, Bao, Aaron, additional, Schierbaum, Luca, additional, Schneider, Sophia, additional, Salmanullah, Daanya, additional, Ben-Dov, Iddo Z., additional, Sagiv, Itamar, additional, Eid, Loai A., additional, Awad, Hazem Subhi H., additional, Al Saffar, Muna, additional, Soliman, Neveen A., additional, Nabhan, Marwa M., additional, Kari, Jameela A., additional, El Desoky, Sherif, additional, Shalaby, Mohamed A., additional, Ooda, Said, additional, Fathy, Hanan M., additional, Mane, Shrikant, additional, Lifton, Richard P., additional, Somers, Michael J.G., additional, and Hildebrandt, Friedhelm, additional

Published
2024
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15. Generation of Monogenic Candidate Genes for Human Nephrotic Syndrome Using 3 Independent Approaches

Author

Klämbt, Verena, Mao, Youying, Schneider, Ronen, Buerger, Florian, Shamseldin, Hanan, Onuchic-Whitford, Ana C., Deutsch, Konstantin, Kitzler, Thomas M., Nakayama, Makiko, Majmundar, Amar J., Mann, Nina, Hugo, Hannah, Widmeier, Eugen, Tan, Weizhen, Rehm, Heidi L., Mane, Shrikant, Lifton, Richard P., Alkuraya, Fowzan S., Shril, Shirlee, and Hildebrandt, Friedhelm

Published
2021
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16. Recessive Mutations in SYNPO2 as a Candidate of Monogenic Nephrotic Syndrome

Author

Mao, Youying, Schneider, Ronen, van der Ven, Peter F.M., Assent, Marvin, Lohanadan, Keerthika, Klämbt, Verena, Buerger, Florian, Kitzler, Thomas M., Deutsch, Konstantin, Nakayama, Makiko, Majmundar, Amar J., Mann, Nina, Hermle, Tobias, Onuchic-Whitford, Ana C., Zhou, Wei, Margam, Nandini Nagarajan, Duncan, Roy, Marquez, Jonathan, Khokha, Mustafa, Fathy, Hanan M., Kari, Jameela A., El Desoky, Sherif, Eid, Loai A., Awad, Hazem Subhi, Al-Saffar, Muna, Mane, Shrikant, Lifton, Richard P., Fürst, Dieter O., Shril, Shirlee, and Hildebrandt, Friedhelm

Published
2021
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17. Exome Sequencing Implicates Impaired GABA Signaling and Neuronal Ion Transport in Trigeminal Neuralgia

Author

Dong, Weilai, Jin, Sheng Chih, Allocco, August, Zeng, Xue, Sheth, Amar H., Panchagnula, Shreyas, Castonguay, Annie, Lorenzo, Louis-Étienne, Islam, Barira, Brindle, Geneviève, Bachand, Karine, Hu, Jamie, Sularz, Agata, Gaillard, Jonathan, Choi, Jungmin, Dunbar, Ashley, Nelson-Williams, Carol, Kiziltug, Emre, Furey, Charuta Gavankar, Conine, Sierra, Duy, Phan Q., Kundishora, Adam J., Loring, Erin, Li, Boyang, Lu, Qiongshi, Zhou, Geyu, Liu, Wei, Li, Xinyue, Sierant, Michael C., Mane, Shrikant, Castaldi, Christopher, López-Giráldez, Francesc, Knight, James R., Sekula, Raymond F., Jr., Simard, J. Marc, Eskandar, Emad N., Gottschalk, Christopher, Moliterno, Jennifer, Günel, Murat, Gerrard, Jason L., Dib-Hajj, Sulayman, Waxman, Stephen G., Barker, Fred G., II, Alper, Seth L., Chahine, Mohamed, Haider, Shozeb, De Koninck, Yves, Lifton, Richard P., and Kahle, Kristopher T.

Published
2020
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18. Author Response: LRRC23 truncation impairs radial spoke 3 head assembly and sperm motility underlying male infertility

Author

Hwang, Jae Yeon, primary, Chai, Pengxin, additional, Nawaz, Shoaib, additional, Choi, Jungmin, additional, Lopez-Giraldez, Francesc, additional, Hussain, Shabir, additional, Bilguvar, Kaya, additional, Mane, Shrikant, additional, Lifton, Richard, additional, Ahmad, Wasim, additional, Zhang, Kai, additional, and Chung, Jean-Ju, additional

Published
2023
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20. Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus

Author

Jin, Sheng Chih, Dong, Weilai, Kundishora, Adam J., Panchagnula, Shreyas, Moreno-De-Luca, Andres, Furey, Charuta G., Allocco, August A., Walker, Rebecca L., Nelson-Williams, Carol, Smith, Hannah, Dunbar, Ashley, Conine, Sierra, Lu, Qiongshi, Zeng, Xue, Sierant, Michael C., Knight, James R., Sullivan, William, Duy, Phan Q., DeSpenza, Tyrone, Reeves, Benjamin C., Karimy, Jason K., Marlier, Arnaud, Castaldi, Christopher, Tikhonova, Irina R., Li, Boyang, Peña, Helena Perez, Broach, James R., Kabachelor, Edith M., Ssenyonga, Peter, Hehnly, Christine, Ge, Li, Keren, Boris, Timberlake, Andrew T., Goto, June, Mangano, Francesco T., Johnston, James M., Butler, William E., Warf, Benjamin C., Smith, Edward R., Schiff, Steven J., Limbrick, Jr, David D., Heuer, Gregory, Jackson, Eric M., Iskandar, Bermans J., Mane, Shrikant, Haider, Shozeb, Guclu, Bulent, Bayri, Yasar, Sahin, Yener, Duncan, Charles C., Apuzzo, Michael L. J., DiLuna, Michael L., Hoffman, Ellen J., Sestan, Nenad, Ment, Laura R., Alper, Seth L., Bilguvar, Kaya, Geschwind, Daniel H., Günel, Murat, Lifton, Richard P., and Kahle, Kristopher T.

Published
2020
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21. Mutations disrupting neuritogenesis genes confer risk for cerebral palsy

Author

Jin, Sheng Chih, Lewis, Sara A., Bakhtiari, Somayeh, Zeng, Xue, Sierant, Michael C., Shetty, Sheetal, Nordlie, Sandra M., Elie, Aureliane, Corbett, Mark A., Norton, Bethany Y., van Eyk, Clare L., Haider, Shozeb, Guida, Brandon S., Magee, Helen, Liu, James, Pastore, Stephen, Vincent, John B., Brunstrom-Hernandez, Janice, Papavasileiou, Antigone, Fahey, Michael C., Berry, Jesia G., Harper, Kelly, Zhou, Chongchen, Zhang, Junhui, Li, Boyang, Zhao, Hongyu, Heim, Jennifer, Webber, Dani L., Frank, Mahalia S. B., Xia, Lei, Xu, Yiran, Zhu, Dengna, Zhang, Bohao, Sheth, Amar H., Knight, James R., Castaldi, Christopher, Tikhonova, Irina R., López-Giráldez, Francesc, Keren, Boris, Whalen, Sandra, Buratti, Julien, Doummar, Diane, Cho, Megan, Retterer, Kyle, Millan, Francisca, Wang, Yangong, Waugh, Jeff L., Rodan, Lance, Cohen, Julie S., Fatemi, Ali, Lin, Angela E., Phillips, John P., Feyma, Timothy, MacLennan, Suzanna C., Vaughan, Spencer, Crompton, Kylie E., Reid, Susan M., Reddihough, Dinah S., Shang, Qing, Gao, Chao, Novak, Iona, Badawi, Nadia, Wilson, Yana A., McIntyre, Sarah J., Mane, Shrikant M., Wang, Xiaoyang, Amor, David J., Zarnescu, Daniela C., Lu, Qiongshi, Xing, Qinghe, Zhu, Changlian, Bilguvar, Kaya, Padilla-Lopez, Sergio, Lifton, Richard P., Gecz, Jozef, MacLennan, Alastair H., and Kruer, Michael C.

Published
2020
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22. De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies

Author

Homsy, Jason, Zaidi, Samir, Shen, Yufeng, Ware, James S, Samocha, Kaitlin E, Karczewski, Konrad J, DePalma, Steven R, McKean, David, Wakimoto, Hiroko, Gorham, Josh, Jin, Sheng Chih, Deanfield, John, Giardini, Alessandro, Porter, George A, Kim, Richard, Bilguvar, Kaya, López-Giráldez, Francesc, Tikhonova, Irina, Mane, Shrikant, Romano-Adesman, Angela, Qi, Hongjian, Vardarajan, Badri, Ma, Lijiang, Daly, Mark, Roberts, Amy E, Russell, Mark W, Mital, Seema, Newburger, Jane W, Gaynor, J William, Breitbart, Roger E, Iossifov, Ivan, Ronemus, Michael, Sanders, Stephan J, Kaltman, Jonathan R, Seidman, Jonathan G, Brueckner, Martina, Gelb, Bruce D, Goldmuntz, Elizabeth, Lifton, Richard P, Seidman, Christine E, and Chung, Wendy K

Subjects
Congenital Structural Anomalies, Genetics, Pediatric, Heart Disease, Cardiovascular, Brain, Child, Congenital Abnormalities, Exome, Heart Defects, Congenital, Humans, Mutation, Nervous System Malformations, Neurogenesis, Prognosis, RNA Splicing, RNA Splicing Factors, RNA, Messenger, RNA-Binding Proteins, Repressor Proteins, Transcription, Genetic, General Science & Technology
Abstract

Congenital heart disease (CHD) patients have an increased prevalence of extracardiac congenital anomalies (CAs) and risk of neurodevelopmental disabilities (NDDs). Exome sequencing of 1213 CHD parent-offspring trios identified an excess of protein-damaging de novo mutations, especially in genes highly expressed in the developing heart and brain. These mutations accounted for 20% of patients with CHD, NDD, and CA but only 2% of patients with isolated CHD. Mutations altered genes involved in morphogenesis, chromatin modification, and transcriptional regulation, including multiple mutations in RBFOX2, a regulator of mRNA splicing. Genes mutated in other cohorts examined for NDD were enriched in CHD cases, particularly those with coexisting NDD. These findings reveal shared genetic contributions to CHD, NDD, and CA and provide opportunities for improved prognostic assessment and early therapeutic intervention in CHD patients.

Published
2015

25. Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci

Author

Sanders, Stephan J, He, Xin, Willsey, A Jeremy, Ercan-Sencicek, A Gulhan, Samocha, Kaitlin E, Cicek, A Ercument, Murtha, Michael T, Bal, Vanessa H, Bishop, Somer L, Dong, Shan, Goldberg, Arthur P, Jinlu, Cai, Keaney, John F, Klei, Lambertus, Mandell, Jeffrey D, Moreno-De-Luca, Daniel, Poultney, Christopher S, Robinson, Elise B, Smith, Louw, Solli-Nowlan, Tor, Su, Mack Y, Teran, Nicole A, Walker, Michael F, Werling, Donna M, Beaudet, Arthur L, Cantor, Rita M, Fombonne, Eric, Geschwind, Daniel H, Grice, Dorothy E, Lord, Catherine, Lowe, Jennifer K, Mane, Shrikant M, Martin, Donna M, Morrow, Eric M, Talkowski, Michael E, Sutcliffe, James S, Walsh, Christopher A, Yu, Timothy W, Consortium, Autism Sequencing, Ledbetter, David H, Martin, Christa Lese, Cook, Edwin H, Buxbaum, Joseph D, Daly, Mark J, Devlin, Bernie, Roeder, Kathryn, and State, Matthew W

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Pediatric, Prevention, Biotechnology, Brain Disorders, Genetics, Mental Health, Intellectual and Developmental Disabilities (IDD), Human Genome, Autism, 2.1 Biological and endogenous factors, Aetiology, Mental health, Autism Spectrum Disorder, Female, Genetic Loci, Genetic Variation, Humans, Male, Protein Interaction Maps, Autism Sequencing Consortium, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Analysis of de novo CNVs (dnCNVs) from the full Simons Simplex Collection (SSC) (N = 2,591 families) replicates prior findings of strong association with autism spectrum disorders (ASDs) and confirms six risk loci (1q21.1, 3q29, 7q11.23, 16p11.2, 15q11.2-13, and 22q11.2). The addition of published CNV data from the Autism Genome Project (AGP) and exome sequencing data from the SSC and the Autism Sequencing Consortium (ASC) shows that genes within small de novo deletions, but not within large dnCNVs, significantly overlap the high-effect risk genes identified by sequencing. Alternatively, large dnCNVs are found likely to contain multiple modest-effect risk genes. Overall, we find strong evidence that de novo mutations are associated with ASD apart from the risk for intellectual disability. Extending the transmission and de novo association test (TADA) to include small de novo deletions reveals 71 ASD risk loci, including 6 CNV regions (noted above) and 65 risk genes (FDR ≤ 0.1).

Published
2015

26. A genome-wide association study of autism using the Simons Simplex Collection: Does reducing phenotypic heterogeneity in autism increase genetic homogeneity?

Author

Chaste, Pauline, Klei, Lambertus, Sanders, Stephan J, Hus, Vanessa, Murtha, Michael T, Lowe, Jennifer K, Willsey, A Jeremy, Moreno-De-Luca, Daniel, Yu, Timothy W, Fombonne, Eric, Geschwind, Daniel, Grice, Dorothy E, Ledbetter, David H, Mane, Shrikant M, Martin, Donna M, Morrow, Eric M, Walsh, Christopher A, Sutcliffe, James S, Lese Martin, Christa, Beaudet, Arthur L, Lord, Catherine, State, Matthew W, Cook, Edwin H, and Devlin, Bernie

Subjects
Humans, Genetic Predisposition to Disease, Family, Autistic Disorder, Phenotype, Polymorphism, Single Nucleotide, Female, Male, Genetic Variation, Genome-Wide Association Study, Autism Spectrum Disorder, Autism, GWAS, Genetics, Heterogeneity, Power, Genetic Testing, Pediatric, Intellectual and Developmental Disabilities (IDD), Mental Health, Human Genome, Brain Disorders, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

BackgroundPhenotypic heterogeneity in autism has long been conjectured to be a major hindrance to the discovery of genetic risk factors, leading to numerous attempts to stratify children based on phenotype to increase power of discovery studies. This approach, however, is based on the hypothesis that phenotypic heterogeneity closely maps to genetic variation, which has not been tested. Our study examines the impact of subphenotyping of a well-characterized autism spectrum disorder (ASD) sample on genetic homogeneity and the ability to discover common genetic variants conferring liability to ASD.MethodsGenome-wide genotypic data of 2576 families from the Simons Simplex Collection were analyzed in the overall sample and phenotypic subgroups defined on the basis of diagnosis, IQ, and symptom profiles. We conducted a family-based association study, as well as estimating heritability and evaluating allele scores for each phenotypic subgroup.ResultsAssociation analyses revealed no genome-wide significant association signal. Subphenotyping did not increase power substantially. Moreover, allele scores built from the most associated single nucleotide polymorphisms, based on the odds ratio in the full sample, predicted case status in subsets of the sample equally well and heritability estimates were very similar for all subgroups.ConclusionsIn genome-wide association analysis of the Simons Simplex Collection sample, reducing phenotypic heterogeneity had at most a modest impact on genetic homogeneity. Our results are based on a relatively small sample, one with greater homogeneity than the entire population; if they apply more broadly, they imply that analysis of subphenotypes is not a productive path forward for discovering genetic risk variants in ASD.

Published
2015

27. Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in insulin-producing adenomas.

Author

Cromer, M, Choi, Murim, Nelson-Williams, Carol, Fonseca, Annabelle, Kunstman, John, Korah, Reju, Overton, John, Mane, Shrikant, Kenney, Barton, Malchoff, Carl, Stalberg, Peter, Akerström, Göran, Westin, Gunnar, Hellman, Per, Carling, Tobias, Björklund, Peyman, and Lifton, Richard

Subjects
YY1, adenylyl cyclase, cAMP, exome sequencing, insulinoma, Adenylyl Cyclases, Adolescent, Adult, Aged, Aged, 80 and over, Base Sequence, Binding Sites, Blood Glucose, Calcium, Calcium Channels, Cohort Studies, Cyclic AMP, Female, Gene Expression Regulation, Humans, Insulin, Insulin-Secreting Cells, Insulinoma, Male, Middle Aged, Molecular Sequence Data, Mutation, Missense, Pancreatic Neoplasms, Protein Binding, YY1 Transcription Factor
Abstract

Insulinomas are pancreatic islet tumors that inappropriately secrete insulin, producing hypoglycemia. Exome and targeted sequencing revealed that 14 of 43 insulinomas harbored the identical somatic mutation in the DNA-binding zinc finger of the transcription factor Yin Yang 1 (YY1). Chromatin immunoprecipitation sequencing (ChIP-Seq) showed that this T372R substitution changes the DNA motif bound by YY1. Global analysis of gene expression demonstrated distinct clustering of tumors with and without YY1(T372R) mutations. Genes showing large increases in expression in YY1(T372R) tumors included ADCY1 (an adenylyl cyclase) and CACNA2D2 (a Ca(2+) channel); both are expressed at very low levels in normal β-cells and show mutation-specific YY1 binding sites. Both gene products are involved in key pathways regulating insulin secretion. Expression of these genes in rat INS-1 cells demonstrated markedly increased insulin secretion. These findings indicate that YY1(T372R) mutations are neomorphic, resulting in constitutive activation of cAMP and Ca(2+) signaling pathways involved in insulin secretion.

Published
2015

28. Homozygous loss of DIAPH1 is a novel cause of microcephaly in humans

Author

Ercan-Sencicek, A Gulhan, Jambi, Samira, Franjic, Daniel, Nishimura, Sayoko, Li, Mingfeng, El-Fishawy, Paul, Morgan, Thomas M, Sanders, Stephan J, Bilguvar, Kaya, Suri, Mohnish, Johnson, Michele H, Gupta, Abha R, Yuksel, Zafer, Mane, Shrikant, Grigorenko, Elena, Picciotto, Marina, Alberts, Arthur S, Gunel, Murat, Šestan, Nenad, and State, Matthew W

Subjects
Biochemistry and Cell Biology, Genetics, Biological Sciences, Pediatric, Neurosciences, Brain Disorders, Intellectual and Developmental Disabilities (IDD), Aetiology, 2.1 Biological and endogenous factors, Adaptor Proteins, Signal Transducing, Adolescent, Adult, Animals, Brain, Carrier Proteins, Cell Line, Child, Child, Preschool, Codon, Nonsense, Female, Formins, Homozygote, Humans, Infant, Male, Mice, Microcephaly, Pedigree, Clinical Sciences, Genetics & Heredity, Clinical sciences
Abstract

The combination of family-based linkage analysis with high-throughput sequencing is a powerful approach to identifying rare genetic variants that contribute to genetically heterogeneous syndromes. Using parametric multipoint linkage analysis and whole exome sequencing, we have identified a gene responsible for microcephaly (MCP), severe visual impairment, intellectual disability, and short stature through the mapping of a homozygous nonsense alteration in a multiply-affected consanguineous family. This gene, DIAPH1, encodes the mammalian Diaphanous-related formin (mDia1), a member of the diaphanous-related formin family of Rho effector proteins. Upon the activation of GTP-bound Rho, mDia1 generates linear actin filaments in the maintenance of polarity during adhesion, migration, and division in immune cells and neuroepithelial cells, and in driving tangential migration of cortical interneurons in the rodent. Here, we show that patients with a homozygous nonsense DIAPH1 alteration (p.Gln778*) have MCP as well as reduced height and weight. diap1 (mDia1 knockout (KO))-deficient mice have grossly normal body and brain size. However, our histological analysis of diap1 KO mouse coronal brain sections at early and postnatal stages shows unilateral ventricular enlargement, indicating that this mutant mouse shows both important similarities as well as differences with human pathology. We also found that mDia1 protein is expressed in human neuronal precursor cells during mitotic cell division and has a major impact in the regulation of spindle formation and cell division.

Published
2015

29. COL4A1 mutations as a potential novel cause of autosomal dominant CAKUT in humans

Author

Kitzler, Thomas M., Schneider, Ronen, Kohl, Stefan, Kolvenbach, Caroline M., Connaughton, Dervla M., Dai, Rufeng, Mann, Nina, Nakayama, Makiko, Majmundar, Amar J., Wu, Chen-Han W., Kari, Jameela A., El Desoky, Sherif M., Senguttuvan, Prabha, Bogdanovic, Radovan, Stajic, Natasa, Valivullah, Zaheer, Lek, Monkol, Mane, Shrikant, Lifton, Richard P., Tasic, Velibor, Shril, Shirlee, and Hildebrandt, Friedhelm

Published
2019
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30. The contribution of de novo coding mutations to autism spectrum disorder.

Author

Ronemus, Michael, Krumm, Niklas, Levy, Dan, Stessman, Holly, Witherspoon, Kali, Vives, Laura, Patterson, Karynne, Smith, Joshua, Paeper, Bryan, Nickerson, Deborah, Dea, Jeanselle, Dong, Shan, Gonzalez, Luis, Mandell, Jeffrey, Mane, Shrikant, Murtha, Michael, Sullivan, Catherine, Wigler, Michael, Yamrom, Boris, Lee, Yoon-ha, Grabowska, Ewa, Dalkic, Ertugrul, Wang, Zihua, Marks, Steven, Andrews, Peter, Leotta, Anthony, Kendall, Jude, Hakker, Inessa, Rosenbaum, Julie, Ma, Beicong, Rodgers, Linda, Troge, Jennifer, Narzisi, Giuseppe, Yoon, Seungtai, Schatz, Michael, Ye, Kenny, McCombie, W, Shendure, Jay, Eichler, Evan, Iossifov, Ivan, ORoak, Brian, Waqar, Zainulabedin, Wei, Liping, State, Matthew, Sanders, Stephan, Willsey, Arthur, and Walker, Michael

Subjects
Child, Child Development Disorders, Pervasive, Cluster Analysis, Exome, Female, Genes, Genetic Predisposition to Disease, Humans, Intelligence Tests, Male, Mutation, Open Reading Frames, Reproducibility of Results
Abstract

Whole exome sequencing has proven to be a powerful tool for understanding the genetic architecture of human disease. Here we apply it to more than 2,500 simplex families, each having a child with an autistic spectrum disorder. By comparing affected to unaffected siblings, we show that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting (LGD) mutations contribute to 12% and 9% of diagnoses, respectively. Including copy number variants, coding de novo mutations contribute to about 30% of all simplex and 45% of female diagnoses. Almost all LGD mutations occur opposite wild-type alleles. LGD targets in affected females significantly overlap the targets in males of lower intelligence quotient (IQ), but neither overlaps significantly with targets in males of higher IQ. We estimate that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation. LGD targets in the joint class overlap with published targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes. Most of the significance for the latter comes from affected females.

Published
2014

31. De Novo Insertions and Deletions of Predominantly Paternal Origin Are Associated with Autism Spectrum Disorder

Author

Dong, Shan, Walker, Michael F, Carriero, Nicholas J, DiCola, Michael, Willsey, A Jeremy, Ye, Adam Y, Waqar, Zainulabedin, Gonzalez, Luis E, Overton, John D, Frahm, Stephanie, Keaney, John F, Teran, Nicole A, Dea, Jeanselle, Mandell, Jeffrey D, Bal, Vanessa Hus, Sullivan, Catherine A, DiLullo, Nicholas M, Khalil, Rehab O, Gockley, Jake, Yuksel, Zafer, Sertel, Sinem M, Ercan-Sencicek, A Gulhan, Gupta, Abha R, Mane, Shrikant M, Sheldon, Michael, Brooks, Andrew I, Roeder, Kathryn, Devlin, Bernie, State, Matthew W, Wei, Liping, and Sanders, Stephan J

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Autism, Human Genome, Intellectual and Developmental Disabilities (IDD), Brain Disorders, Mental Health, Pediatric, Aetiology, 2.1 Biological and endogenous factors, Mental health, Child, Child Development Disorders, Pervasive, DNA, DNA-Binding Proteins, Female, Fragile X Mental Retardation Protein, Frameshift Mutation, GTP-Binding Proteins, Humans, Male, Nerve Tissue Proteins, Pedigree, Phenotype, Sequence Deletion, Sex Factors, Biochemistry and Cell Biology, Medical Physiology, Biological sciences
Abstract

Whole-exome sequencing (WES) studies have demonstrated the contribution of de novo loss-of-function single-nucleotide variants (SNVs) to autism spectrum disorder (ASD). However, challenges in the reliable detection of de novo insertions and deletions (indels) have limited inclusion of these variants in prior analyses. By applying a robust indel detection method to WES data from 787 ASD families (2,963 individuals), we demonstrate that de novo frameshift indels contribute to ASD risk (OR = 1.6; 95% CI = 1.0-2.7; p = 0.03), are more common in female probands (p = 0.02), are enriched among genes encoding FMRP targets (p = 6 × 10(-9)), and arise predominantly on the paternal chromosome (p < 0.001). On the basis of mutation rates in probands versus unaffected siblings, we conclude that de novo frameshift indels contribute to risk in approximately 3% of individuals with ASD. Finally, by observing clustering of mutations in unrelated probands, we uncover two ASD-associated genes: KMT2E (MLL5), a chromatin regulator, and RIMS1, a regulator of synaptic vesicle release.

Published
2014

32. Exome sequencing identifies a likely causative variant in 53% of families with ciliopathy-related features on renal ultrasound after excluding NPHP1 deletions

Author

Deutsch, Konstantin, Klämbt, Verena, Kitzler, Thomas M., Jobst-Schwan, Tilman, Schneider, Ronen, Buerger, Florian, Seltzsam, Steve, El Desoky, Sherif, Kari, Jameela A., Hafeez, Farkhanda, Szczepańska, Maria, Eid, Loai A., Awad, Hazem S., Al-Saffar, Muna, Soliman, Neveen A., Tasic, Velibor, Nicolas-Frank, Camille, Yousef, Kirollos, Schierbaum, Luca M., Schneider, Sophia, Halawi, Abdul, Elmubarak, Izzeldin, Lemberg, Katharina, Shril, Shirlee, Mane, Shrikant M., Rodig, Nancy, and Hildebrandt, Friedhelm

Published
2024
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33. Modest impact on risk for autism spectrum disorder of rare copy number variants at 15q11.2, specifically breakpoints 1 to 2.

Author

Chaste, Pauline, Sanders, Stephan, Mohan, Kommu, Klei, Lambertus, Song, Youeun, Murtha, Michael, Hus, Vanessa, Lowe, Jennifer, Willsey, Arthur, Moreno-De-Luca, Daniel, Yu, Timothy, Fombonne, Eric, Geschwind, Daniel, Grice, Dorothy, Ledbetter, David, Lord, Catherine, Mane, Shrikant, Martin, Donna, Morrow, Eric, Walsh, Christopher, Sutcliffe, James, State, Matthew, Martin, Christa, Devlin, Bernie, Beaudet, Arthur, Cook, Edwin, and Kim, Soo-Jeong

Subjects
15q11.2, autism, deletion, duplication, penetrance, Adult, Child, Child Development Disorders, Pervasive, Chromosome Deletion, Chromosomes, Human, Pair 15, DNA Copy Number Variations, Female, Genetic Predisposition to Disease, Humans, Male
Abstract

The proximal region of chromosome 15 is one of the genomic hotspots for copy number variants (CNVs). Among the rearrangements observed in this region, CNVs from the interval between the common breakpoints 1 and 2 (BP1 and BP2) have been reported cosegregating with autism spectrum disorder (ASD). Although evidence supporting an association between BP1-BP2 CNVs and autism accumulates, the magnitude of the effect of BP1-BP2 CNVs remains elusive, posing a great challenge to recurrence-risk counseling. To gain further insight into their pathogenicity for ASD, we estimated the penetrance of the BP1-BP2 CNVs for ASD as well as their effects on ASD-related phenotypes in a well-characterized ASD sample (n = 2525 families). Transmission disequilibrium test revealed significant preferential transmission only for the duplicated chromosome in probands (20T:9NT). The penetrance of the BP1-BP2 CNVs for ASD was low, conferring additional risks of 0.3% (deletion) and 0.8% (duplication). Stepwise regression analyses suggest a greater effect of the CNVs on ASD-related phenotype in males and when maternally inherited. Taken together, the results are consistent with BP1-BP2 CNVs as risk factors for autism. However, their effect is modest, more akin to that seen for common variants. To be consistent with the current American College of Medical Genetics guidelines for interpretation of postnatal CNV, the BP1-BP2 deletion and duplication CNVs would probably best be classified as variants of uncertain significance (VOUS): they appear to have an impact on risk, but one so modest that these CNVs do not merit pathogenic status.

Published
2014

34. Multilineage somatic activating mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia.

Author

Lim, Young H, Ovejero, Diana, Sugarman, Jeffrey S, Deklotz, Cynthia MC, Maruri, Ann, Eichenfield, Lawrence F, Kelley, Patrick K, Jüppner, Harald, Gottschalk, Michael, Tifft, Cynthia J, Gafni, Rachel I, Boyce, Alison M, Cowen, Edward W, Bhattacharyya, Nisan, Guthrie, Lori C, Gahl, William A, Golas, Gretchen, Loring, Erin C, Overton, John D, Mane, Shrikant M, Lifton, Richard P, Levy, Moise L, Collins, Michael T, and Choate, Keith A

Subjects
Skin, Humans, Nevus, Nevus, Pigmented, Skin Neoplasms, Osteomalacia, Hypophosphatemia, GTP Phosphohydrolases, Fibroblast Growth Factors, Membrane Proteins, Sequence Analysis, DNA, Gene Expression Regulation, Developmental, Mutation, Adolescent, Child, Female, Male, Proto-Oncogene Proteins p21(ras), Exome, Fibroblast Growth Factor-23, Kidney Disease, Rare Diseases, Genetics, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Underpinning research, Aetiology, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Pathologically elevated serum levels of fibroblast growth factor-23 (FGF23), a bone-derived hormone that regulates phosphorus homeostasis, result in renal phosphate wasting and lead to rickets or osteomalacia. Rarely, elevated serum FGF23 levels are found in association with mosaic cutaneous disorders that affect large proportions of the skin and appear in patterns corresponding to the migration of ectodermal progenitors. The cause and source of elevated serum FGF23 is unknown. In those conditions, such as epidermal and large congenital melanocytic nevi, skin lesions are variably associated with other abnormalities in the eye, brain and vasculature. The wide distribution of involved tissues and the appearance of multiple segmental skin and bone lesions suggest that these conditions result from early embryonic somatic mutations. We report five such cases with elevated serum FGF23 and bone lesions, four with large epidermal nevi and one with a giant congenital melanocytic nevus. Exome sequencing of blood and affected skin tissue identified somatic activating mutations of HRAS or NRAS in each case without recurrent secondary mutation, and we further found that the same mutation is present in dysplastic bone. Our finding of somatic activating RAS mutation in bone, the endogenous source of FGF23, provides the first evidence that elevated serum FGF23 levels, hypophosphatemia and osteomalacia are associated with pathologic Ras activation and may provide insight in the heretofore limited understanding of the regulation of FGF23.

Published
2014

35. Exome sequencing identifies a likely causative variant in 53% of families with ciliopathy-related features on renal ultrasound after excluding NPHP1 deletions

Author

Deutsch, Konstantin, primary, Klämbt, Verena, additional, Kitzler, Thomas M., additional, Jobst-Schwan, Tilman, additional, Schneider, Ronen, additional, Buerger, Florian, additional, Seltzsam, Steve, additional, El Desoky, Sherif, additional, Kari, Jameela A., additional, Hafeez, Farkhanda, additional, Szczepańska, Maria, additional, Eid, Loai A., additional, Awad, Hazem S., additional, Al-Saffar, Muna, additional, Soliman, Neveen A., additional, Tasic, Velibor, additional, Nicolas-Frank, Camille, additional, Yousef, Kirollos, additional, Schierbaum, Luca M., additional, Schneider, Sophia, additional, Halawi, Abdul, additional, Elmubarak, Izzeldin, additional, Lemberg, Katharina, additional, Shril, Shirlee, additional, Mane, Shrikant M., additional, Rodig, Nancy, additional, and Hildebrandt, Friedhelm, additional

Published
2023
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36. Coexpression Networks Implicate Human Midfetal Deep Cortical Projection Neurons in the Pathogenesis of Autism

Author

Willsey, A Jeremy, Sanders, Stephan J, Li, Mingfeng, Dong, Shan, Tebbenkamp, Andrew T, Muhle, Rebecca A, Reilly, Steven K, Lin, Leon, Fertuzinhos, Sofia, Miller, Jeremy A, Murtha, Michael T, Bichsel, Candace, Niu, Wei, Cotney, Justin, Ercan-Sencicek, A Gulhan, Gockley, Jake, Gupta, Abha R, Han, Wenqi, He, Xin, Hoffman, Ellen J, Klei, Lambertus, Lei, Jing, Liu, Wenzhong, Liu, Li, Lu, Cong, Xu, Xuming, Zhu, Ying, Mane, Shrikant M, Lein, Ed S, Wei, Liping, Noonan, James P, Roeder, Kathryn, Devlin, Bernie, Sestan, Nenad, and State, Matthew W

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Neurosciences, Mental Health, Intellectual and Developmental Disabilities (IDD), Pediatric, Brain Disorders, Clinical Research, Autism, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Neurological, Mental health, Animals, Brain, Child Development Disorders, Pervasive, Exome, Female, Fetus, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Mice, Mutation, Neurons, Prefrontal Cortex, Sequence Analysis, DNA, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Autism spectrum disorder (ASD) is a complex developmental syndrome of unknown etiology. Recent studies employing exome- and genome-wide sequencing have identified nine high-confidence ASD (hcASD) genes. Working from the hypothesis that ASD-associated mutations in these biologically pleiotropic genes will disrupt intersecting developmental processes to contribute to a common phenotype, we have attempted to identify time periods, brain regions, and cell types in which these genes converge. We have constructed coexpression networks based on the hcASD "seed" genes, leveraging a rich expression data set encompassing multiple human brain regions across human development and into adulthood. By assessing enrichment of an independent set of probable ASD (pASD) genes, derived from the same sequencing studies, we demonstrate a key point of convergence in midfetal layer 5/6 cortical projection neurons. This approach informs when, where, and in what cell types mutations in these specific genes may be productively studied to clarify ASD pathophysiology.

Published
2013

37. Adjusting head circumference for covariates in autism: clinical correlates of a highly heritable continuous trait.

Author

Chaste, Pauline, Klei, Lambertus, Sanders, Stephan, Murtha, Michael, Hus, Vanessa, Lowe, Jennifer, Willsey, Arthur, Moreno-De-Luca, Daniel, Yu, Timothy, Fombonne, Eric, Geschwind, Daniel, Grice, Dorothy, Ledbetter, David, Lord, Catherine, Mane, Shrikant, Lese Martin, Christa, Martin, Donna, Morrow, Eric, Walsh, Christopher, Sutcliffe, James, State, Matthew, Devlin, Bernie, Cook, Edwin, and Kim, Soo-Jeong

Subjects
ASD, IQ, autism spectrum disorder, body metrics, genetic ancestry, head circumference, Adult, Autistic Disorder, Body Weights and Measures, Child, Family, Female, Head, Humans, Intelligence, Male, Quantitative Trait, Heritable
Abstract

BACKGROUND: Brain development follows a different trajectory in children with autism spectrum disorders (ASD) than in typically developing children. A proxy for neurodevelopment could be head circumference (HC), but studies assessing HC and its clinical correlates in ASD have been inconsistent. This study investigates HC and clinical correlates in the Simons Simplex Collection cohort. METHODS: We used a mixed linear model to estimate effects of covariates and the deviation from the expected HC given parental HC (genetic deviation). After excluding individuals with incomplete data, 7225 individuals in 1891 families remained for analysis. We examined the relationship between HC/genetic deviation of HC and clinical parameters. RESULTS: Gender, age, height, weight, genetic ancestry, and ASD status were significant predictors of HC (estimate of the ASD effect = .2 cm). HC was approximately normally distributed in probands and unaffected relatives, with only a few outliers. Genetic deviation of HC was also normally distributed, consistent with a random sampling of parental genes. Whereas larger HC than expected was associated with ASD symptom severity and regression, IQ decreased with the absolute value of the genetic deviation of HC. CONCLUSIONS: Measured against expected values derived from covariates of ASD subjects, statistical outliers for HC were uncommon. HC is a strongly heritable trait, and population norms for HC would be far more accurate if covariates including genetic ancestry, height, and age were taken into account. The association of diminishing IQ with absolute deviation from predicted HC values suggests HC could reflect subtle underlying brain development and warrants further investigation.

Published
2013

38. Dominant PAX2 mutations may cause steroid-resistant nephrotic syndrome and FSGS in children

Author

Vivante, Asaf, Chacham, Orna Staretz, Shril, Shirlee, Schreiber, Ruth, Mane, Shrikant M., Pode-Shakked, Ben, and Soliman, Neveen A.

Subjects
Gene mutations -- Research, Nephrotic syndrome -- Risk factors -- Genetic aspects, Pediatric research, Health
Abstract

Background Heterozygous PAX2 mutations cause renal coloboma syndrome (RCS) [OMIM no. 120330]. RCS is a renal syndromic disease encompassing retinal coloboma and sensorineural hearing loss. Recently, a causative role for PAX2 was reported in adult-onset nephrotic syndrome secondary to focal segmental glomerulosclerosis (FSGS). However, the prevalence of PAX2 mutations among large cohort of children with steroid-resistant nephrotic syndrome (SRNS) and FSGS has not been systematically studied. Methods We employed whole-exome sequencing (WES) to identify the percentage of SRNS cases explained by monogenic mutations in known genes of SRNS/FSGS. As PAX2 mutations are not an established cause of childhood FSGS, we evaluated a cohort of 215 unrelated families with SRNS, in whom no underlying genetic etiology had been previously established. Results Using WES, we identified 3 novel causative heterozygous PAX2 mutations in 3 out of the 215 unrelated index cases studied (1.3%). All three cases were detected in individuals from families with more than one affected and compatible with an autosomal dominant mode of inheritance (3/57 familial cases studied (5.2%)). The clinical diagnosis in three out of four pediatric index patients was done during routine medical evaluation. Conclusions Our findings demonstrate high frequency of PAX2 mutations in familial form of SRNS (5.2%) and further expand the phenotypic spectrum of PAX2 heterozygous mutations to include autosomal dominant childhood-onset FSGS. These results highlight the importance of including PAX2 in the list of genes known to cause FSGS in children., Author(s): Asaf Vivante [sup.1] [sup.2] , Orna Staretz Chacham [sup.3] , Shirlee Shril [sup.1] , Ruth Schreiber [sup.4] , Shrikant M. Mane [sup.5] , Ben Pode-Shakked [sup.2] [sup.6] , Neveen [...]

Published
2019
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39. De novo mutations in histone-modifying genes in congenital heart disease.

Author

Zaidi, Samir, Choi, Murim, Wakimoto, Hiroko, Ma, Lijiang, Jiang, Jianming, Overton, John, Romano-Adesman, Angela, Bjornson, Robert, Breitbart, Roger, Brown, Kerry, Carriero, Nicholas, Cheung, Yee, Deanfield, John, DePalma, Steve, Fakhro, Khalid, Glessner, Joseph, Hakonarson, Hakon, Italia, Michael, Kaltman, Jonathan, Kaski, Juan, Kim, Richard, Kline, Jennie, Lee, Teresa, Leipzig, Jeremy, Lopez, Alexander, Mane, Shrikant, Mitchell, Laura, Newburger, Jane, Parfenov, Michael, Peer, Itsik, Porter, George, Roberts, Amy, Sachidanandam, Ravi, Subramanian, Sailakshmi, Tikhonova, Irina, Wang, Wei, Warburton, Dorothy, White, Peter, Williams, Ismee, Zhao, Hongyu, Seidman, Jonathan, Brueckner, Martina, Chung, Wendy, Gelb, Bruce, Goldmuntz, Elizabeth, Seidman, Christine, Lifton, Richard, Seiden, Howard, State, Matthew, and Sanders, Stephan

Subjects
Adult, Case-Control Studies, Child, Chromatin, DNA Mutational Analysis, Enhancer Elements, Genetic, Exome, Female, Genes, Developmental, Heart Diseases, Histones, Humans, Lysine, Male, Methylation, Mutation, Odds Ratio, Promoter Regions, Genetic
Abstract

Congenital heart disease (CHD) is the most frequent birth defect, affecting 0.8% of live births. Many cases occur sporadically and impair reproductive fitness, suggesting a role for de novo mutations. Here we compare the incidence of de novo mutations in 362 severe CHD cases and 264 controls by analysing exome sequencing of parent-offspring trios. CHD cases show a significant excess of protein-altering de novo mutations in genes expressed in the developing heart, with an odds ratio of 7.5 for damaging (premature termination, frameshift, splice site) mutations. Similar odds ratios are seen across the main classes of severe CHD. We find a marked excess of de novo mutations in genes involved in the production, removal or reading of histone 3 lysine 4 (H3K4) methylation, or ubiquitination of H2BK120, which is required for H3K4 methylation. There are also two de novo mutations in SMAD2, which regulates H3K27 methylation in the embryonic left-right organizer. The combination of both activating (H3K4 methylation) and inactivating (H3K27 methylation) chromatin marks characterizes poised promoters and enhancers, which regulate expression of key developmental genes. These findings implicate de novo point mutations in several hundreds of genes that collectively contribute to approximately 10% of severe CHD.

Published
2013

40. Genomic Analysis of Non-NF2 Meningiomas Reveals Mutations in TRAF7, KLF4, AKT1, and SMO

Author

Clark, Victoria E, Erson-Omay, E Zeynep, Serin, Akdes, Yin, Jun, Cotney, Justin, Özduman, Koray, Avşar, Timuçin, Li, Jie, Murray, Phillip B, Henegariu, Octavian, Yilmaz, Saliha, Günel, Jennifer Moliterno, Carrión-Grant, Geneive, Yılmaz, Baran, Grady, Conor, Tanrıkulu, Bahattin, Bakırcıoğlu, Mehmet, Kaymakçalan, Hande, Caglayan, Ahmet Okay, Sencar, Leman, Ceyhun, Emre, Atik, A Fatih, Bayri, Yaşar, Bai, Hanwen, Kolb, Luis E, Hebert, Ryan M, Omay, S Bulent, Mishra-Gorur, Ketu, Choi, Murim, Overton, John D, Holland, Eric C, Mane, Shrikant, State, Matthew W, Bilgüvar, Kaya, Baehring, Joachim M, Gutin, Philip H, Piepmeier, Joseph M, Vortmeyer, Alexander, Brennan, Cameron W, Pamir, M Necmettin, Kılıç, Türker, Lifton, Richard P, Noonan, James P, Yasuno, Katsuhito, and Günel, Murat

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Brain Disorders, Rare Diseases, Brain Cancer, Neurosciences, Human Genome, Cancer, Adult, Aged, Aged, 80 and over, Brain Neoplasms, Chromosomes, Human, Pair 22, DNA Mutational Analysis, Female, Genes, Neurofibromatosis 2, Genomic Instability, Genomics, Humans, Kruppel-Like Factor 4, Kruppel-Like Transcription Factors, Male, Meningeal Neoplasms, Meningioma, Middle Aged, Mutation, Neoplasm Grading, Proto-Oncogene Proteins c-akt, Receptors, G-Protein-Coupled, Smoothened Receptor, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, General Science & Technology
Abstract

We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1(E17K), a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ~5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive-nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics.

Published
2013

41. CELA2A mutations predispose to early-onset atherosclerosis and metabolic syndrome and affect plasma insulin and platelet activation

Author

Esteghamat, Fatemehsadat, Broughton, James S., Smith, Emily, Cardone, Rebecca, Tyagi, Tarun, Guerra, Mateus, Szabó, András, Ugwu, Nelson, Mani, Mitra V., Azari, Bani, Kayingo, Gerald, Chung, Sunny, Fathzadeh, Mohsen, Weiss, Ephraim, Bender, Jeffrey, Mane, Shrikant, Lifton, Richard P., Adeniran, Adebowale, Nathanson, Michael H., Gorelick, Fred S., Hwa, John, Sahin-Tóth, Miklós, Belfort-DeAguiar, Renata, Kibbey, Richard G., and Mani, Arya

Published
2019
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42. Insights into genetics, human biology and disease gleaned from family based genomic studies

Author

Posey, Jennifer E., O’Donnell-Luria, Anne H., Chong, Jessica X., Harel, Tamar, Jhangiani, Shalini N., Coban Akdemir, Zeynep H., Buyske, Steven, Pehlivan, Davut, Carvalho, Claudia M. B., Baxter, Samantha, Sobreira, Nara, Liu, Pengfei, Wu, Nan, Rosenfeld, Jill A., Kumar, Sushant, Avramopoulos, Dimitri, White, Janson J., Doheny, Kimberly F., Witmer, P. Dane, Boehm, Corinne, Sutton, V. Reid, Muzny, Donna M., Boerwinkle, Eric, Günel, Murat, Nickerson, Deborah A., Mane, Shrikant, MacArthur, Daniel G., Gibbs, Richard A., Hamosh, Ada, Lifton, Richard P., Matise, Tara C., Rehm, Heidi L., Gerstein, Mark, Bamshad, Michael J., Valle, David, Lupski, James R., and Centers for Mendelian Genomics

Published
2019
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43. Common genetic variants, acting additively, are a major source of risk for autism.

Author

Klei, Lambertus, Sanders, Stephan, Murtha, Michael, Hus, Vanessa, Lowe, Jennifer, Willsey, Arthur, Moreno-De-Luca, Daniel, Yu, Timothy, Fombonne, Eric, Geschwind, Daniel, Grice, Dorothy, Ledbetter, David, Lord, Catherine, Mane, Shrikant, Martin, Christa, Martin, Donna, Morrow, Eric, Walsh, Christopher, Melhem, Nadine, Chaste, Pauline, Sutcliffe, James, State, Matthew, Cook, Edwin, Roeder, Kathryn, and Devlin, Bernie

Abstract

BACKGROUND: Autism spectrum disorders (ASD) are early onset neurodevelopmental syndromes typified by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive behaviors. While rare and especially de novo genetic variation are known to affect liability, whether common genetic polymorphism plays a substantial role is an open question and the relative contribution of genes and environment is contentious. It is probable that the relative contributions of rare and common variation, as well as environment, differs between ASD families having only a single affected individual (simplex) versus multiplex families who have two or more affected individuals. METHODS: By using quantitative genetics techniques and the contrast of ASD subjects to controls, we estimate what portion of liability can be explained by additive genetic effects, known as narrow-sense heritability. We evaluate relatives of ASD subjects using the same methods to evaluate the assumptions of the additive model and partition families by simplex/multiplex status to determine how heritability changes with status. RESULTS: By analyzing common variation throughout the genome, we show that common genetic polymorphism exerts substantial additive genetic effects on ASD liability and that simplex/multiplex family status has an impact on the identified composition of that risk. As a fraction of the total variation in liability, the estimated narrow-sense heritability exceeds 60% for ASD individuals from multiplex families and is approximately 40% for simplex families. By analyzing parents, unaffected siblings and alleles not transmitted from parents to their affected children, we conclude that the data for simplex ASD families follow the expectation for additive models closely. The data from multiplex families deviate somewhat from an additive model, possibly due to parental assortative mating. CONCLUSIONS: Our results, when viewed in the context of results from genome-wide association studies, demonstrate that a myriad of common variants of very small effect impacts ASD liability.

Published
2012

44. Complement Factor H Polymorphism in Age-Related Macular Degeneration

Author

Klein, Robert J., Zeiss, Caroline, Chew, Emily Y., Tsai, Jen-Yue, Sackler, Richard S., Haynes, Chad, Henning, Alice K., SanGiovanni, John Paul, Mane, Shrikant M., Mayne, Susan T., Bracken, Michael B., Ferris, Frederick L., Ott, Jurg, Barnstable, Colin, and Hoh, Josephine

Published
2005

45. Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations.

Author

Bilgüvar, Kaya, Oztürk, Ali Kemal, Louvi, Angeliki, Kwan, Kenneth Y, Choi, Murim, Tatli, Burak, Yalnizoğlu, Dilek, Tüysüz, Beyhan, Cağlayan, Ahmet Okay, Gökben, Sarenur, Kaymakçalan, Hande, Barak, Tanyeri, Bakircioğlu, Mehmet, Yasuno, Katsuhito, Ho, Winson, Sanders, Stephan, Zhu, Ying, Yilmaz, Sanem, Dinçer, Alp, Johnson, Michele H, Bronen, Richard A, Koçer, Naci, Per, Hüseyin, Mane, Shrikant, Pamir, Mehmet Necmettin, Yalçinkaya, Cengiz, Kumandaş, Sefer, Topçu, Meral, Ozmen, Meral, Sestan, Nenad, Lifton, Richard P, State, Matthew W, and Günel, Murat

Subjects
Brain, Animals, Humans, Mice, Microcephaly, Brain Diseases, Nerve Tissue Proteins, Pedigree, DNA Mutational Analysis, Base Sequence, Genes, Recessive, Mutation, Molecular Sequence Data, Female, Male, Genes, Recessive, General Science & Technology
Abstract

The development of the human cerebral cortex is an orchestrated process involving the generation of neural progenitors in the periventricular germinal zones, cell proliferation characterized by symmetric and asymmetric mitoses, followed by migration of post-mitotic neurons to their final destinations in six highly ordered, functionally specialized layers. An understanding of the molecular mechanisms guiding these intricate processes is in its infancy, substantially driven by the discovery of rare mutations that cause malformations of cortical development. Mapping of disease loci in putative Mendelian forms of malformations of cortical development has been hindered by marked locus heterogeneity, small kindred sizes and diagnostic classifications that may not reflect molecular pathogenesis. Here we demonstrate the use of whole-exome sequencing to overcome these obstacles by identifying recessive mutations in WD repeat domain 62 (WDR62) as the cause of a wide spectrum of severe cerebral cortical malformations including microcephaly, pachygyria with cortical thickening as well as hypoplasia of the corpus callosum. Some patients with mutations in WDR62 had evidence of additional abnormalities including lissencephaly, schizencephaly, polymicrogyria and, in one instance, cerebellar hypoplasia, all traits traditionally regarded as distinct entities. In mice and humans, WDR62 transcripts and protein are enriched in neural progenitors within the ventricular and subventricular zones. Expression of WDR62 in the neocortex is transient, spanning the period of embryonic neurogenesis. Unlike other known microcephaly genes, WDR62 does not apparently associate with centrosomes and is predominantly nuclear in localization. These findings unify previously disparate aspects of cerebral cortical development and highlight the use of whole-exome sequencing to identify disease loci in settings in which traditional methods have proved challenging.

Published
2010

46. 169 Exome Sequencing Implicates Endothelial Ras Signaling Network in Vein of Galen Aneurysmal Malformation

Author

Mekbib, Kedous Y., primary, Zhao, Shujuan, additional, Nelson-Williams, Carol, additional, Prendergast, Andrew, additional, Zeng, Xue, additional, Rolle, Myron, additional, Shohfi, John, additional, Smith, Hannah, additional, Ocken, Jack, additional, Moyer, Quentin, additional, Piwowarczyk, Paulina, additional, Allington, Garrett, additional, Dong, Weilai, additional, van der Ent, Martijn A., additional, Chen, Di, additional, Li, Boyang, additional, Duran, Daniel, additional, Mane, Shrikant M., additional, Walcott, Brian Patrick, additional, Stapleton, Christopher J., additional, Aagaard-Kienitz, Beverly, additional, Rodesch, Georges, additional, Jackson, Eric M., additional, Smith, Edward R., additional, Orbach, Darren, additional, Berenstein, Alejandro, additional, Bilguvar, Kaya, additional, Zhao, Hongyu, additional, Erson-Omay, Zeynep, additional, King, Philip D., additional, Huttner, Anita, additional, Lifton, Richard, additional, Boggon, Titus, additional, Nicoli, Stefania, additional, Jin, Sheng Chih, additional, and Kahle, Kristopher, additional

Published
2023
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47. Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial–mesenchymal transition

Author

Zhao, Siming, Bellone, Stefania, Lopez, Salvatore, Thakral, Durga, Schwab, Carlton, English, Diana P., Black, Jonathan, Cocco, Emiliano, Choi, Jungmin, Zammataro, Luca, Predolini, Federica, Bonazzoli, Elena, Bi, Mark, Buza, Natalia, Hui, Pei, Wong, Serena, Abu-Khalaf, Maysa, Ravaggi, Antonella, Bignotti, Eliana, Bandiera, Elisabetta, Romani, Chiara, Todeschini, Paola, Tassi, Renata, Zanotti, Laura, Odicino, Franco, Pecorelli, Sergio, Donzelli, Carla, Ardighieri, Laura, Facchetti, Fabio, Falchetti, Marcella, Silasi, Dan-Arin, Ratner, Elena, Azodi, Masoud, Schwartz, Peter E., Mane, Shrikant, Angioli, Roberto, Terranova, Corrado, Quick, Charles Matthew, Edraki, Babak, Bilgüvar, Kaya, Lee, Moses, Choi, Murim, Stiegler, Amy L., Boggon, Titus J., Schlessinger, Joseph, Lifton, Richard P., and Santin, Alessandro D.

Published
2016

48. Advillin acts upstream of phospholipase C [epsilon]1 in steroid-resistant nephrotic syndrome

Author

Rao, Jia, Ashraf, Shazia, Tan, Weizhen, van der Ven, Amelie T., Gee, Heon Yung, Braun, Daniela A., Feher, Krisztina, George, Sudeep P., Esmaeilniakooshkghazi, Amin, Choi, Won-Il, Jobst-Schwan, Tilman, Schneider, Ronen, Schmidt, Johanna Magdalena, Widmeier, Eugen, Warejko, Jillian K., Hermle, Tobias, Schapiro, David, Lovric, Svjetlana, Shril, Shirlee, Daga, Ankana, Nayir, Ahmet, Shenoy, Mohan, Tse, Yincent, Bald, Martin, Helmchen, Udo, Mir, Sevgi, Berdeli, Afig, Kari, Jameela A., Desoky, Sherif El, Soliman, Neveen A., Bagga, Arvind, Mane, Shrikant, Jairajpuri, Mohamad A., Lifton, Richard P., Khurana, Seema, Martins, Jose C., and Hildebrandt, Friedhelm

Subjects
Nephrotic syndrome -- Causes of -- Research, Cytoskeleton -- Research, Chronic kidney failure -- Genetic aspects, Health care industry
Abstract

Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of chronic kidney disease. Here, we identified recessive mutations in the gene encoding the actin-binding protein advillin (AVIL) in 3 unrelated families with SRNS. While all AVIL mutations resulted in a marked loss of its actin-bundling ability, truncation of AVIL also disrupted colocalization with F-actin, thereby leading to impaired actin binding and severing. Additionally, AVIL colocalized and interacted with the phospholipase enzyme PLCE1 and with the ARP2/3 actin-modulating complex. Knockdown of AVIL in human podocytes reduced actin stress fibers at the cell periphery, prevented recruitment of PLCE1 to the ARP3-rich lamellipodia, blocked EGF-induced generation of diacylglycerol (DAG) by PLCE1, and attenuated the podocyte migration rate (PMR). These effects were reversed by overexpression of WT AVIL but not by overexpression of any of the 3 patient-derived AVIL mutants. The PMR was increased by overexpression of WT Avilor PLCE1, or by EGF stimulation; however, this increased PMR was ameliorated by inhibition of the ARP2/3 complex, indicating that ARP-dependent lamellipodia formation occurs downstream of AVIL and PLCE1 function. Together, these results delineate a comprehensive pathogenic axis of SRNS that integrates loss of AVIL function with alterations in the action of PLCE1, an established SRNS protein., Introduction Nephrotic syndrome (NS) is characterized by proteinuria caused by disruption of the glomerular filtration barrier (1). It is the second most frequent cause of chronic kidney disease before the [...]

Published
2017
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49. Table S3 from Early Assessment of Lung Cancer Immunotherapy Response via Circulating Tumor DNA

Author

Goldberg, Sarah B., primary, Narayan, Azeet, primary, Kole, Adam J., primary, Decker, Roy H., primary, Teysir, Jimmitti, primary, Carriero, Nicholas J., primary, Lee, Angela, primary, Nemati, Roxanne, primary, Nath, Sameer K., primary, Mane, Shrikant M., primary, Deng, Yanhong, primary, Sukumar, Nitin, primary, Zelterman, Daniel, primary, Boffa, Daniel J., primary, Politi, Katerina, primary, Gettinger, Scott N., primary, Wilson, Lynn D., primary, Herbst, Roy S., primary, and Patel, Abhijit A., primary

Published
2023
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50. Supplementary Methods, Figures S1-6, Tables S1,2,4,6-8 from Early Assessment of Lung Cancer Immunotherapy Response via Circulating Tumor DNA

Author

Goldberg, Sarah B., primary, Narayan, Azeet, primary, Kole, Adam J., primary, Decker, Roy H., primary, Teysir, Jimmitti, primary, Carriero, Nicholas J., primary, Lee, Angela, primary, Nemati, Roxanne, primary, Nath, Sameer K., primary, Mane, Shrikant M., primary, Deng, Yanhong, primary, Sukumar, Nitin, primary, Zelterman, Daniel, primary, Boffa, Daniel J., primary, Politi, Katerina, primary, Gettinger, Scott N., primary, Wilson, Lynn D., primary, Herbst, Roy S., primary, and Patel, Abhijit A., primary

Published
2023
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