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1. Correction: Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Author

Matuozzo, Daniela, Talouarn, Estelle, Marchal, Astrid, Zhang, Peng, Manry, Jeremy, Seeleuthner, Yoann, Zhang, Yu, Bolze, Alexandre, Chaldebas, Matthieu, Milisavljevic, Baptiste, Gervais, Adrian, Bastard, Paul, Asano, Takaki, Bizien, Lucy, Barzaghi, Federica, Abolhassani, Hassan, Tayoun, Ahmad Abou, Aiuti, Alessandro, Darazam, Ilad Alavi, Allende, Luis M., Alonso-Arias, Rebeca, Arias, Andrés Augusto, Aytekin, Gokhan, Bergman, Peter, Bondesan, Simone, Bryceson, Yenan T., Bustos, Ingrid G., Cabrera-Marante, Oscar, Carcel, Sheila, Carrera, Paola, Casari, Giorgio, Chaïbi, Khalil, Colobran, Roger, Condino-Neto, Antonio, Covill, Laura E., Delmonte, Ottavia M., Zein, Loubna El, Flores, Carlos, Gregersen, Peter K., Gut, Marta, Haerynck, Filomeen, Halwani, Rabih, Hancerli, Selda, Hammarström, Lennart, Hatipoğlu, Nevin, Karbuz, Adem, Keles, Sevgi, Kyheng, Christèle, Leon-Lopez, Rafael, Franco, Jose Luis, Mansouri, Davood, Martinez-Picado, Javier, Akcan, Ozge Metin, Migeotte, Isabelle, Morange, Pierre-Emmanuel, Morelle, Guillaume, Martin-Nalda, Andrea, Novelli, Giuseppe, Novelli, Antonio, Ozcelik, Tayfun, Palabiyik, Figen, Pan-Hammarström, Qiang, de Diego, Rebeca Pérez, Planas-Serra, Laura, Pleguezuelo, Daniel E., Prando, Carolina, Pujol, Aurora, Reyes, Luis Felipe, Rivière, Jacques G., Rodriguez-Gallego, Carlos, Rojas, Julian, Rovere-Querini, Patrizia, Schlüter, Agatha, Shahrooei, Mohammad, Sobh, Ali, Soler-Palacin, Pere, Tandjaoui-Lambiotte, Yacine, Tipu, Imran, Tresoldi, Cristina, Troya, Jesus, van de Beek, Diederik, Zatz, Mayana, Zawadzki, Pawel, Al-Muhsen, Saleh Zaid, Alosaimi, Mohammed Faraj, Alsohime, Fahad M., Baris-Feldman, Hagit, Butte, Manish J., Constantinescu, Stefan N., Cooper, Megan A., Dalgard, Clifton L., Fellay, Jacques, Heath, James R., Lau, Yu-Lung, Lifton, Richard P., Maniatis, Tom, Mogensen, Trine H., von Bernuth, Horst, Lermine, Alban, Vidaud, Michel, Boland, Anne, Deleuze, Jean-François, Nussbaum, Robert, Kahn-Kirby, Amanda, Mentre, France, Tubiana, Sarah, Gorochov, Guy, Tubach, Florence, Hausfater, Pierre, Meyts, Isabelle, Zhang, Shen-Ying, Puel, Anne, Notarangelo, Luigi D., Boisson-Dupuis, Stephanie, Su, Helen C., Boisson, Bertrand, Jouanguy, Emmanuelle, Casanova, Jean-Laurent, Zhang, Qian, Abel, Laurent, and Cobat, Aurélie

Published
2024
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2. Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Author

Matuozzo, Daniela, Talouarn, Estelle, Marchal, Astrid, Zhang, Peng, Manry, Jeremy, Seeleuthner, Yoann, Zhang, Yu, Bolze, Alexandre, Chaldebas, Matthieu, Milisavljevic, Baptiste, Gervais, Adrian, Bastard, Paul, Asano, Takaki, Bizien, Lucy, Barzaghi, Federica, Abolhassani, Hassan, Abou Tayoun, Ahmad, Aiuti, Alessandro, Alavi Darazam, Ilad, Allende, Luis M, Alonso-Arias, Rebeca, Arias, Andrés Augusto, Aytekin, Gokhan, Bergman, Peter, Bondesan, Simone, Bryceson, Yenan T, Bustos, Ingrid G, Cabrera-Marante, Oscar, Carcel, Sheila, Carrera, Paola, Casari, Giorgio, Chaïbi, Khalil, Colobran, Roger, Condino-Neto, Antonio, Covill, Laura E, Delmonte, Ottavia M, El Zein, Loubna, Flores, Carlos, Gregersen, Peter K, Gut, Marta, Haerynck, Filomeen, Halwani, Rabih, Hancerli, Selda, Hammarström, Lennart, Hatipoğlu, Nevin, Karbuz, Adem, Keles, Sevgi, Kyheng, Christèle, Leon-Lopez, Rafael, Franco, Jose Luis, Mansouri, Davood, Martinez-Picado, Javier, Metin Akcan, Ozge, Migeotte, Isabelle, Morange, Pierre-Emmanuel, Morelle, Guillaume, Martin-Nalda, Andrea, Novelli, Giuseppe, Novelli, Antonio, Ozcelik, Tayfun, Palabiyik, Figen, Pan-Hammarström, Qiang, de Diego, Rebeca Pérez, Planas-Serra, Laura, Pleguezuelo, Daniel E, Prando, Carolina, Pujol, Aurora, Reyes, Luis Felipe, Rivière, Jacques G, Rodriguez-Gallego, Carlos, Rojas, Julian, Rovere-Querini, Patrizia, Schlüter, Agatha, Shahrooei, Mohammad, Sobh, Ali, Soler-Palacin, Pere, Tandjaoui-Lambiotte, Yacine, Tipu, Imran, Tresoldi, Cristina, Troya, Jesus, van de Beek, Diederik, Zatz, Mayana, Zawadzki, Pawel, Al-Muhsen, Saleh Zaid, Alosaimi, Mohammed Faraj, Alsohime, Fahad M, Baris-Feldman, Hagit, Butte, Manish J, Constantinescu, Stefan N, Cooper, Megan A, Dalgard, Clifton L, Fellay, Jacques, Heath, James R, Lau, Yu-Lung, Lifton, Richard P, Maniatis, Tom, Mogensen, Trine H, von Bernuth, Horst, Lermine, Alban, and Vidaud, Michel

Subjects
Clinical Research, Infectious Diseases, Pneumonia & Influenza, Genetics, Human Genome, Prevention, 2.1 Biological and endogenous factors, Aetiology, Humans, Young Adult, Adult, Middle Aged, COVID-19, SARS-CoV-2, Toll-Like Receptor 3, Toll-Like Receptor 7, Interferon Type I, Autoantibodies, COVID Human Genetic Effort, COVIDeF Study Group, French COVID Cohort Study Group, CoV-Contact Cohort, COVID-STORM Clinicians, COVID Clinicians, Orchestra Working Group, Amsterdam UMC Covid-19 Biobank, NIAID-USUHS COVID Study Group, Immunity, Rare variants, Type I interferon, Clinical Sciences
Abstract

BackgroundWe previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P = 1.1 × 10-4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3-8.2], P = 2.1 × 10-4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1-2635.4], P = 3.4 × 10-3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3-8.4], P = 7.7 × 10-8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10-5).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.

Published
2023

3. Whole-exome sequencing reveals damaging gene variants associated with hypoalphalipoproteinemia

Author

Dong, Weilai, Wong, Karen HY, Liu, Youbin, Levy-Sakin, Michal, Hung, Wei-Chien, Li, Mo, Li, Boyang, Jin, Sheng Chih, Choi, Jungmin, Lopez-Giraldez, Francesc, Vaka, Dedeepya, Poon, Annie, Chu, Catherine, Lao, Richard, Balamir, Melek, Movsesyan, Irina, Malloy, Mary J, Zhao, Hongyu, Kwok, Pui-Yan, Kane, John P, Lifton, Richard P, and Pullinger, Clive R

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Atherosclerosis, Heart Disease - Coronary Heart Disease, Cardiovascular, Human Genome, Clinical Research, Cancer, Cancer Genomics, Heart Disease, 2.1 Biological and endogenous factors, Cholesterol, HDL, Genome-Wide Association Study, Heterozygote, Humans, Hypoalphalipoproteinemias, Exome Sequencing, dyslipidemia, genetics, HDL, LDL, lipoproteins, prebeta-1 HDL, reverse cholesterol transport, triglycerides, Biochemistry and Cell Biology, Medical Biochemistry and Metabolomics, Biochemistry & Molecular Biology, Biochemistry and cell biology, Medical biochemistry and metabolomics
Abstract

Low levels of high density lipoprotein-cholesterol (HDL-C) are associated with an elevated risk of arteriosclerotic coronary heart disease. Heritability of HDL-C levels is high. In this research discovery study, we used whole-exome sequencing to identify damaging gene variants that may play significant roles in determining HDL-C levels. We studied 204 individuals with a mean HDL-C level of 27.8 ± 6.4 mg/dl (range: 4-36 mg/dl). Data were analyzed by statistical gene burden testing and by filtering against candidate gene lists. We found 120 occurrences of probably damaging variants (116 heterozygous; four homozygous) among 45 of 104 recognized HDL candidate genes. Those with the highest prevalence of damaging variants were ABCA1 (n = 20), STAB1 (n = 9), OSBPL1A (n = 8), CPS1 (n = 8), CD36 (n = 7), LRP1 (n = 6), ABCA8 (n = 6), GOT2 (n = 5), AMPD3 (n = 5), WWOX (n = 4), and IRS1 (n = 4). Binomial analysis for damaging missense or loss-of-function variants identified the ABCA1 and LDLR genes at genome-wide significance. In conclusion, whole-exome sequencing of individuals with low HDL-C showed the burden of damaging rare variants in the ABCA1 and LDLR genes is particularly high and revealed numerous occurrences in HDL candidate genes, including many genes identified in genome-wide association study reports. Many of these genes are involved in cancer biology, which accords with epidemiologic findings of the association of HDL deficiency with increased risk of cancer, thus presenting a new area of interest in HDL genomics.

Published
2022

4. 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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5. 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

6. 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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7. The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies

Author

Manry, Jérémy, Bastard, Paul, Gervais, Adrian, Le Voyer, Tom, Rosain, Jérémie, Philippot, Quentin, Michailidis, Eleftherios, Hoffmann, Hans-Heinrich, Eto, Shohei, Garcia-Prat, Marina, Bizien, Lucy, Parra-Martínez, Alba, Yang, Rui, Haljasmägi, Liis, Migaud, Mélanie, Särekannu, Karita, Maslovskaja, Julia, de Prost, Nicolas, Tandjaoui-Lambiotte, Yacine, Luyt, Charles-Edouard, Amador-Borrero, Blanca, Gaudet, Alexandre, Poissy, Julien, Morel, Pascal, Richard, Pascale, Cognasse, Fabrice, Troya, Jesús, Trouillet-Assant, Sophie, Belot, Alexandre, Saker, Kahina, Garçon, Pierre, Rivière, Jacques G., Lagier, Jean-Christophe, Gentile, Stéphanie, Rosen, Lindsey B., Shaw, Elana, Morio, Tomohiro, Tanaka, Junko, Dalmau, David, Tharaux, Pierre-Louis, Sene, Damien, Stepanian, Alain, Mégarbane, Bruno, Triantafyllia, Vasiliki, Fekkar, Arnaud, Heath, James R., Franco, José Luis, Anaya, Juan-Manuel, Solé-Violán, Jordi, Imberti, Luisa, Biondi, Andrea, Bonfanti, Paolo, Castagnoli, Riccardo, Delmonte, Ottavia M., Zhang, Yu, Snow, Andrew L., Holland, Steven M., Biggs, Catherine M., Moncada-Vélez, Marcela, Arias, Andrés Augusto, Lorenzo, Lazaro, Boucherit, Soraya, Anglicheau, Dany, Planas, Anna M., Haerynck, Filomeen, Duvlis, Sotirija, Ozcelik, Tayfun, Keles, Sevgi, Bousfiha, Ahmed A., Bakkouri, Jalila El, Ramirez-Santana, Carolina, Paul, Stéphane, Pan-Hammarström, Qiang, Hammarström, Lennart, Dupont, Annabelle, Kurolap, Alina, Metz, Christine N., Aiuti, Alessandro, Casari, Giorgio, Lampasona, Vito, Ciceri, Fabio, Barreiros, Lucila A., Dominguez-Garrido, Elena, Vidigal, Mateus, Zatz, Mayana, van de Beek, Diederik, Sahanic, Sabina, Tancevski, Ivan, Stepanovskyy, Yurii, Boyarchuk, Oksana, Nukui, Yoko, Tsumura, Miyuki, Vidaur, Loreto, Tangye, Stuart G., Burrel, Sonia, Duffy, Darragh, Quintana-Murci, Lluis, Klocperk, Adam, Kann, Nelli Y., Shcherbina, Anna, Lau, Yu-Lung, Leung, Daniel, Coulongeat, Matthieu, Marlet, Julien, Koning, Rutger, Reyes, Luis Felipe, Chauvineau-Grenier, Angélique, Venet, Fabienne, Monneret, Guillaume, Nussenzweig, Michel C., Arrestier, Romain, Boudhabhay, Idris, Baris-Feldman, Hagit, Hagin, David, Wauters, Joost, Meyts, Isabelle, Dyer, Adam H., Kennelly, Sean P., Bourke, Nollaig M., Halwani, Rabih, Sharif-Askari, Fatemeh Saheb, Dorgham, Karim, Sallette, Jérôme, Sedkaoui, Souad Mehlal, AlKhater, Suzan, Rigo-Bonnin, Raúl, Morandeira, Francisco, Roussel, Lucie, Vinh, Donald C., Erikstrup, Christian, Condino-Neto, Antonio, Prando, Carolina, Bondarenko, Anastasiia, Spaan, András N., Gilardin, Laurent, Fellay, Jacques, Lyonnet, Stanislas, Bilguvar, Kaya, Lifton, Richard P., Mane, Shrikant, Anderson, Mark S., Boisson, Bertrand, Béziat, Vivien, Zhang, Shen-Ying, Andreakos, Evangelos, Hermine, Olivier, Pujol, Aurora, Peterson, Pärt, Mogensen, Trine H., Rowen, Lee, Mond, James, Debette, Stéphanie, de Lamballerie, Xavier, Burdet, Charles, Bouadma, Lila, Zins, Marie, Soler-Palacin, Pere, Colobran, Roger, Gorochov, Guy, Solanich, Xavier, Susen, Sophie, Martinez-Picado, Javier, Raoult, Didier, Vasse, Marc, Gregersen, Peter K., Piemonti, Lorenzo, Rodríguez-Gallego, Carlos, Notarangelo, Luigi D., Su, Helen C., Kisand, Kai, Okada, Satoshi, Puel, Anne, Jouanguy, Emmanuelle, Rice, Charles M., Tiberghien, Pierre, Zhang, Qian, Casanova, Jean-Laurent, Abel, Laurent, and Cobat, Aurélie

Published
2022

8. EM-mosaic detects mosaic point mutations that contribute to congenital heart disease

Author

Hsieh, Alexander, Morton, Sarah U, Willcox, Jon AL, Gorham, Joshua M, Tai, Angela C, Qi, Hongjian, DePalma, Steven, McKean, David, Griffin, Emily, Manheimer, Kathryn B, Bernstein, Daniel, Kim, Richard W, Newburger, Jane W, Porter, George A, Srivastava, Deepak, Tristani-Firouzi, Martin, Brueckner, Martina, Lifton, Richard P, Goldmuntz, Elizabeth, Gelb, Bruce D, Chung, Wendy K, Seidman, Christine E, Seidman, JG, and Shen, Yufeng

Subjects
Biological Sciences, Genetics, Cardiovascular, Human Genome, Clinical Research, Heart Disease, 2.1 Biological and endogenous factors, Aetiology, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Adolescent, Adult, Child, Child, Preschool, Heart Defects, Congenital, Humans, Infant, Mosaicism, Point Mutation, Software, Young Adult, Mosaic, Somatic, Congenital heart disease, Exome sequencing, Clinical Sciences
Abstract

BackgroundThe contribution of somatic mosaicism, or genetic mutations arising after oocyte fertilization, to congenital heart disease (CHD) is not well understood. Further, the relationship between mosaicism in blood and cardiovascular tissue has not been determined.MethodsWe developed a new computational method, EM-mosaic (Expectation-Maximization-based detection of mosaicism), to analyze mosaicism in exome sequences derived primarily from blood DNA of 2530 CHD proband-parent trios. To optimize this method, we measured mosaic detection power as a function of sequencing depth. In parallel, we analyzed our cohort using MosaicHunter, a Bayesian genotyping algorithm-based mosaic detection tool, and compared the two methods. The accuracy of these mosaic variant detection algorithms was assessed using an independent resequencing method. We then applied both methods to detect mosaicism in cardiac tissue-derived exome sequences of 66 participants for which matched blood and heart tissue was available.ResultsEM-mosaic detected 326 mosaic mutations in blood and/or cardiac tissue DNA. Of the 309 detected in blood DNA, 85/97 (88%) tested were independently confirmed, while 7/17 (41%) candidates of 17 detected in cardiac tissue were confirmed. MosaicHunter detected an additional 64 mosaics, of which 23/46 (50%) among 58 candidates from blood and 4/6 (67%) of 6 candidates from cardiac tissue confirmed. Twenty-five mosaic variants altered CHD-risk genes, affecting 1% of our cohort. Of these 25, 22/22 candidates tested were confirmed. Variants predicted as damaging had higher variant allele fraction than benign variants, suggesting a role in CHD. The estimated true frequency of mosaic variants above 10% mosaicism was 0.14/person in blood and 0.21/person in cardiac tissue. Analysis of 66 individuals with matched cardiac tissue available revealed both tissue-specific and shared mosaicism, with shared mosaics generally having higher allele fraction.ConclusionsWe estimate that ~ 1% of CHD probands have a mosaic variant detectable in blood that could contribute to cardiac malformations, particularly those damaging variants with relatively higher allele fraction. Although blood is a readily available DNA source, cardiac tissues analyzed contributed ~ 5% of somatic mosaic variants identified, indicating the value of tissue mosaicism analyses.

Published
2020

9. De novo Damaging Variants, Clinical Phenotypes and Post-Operative Outcomes in Congenital Heart Disease

Author

Boskovski, Marko T, Homsy, Jason, Nathan, Meena, Sleeper, Lynn A, Morton, Sarah, Manheimer, Kathryn B, Tai, Angela, Gorham, Joshua, Lewis, Matthew, Swartz, Michael, Alfieris, George M, Bacha, Emile A, Karimi, Mohsen, Meyer, David, Nguyen, Khanh, Bernstein, Daniel, Romano-Adesman, Angela, Porter, George A, Goldmuntz, Elizabeth, Chung, Wendy K, Srivastava, Deepak, Kaltman, Jonathan R, Tristani-Firouzi, Martin, Lifton, Richard, Roberts, Amy E, Gaynor, J William, Gelb, Bruce D, Kim, Richard, Seidman, Jonathan G, Brueckner, Martina, Mayer, John E, Newburger, Jane W, and Seidman, Christine E

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Genetics, Patient Safety, Congenital Structural Anomalies, Clinical Research, Human Genome, Transplantation, Heart Disease, Cardiovascular, Pediatric, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Adolescent, Child, Child, Preschool, Chromosomes, Human, Pair 15, Chromosomes, Human, Pair 3, DNA Copy Number Variations, Female, Heart Defects, Congenital, Heart Transplantation, Humans, Infant, Kaplan-Meier Estimate, Machine Learning, Male, Odds Ratio, Phenotype, Proportional Hazards Models, Exome Sequencing, genomics, congenital heart disease, heart transplantation, mortality, survival, Medical Biotechnology, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology
Abstract

BackgroundDe novo genic and copy number variants are enriched in patients with congenital heart disease, particularly those with extra-cardiac anomalies. The impact of de novo damaging variants on outcomes following cardiac repair is unknown.MethodsWe studied 2517 patients with congenital heart disease who had undergone whole-exome sequencing as part of the CHD GENES study (Congenital Heart Disease Genetic Network).ResultsTwo hundred ninety-four patients (11.7%) had clinically significant de novo variants. Patients with de novo damaging variants were 2.4 times more likely to have extra-cardiac anomalies (P=5.63×10-12). In 1268 patients (50.4%) who had surgical data available and underwent open-heart surgery exclusive of heart transplantation as their first operation, we analyzed transplant-free survival following the first operation. Median follow-up was 2.65 years. De novo variants were associated with worse transplant-free survival (hazard ratio, 3.51; P=5.33×10-04) and longer times to final extubation (hazard ratio, 0.74; P=0.005). As de novo variants had a significant interaction with extra-cardiac anomalies for transplant-free survival (P=0.003), de novo variants conveyed no additional risk for transplant-free survival for patients with these anomalies (adjusted hazard ratio, 1.96; P=0.06). By contrast, de novo variants in patients without extra-cardiac anomalies were associated with worse transplant-free survival during follow-up (hazard ratio, 11.21; P=1.61×10-05) than that of patients with no de novo variants. Using agnostic machine-learning algorithms, we identified de novo copy number variants at 15q25.2 and 15q11.2 as being associated with worse transplant-free survival and 15q25.2, 22q11.21, and 3p25.2 as being associated with prolonged time to final extubation.ConclusionsIn patients with congenital heart disease undergoing open-heart surgery, de novo variants were associated with worse transplant-free survival and longer times on the ventilator. De novo variants were most strongly associated with adverse outcomes among patients without extra-cardiac anomalies, suggesting a benefit for preoperative genetic testing even when genetic abnormalities are not suspected during routine clinical practice. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01196182.

Published
2020

10. Systems Analysis Implicates WAVE2 Complex in the Pathogenesis of Developmental Left-Sided Obstructive Heart Defects.

Author

Edwards, Jonathan J, Rouillard, Andrew D, Fernandez, Nicolas F, Wang, Zichen, Lachmann, Alexander, Shankaran, Sunita S, Bisgrove, Brent W, Demarest, Bradley, Turan, Nahid, Srivastava, Deepak, Bernstein, Daniel, Deanfield, John, Giardini, Alessandro, Porter, George, Kim, Richard, Roberts, Amy E, Newburger, Jane W, Goldmuntz, Elizabeth, Brueckner, Martina, Lifton, Richard P, Seidman, Christine E, Chung, Wendy K, Tristani-Firouzi, Martin, Yost, H Joseph, Ma'ayan, Avi, and Gelb, Bruce D

Subjects
CHD, congenital heart disease, CORUM, Comprehensive Resource of Mammalian Protein Complexes, CRISPR, clustered regularly interspaced short palindromic repeats, CTD, conotruncal defect, GOBP, Gene Ontology biological processes, HHE, high heart expression, HLHS, hypoplastic left heart syndrome, HTX, heterotaxy, LVOTO, left ventricular outflow tract obstruction, MGI, Mouse Genome Informatics, PCGC, Pediatric Cardiac Genomics Consortium, PPI, protein-protein interaction, congenital heart disease, systems biology, translational genomics, CHD, CORUM, Comprehensive Resource of Mammalian Protein Complexes, CRISPR, clustered regularly interspaced short palindromic repeats, CTD, conotruncal defect, GOBP, Gene Ontology biological processes, HHE, high heart expression, HLHS, hypoplastic left heart syndrome, HTX, heterotaxy, LVOTO, left ventricular outflow tract obstruction, MGI, Mouse Genome Informatics, PCGC, Pediatric Cardiac Genomics Consortium, PPI, protein-protein interaction, Cardiorespiratory Medicine and Haematology, Clinical Sciences
Abstract

Genetic variants are the primary driver of congenital heart disease (CHD) pathogenesis. However, our ability to identify causative variants is limited. To identify causal CHD genes that are associated with specific molecular functions, the study used prior knowledge to filter de novo variants from 2,881 probands with sporadic severe CHD. This approach enabled the authors to identify an association between left ventricular outflow tract obstruction lesions and genes associated with the WAVE2 complex and regulation of small GTPase-mediated signal transduction. Using CRISPR zebrafish knockdowns, the study confirmed that WAVE2 complex proteins brk1, nckap1, and wasf2 and the regulators of small GTPase signaling cul3a and racgap1 are critical to cardiac development.

Published
2020

11. De novo mutations in the BMP signaling pathway in lambdoid craniosynostosis

Author

Timberlake, Andrew T., Kiziltug, Emre, Jin, Sheng Chih, Nelson-Williams, Carol, Loring, Erin, Allocco, August, Marlier, Arnaud, Banka, Siddharth, Stuart, Helen, Passos-Buenos, Maria Rita, Rosa, Rafael, Rogatto, Silvia R., Tonne, Elin, Stiegler, Amy L., Boggon, Titus J., Alperovich, Michael, Steinbacher, Derek, Staffenberg, David A., Flores, Roberto L., Persing, John A., Kahle, Kristopher T., and Lifton, Richard P.

Published
2023
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12. De novo variants implicate chromatin modification, transcriptional regulation, and retinoic acid signaling in syndromic craniosynostosis

Author

Timberlake, Andrew T., McGee, Stephen, Allington, Garrett, Kiziltug, Emre, Wolfe, Erin M., Stiegler, Amy L., Boggon, Titus J., Sanyoura, May, Morrow, Michelle, Wenger, Tara L., Fernandes, Erica M., Caluseriu, Oana, Persing, John A., Jin, Sheng Chih, Lifton, Richard P., Kahle, Kristopher T., and Kruszka, Paul

Published
2023
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13. Centers for Mendelian Genomics: A decade of facilitating gene discovery

Author

Adams, Marcia, Aguet, François, Akay, Gulsen, Anderson, Peter, Antonescu, Corina, Arachchi, Harindra M., Atik, Mehmed M., Austin-Tse, Christina A., Babb, Larry, Bacus, Tamara J., Bahrambeigi, Vahid, Balasubramanian, Suganthi, Bayram, Yavuz, Beaudet, Arthur L., Beck, Christine R., Belmont, John W., Below, Jennifer E., Bilguvar, Kaya, Boehm, Corinne D., Boerwinkle, Eric, Boone, Philip M., Bowne, Sara J., Brand, Harrison, Buckingham, Kati J., Byrne, Alicia B., Calame, Daniel, Campbell, Ian M., Cao, Xiaolong, Carvalho, Claudia, Chander, Varuna, Chang, Jaime, Chao, Katherine R., Chinn, Ivan K., Clarke, Declan, Collins, Ryan L., Cummings, Beryl, Dardas, Zain, Dawood, Moez, Delano, Kayla, DiTroia, Stephanie P., Doddapaneni, Harshavardhan, Du, Haowei, Du, Renqian, Duan, Ruizhi, Eldomery, Mohammad, Eng, Christine M., England, Eleina, Evangelista, Emily, Everett, Selin, Fatih, Jawid, Felsenfeld, Adam, Francioli, Laurent C., Frazar, Christian D., Fu, Jack, Gamarra, Emmanuel, Gambin, Tomasz, Gan, Weiniu, Gandhi, Mira, Ganesh, Vijay S., Garimella, Kiran V., Gauthier, Laura D., Giroux, Danielle, Gonzaga-Jauregui, Claudia, Goodrich, Julia K., Gordon, William W., Griffith, Sean, Grochowski, Christopher M., Gu, Shen, Gudmundsson, Sanna, Hall, Stacey J., Hansen, Adam, Harel, Tamar, Harmanci, Arif O., Herman, Isabella, Hetrick, Kurt, Hijazi, Hadia, Horike-Pyne, Martha, Hsu, Elvin, Hu, Jianhong, Huang, Yongqing, Hurless, Jameson R., Jahl, Steve, Jarvik, Gail P., Jiang, Yunyun, Johanson, Eric, Jolly, Angad, Karaca, Ender, Khayat, Michael, Knight, James, Kolar, J. Thomas, Kumar, Sushant, Lalani, Seema, Laricchia, Kristen M., Larkin, Kathryn E., Leal, Suzanne M., Lemire, Gabrielle, Lewis, Richard A., Li, He, Ling, Hua, Lipson, Rachel B., Liu, Pengfei, Lovgren, Alysia Kern, López-Giráldez, Francesc, MacMillan, Melissa P., Mangilog, Brian E., Mano, Stacy, Marafi, Dana, Marosy, Beth, Marshall, Jamie L., Martin, Renan, Marvin, Colby T., Mawhinney, Michelle, McGee, Sean, McGoldrick, Daniel J., Mehaffey, Michelle, Mekonnen, Betselote, Meng, Xiaolu, Mitani, Tadahiro, Miyake, Christina Y., Mohr, David, Morris, Shaine, Mullen, Thomas E., Murdock, David R., Murugan, Mullai, Muzny, Donna M., Myers, Ben, Neira, Juanita, Nguyen, Kevin K., Nielsen, Patrick M., Nudelman, Natalie, O’Heir, Emily, O’Leary, Melanie C., Ongaco, Chrissie, Orange, Jordan, Osei-Owusu, Ikeoluwa A., Paine, Ingrid S., Pais, Lynn S., Paschall, Justin, Patterson, Karynne, Pehlivan, Davut, Pelle, Benjamin, Penney, Samantha, Perez de Acha Chavez, Jorge, Pierce-Hoffman, Emma, Poli, Cecilia M., Punetha, Jaya, Radhakrishnan, Aparna, Richardson, Matthew A., Rodrigues, Eliete, Roote, Gwendolin T., Rosenfeld, Jill A., Ryke, Erica L., Sabo, Aniko, Sanchez, Alice, Schrauwen, Isabelle, Scott, Daryl A., Sedlazeck, Fritz, Serrano, Jillian, Shaw, Chad A., Shelford, Tameka, Shively, Kathryn M., Singer-Berk, Moriel, Smith, Joshua D., Snow, Hana, Snyder, Grace, Solomonson, Matthew, Son, Rachel G., Song, Xiaofei, Stankiewicz, Pawel, Stephan, Taylorlyn, Sutton, V. Reid, Sveden, Abigail, Sánchez, Diana Cornejo, Tackett, Monica, Talkowski, Michael, Threlkeld, Machiko S., Tiao, Grace, Udler, Miriam S., Vail, Laura, Valivullah, Zaheer, Valkanas, Elise, VanNoy, Grace E., Wang, Qingbo S., Wang, Gao, Wang, Lu, Wangler, Michael F., Watts, Nicholas A., Weisburd, Ben, Weiss, Jeffrey M., Wheeler, Marsha M., White, Janson J., Williamson, Clara E., Wilson, Michael W., Wiszniewski, Wojciech, Withers, Marjorie A., Witmer, Dane, Witzgall, Lauren, Wohler, Elizabeth, Wojcik, Monica H., Wong, Isaac, Wood, Jordan C., Wu, Nan, Xing, Jinchuan, Yang, Yaping, Yi, Qian, Yuan, Bo, Zeiger, Jordan E., Zhang, Chaofan, Zhang, Peng, Zhang, Yan, Zhang, Xiaohong, Zhang, Yeting, Zhang, Shifa, Zoghbi, Huda, van den Veyver, Igna, Baxter, Samantha M., Posey, Jennifer E., Lake, Nicole J., Sobreira, Nara, Chong, Jessica X., Buyske, Steven, Blue, Elizabeth E., Chadwick, Lisa H., Coban-Akdemir, Zeynep H., Doheny, Kimberly F., Davis, Colleen P., Lek, Monkol, Wellington, Christopher, Jhangiani, Shalini N., Gerstein, Mark, Gibbs, Richard A., Lifton, Richard P., MacArthur, Daniel G., Matise, Tara C., Lupski, James R., Valle, David, Bamshad, Michael J., Hamosh, Ada, Mane, Shrikant, Nickerson, Deborah A., Rehm, Heidi L., and O’Donnell-Luria, Anne

Published
2022
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15. Integrated mutational landscape analysis of uterine leiomyosarcomas

Author

Choi, Jungmin, Manzano, Aranzazu, Dong, Weilai, Bellone, Stefania, Bonazzoli, Elena, Zammataro, Luca, Yao, Xiaotong, Deshpande, Aditya, Zaidi, Samir, Guglielmi, Adele, Gnutti, Barbara, Nagarkatti, Nupur, Tymon-Rosario, Joan R., Harold, Justin, Mauricio, Dennis, Zeybek, Burak, Menderes, Gulden, Altwerger, Gary, Jeong, Kyungjo, Zhao, Siming, Buza, Natalia, Hui, Pei, Ravaggi, Antonella, Bignotti, Eliana, Romani, Chiara, Todeschini, Paola, Zanotti, Laura, Odicino, Franco, Pecorelli, Sergio, Ardighieri, Laura, Bilguvar, Kaya, Quick, Charles M., Silasi, Dan-Arin, Huang, Gloria S., Andikyan, Vaagn, Clark, Mitchell, Ratner, Elena, Azodi, Masoud, Imielinski, Marcin, Schwartz, Peter E., Alexandrov, Ludmil B., Lifton, Richard P., Schlessinger, Joseph, and Santin, Alessandro D.

Published
2021

16. 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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17. CARD14-associated papulosquamous eruption: A spectrum including features of psoriasis and pityriasis rubra pilaris

Author

Craiglow, Brittany G, Boyden, Lynn M, Hu, Ronghua, Virtanen, Marie, Su, John, Rodriguez, Gabriela, McCarthy, Catherine, Luna, Paula, Larralde, Margarita, Humphrey, Stephen, Holland, Kristen E, Hogeling, Marcia, Hidalgo-Matlock, Benjamin, Ferrari, Bruno, Fernandez-Faith, Esteban, Drolet, Beth, Cordoro, Kelly M, Bowcock, Anne M, Antaya, Richard J, Ashack, Kurt, Ashack, Richard J, Lifton, Richard P, Milstone, Leonard M, Paller, Amy S, and Choate, Keith A

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Psoriasis, Rare Diseases, Genetics, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Age of Onset, CARD Signaling Adaptor Proteins, Child, Child, Preschool, Dermatologic Agents, Facial Dermatoses, Genetic Testing, Guanylate Cyclase, Humans, Infant, Infant, Newborn, Membrane Proteins, Phenotype, Pityriasis Rubra Pilaris, Retreatment, Skin Diseases, Papulosquamous, Ustekinumab, CARD14, genetics, pityriasis rubra pilaris, psoriasis, treatment, ustekinumab, Dermatology & Venereal Diseases, Clinical sciences
Abstract

BackgroundHeterozygous mutations in caspase recruitment domain family member 14 gene (CARD14) have been shown to be associated with psoriasis and familial pityriasis rubra pilaris (PRP). Many subjects with CARD14 mutations display features of both disorders, which can result in diagnostic uncertainty. In addition, these eruptions are often recalcitrant to conventional psoriasis therapies such as methotrexate, oral retinoids, and tumor necrosis factor-α inhibitors.ObjectiveWe sought to describe the clinical characteristics, family history, and response to therapy in subjects with papulosquamous eruptions due to mutations in CARD14.MethodsSubjects were referred for genetic testing as part of a registry of subjects with inherited disorders of keratinization. DNA was isolated from blood or saliva, and multiplex targeted sequencing or whole exome sequencing was performed. Clinical histories of subjects with CARD14 mutations were reviewed.ResultsWe identified 15 kindreds with CARD14-associated papulosquamous eruption (CAPE). Characteristic features of CAPE include early age of onset; prominent involvement of the cheeks, chin, and ears; family history of psoriasis or PRP; minimal response to conventional topical and systemic psoriasis therapies; and improvement with ustekinumab.LimitationsRelatively small sample size.ConclusionsMany subjects with CARD14 mutations display characteristics of both psoriasis and PRP. We propose the term CARD14-associated papulosquamous eruption to describe this spectrum of disease. Subjects with clinical features suggestive of CAPE should undergo CARD14 sequencing and may benefit from treatment with ustekinumab.

Published
2018

18. The Psychiatric Cell Map Initiative: A Convergent Systems Biological Approach to Illuminating Key Molecular Pathways in Neuropsychiatric Disorders

Author

Willsey, A Jeremy, Morris, Montana T, Wang, Sheng, Willsey, Helen R, Sun, Nawei, Teerikorpi, Nia, Baum, Tierney B, Cagney, Gerard, Bender, Kevin J, Desai, Tejal A, Srivastava, Deepak, Davis, Graeme W, Doudna, Jennifer, Chang, Edward, Sohal, Vikaas, Lowenstein, Daniel H, Li, Hao, Agard, David, Keiser, Michael J, Shoichet, Brian, von Zastrow, Mark, Mucke, Lennart, Finkbeiner, Steven, Gan, Li, Sestan, Nenad, Ward, Michael E, Huttenhain, Ruth, Nowakowski, Tomasz J, Bellen, Hugo J, Frank, Loren M, Khokha, Mustafa K, Lifton, Richard P, Kampmann, Martin, Ideker, Trey, State, Matthew W, and Krogan, Nevan J

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Brain Disorders, Schizophrenia, Rare Diseases, Mental Illness, Biotechnology, Neurosciences, Mental Health, Intellectual and Developmental Disabilities (IDD), 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Mental health, Neurological, Good Health and Well Being, Chromosome Mapping, Gene Regulatory Networks, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Humans, Neurobiology, Neurodevelopmental Disorders, Neuropsychiatry, Systems Biology, convergence, genetics, interactome, network, neurodevelopmental disorder, pathway, proteomics, psychiatric cell map initiative, psychiatric disorder, psychiatry, systems biology, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Although gene discovery in neuropsychiatric disorders, including autism spectrum disorder, intellectual disability, epilepsy, schizophrenia, and Tourette disorder, has accelerated, resulting in a large number of molecular clues, it has proven difficult to generate specific hypotheses without the corresponding datasets at the protein complex and functional pathway level. Here, we describe one path forward-an initiative aimed at mapping the physical and genetic interaction networks of these conditions and then using these maps to connect the genomic data to neurobiology and, ultimately, the clinic. These efforts will include a team of geneticists, structural biologists, neurobiologists, systems biologists, and clinicians, leveraging a wide array of experimental approaches and creating a collaborative infrastructure necessary for long-term investigation. This initiative will ultimately intersect with parallel studies that focus on other diseases, as there is a significant overlap with genes implicated in cancer, infectious disease, and congenital heart defects.

Published
2018

20. PPIL4 is essential for brain angiogenesis and implicated in intracranial aneurysms in humans

Author

Barak, Tanyeri, Ristori, Emma, Ercan-Sencicek, A. Gulhan, Miyagishima, Danielle F., Nelson-Williams, Carol, Dong, Weilai, Jin, Sheng Chih, Prendergast, Andrew, Armero, William, Henegariu, Octavian, Erson-Omay, E. Zeynep, Harmancı, Akdes Serin, Guy, Mikhael, Gültekin, Batur, Kilic, Deniz, Rai, Devendra K., Goc, Nükte, Aguilera, Stephanie Marie, Gülez, Burcu, Altinok, Selin, Ozcan, Kent, Yarman, Yanki, Coskun, Süleyman, Sempou, Emily, Deniz, Engin, Hintzen, Jared, Cox, Andrew, Fomchenko, Elena, Jung, Su Woong, Ozturk, Ali Kemal, Louvi, Angeliki, Bilgüvar, Kaya, Connolly, Jr., E. Sander, Khokha, Mustafa K., Kahle, Kristopher T., Yasuno, Katsuhito, Lifton, Richard P., Mishra-Gorur, Ketu, Nicoli, Stefania, and Günel, Murat

Published
2021
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21. 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, Human Genome, 1.1 Normal biological development and functioning, 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

22. 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, Pediatric, Congenital Structural Anomalies, Congenital Heart Disease, Cardiovascular, Heart Disease, Clinical Research, Rare Diseases, Human Genome, 2.1 Biological and endogenous factors, 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

23. Inherited PD-1 deficiency underlies tuberculosis and autoimmunity in a child

Author

Ogishi, Masato, Yang, Rui, Aytekin, Caner, Langlais, David, Bourgey, Mathieu, Khan, Taushif, Ali, Fatima Al, Rahman, Mahbuba, Delmonte, Ottavia M., Chrabieh, Maya, Zhang, Peng, Gruber, Conor, Pelham, Simon J., Spaan, András N., Rosain, Jérémie, Lei, Wei-Te, Drutman, Scott, Hellmann, Matthew D., Callahan, Margaret K., Adamow, Matthew, Wong, Phillip, Wolchok, Jedd D., Rao, Geetha, Ma, Cindy S., Nakajima, Yuka, Yaguchi, Tomonori, Chamoto, Kenji, Williams, Samuel C., Emile, Jean-Francois, Rozenberg, Flore, Glickman, Michael S., Rapaport, Franck, Kerner, Gaspard, Allington, Garrett, Tezcan, Ilhan, Cagdas, Deniz, Hosnut, Ferda O., Dogu, Figen, Ikinciogullari, Aydan, Rao, V. Koneti, Kainulainen, Leena, Béziat, Vivien, Bustamante, Jacinta, Vilarinho, Silvia, Lifton, Richard P., Boisson, Bertrand, Abel, Laurent, Bogunovic, Dusan, Marr, Nico, Notarangelo, Luigi D., Tangye, Stuart G., Honjo, Tasuku, Gros, Philippe, Boisson-Dupuis, Stéphanie, and Casanova, Jean-Laurent

Published
2021
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24. 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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25. 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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26. DAAM2 Variants Cause Nephrotic Syndrome via Actin Dysregulation

Author

Schneider, Ronen, Deutsch, Konstantin, Hoeprich, Gregory J., Marquez, Jonathan, Hermle, Tobias, Braun, Daniela A., Seltzsam, Steve, Kitzler, Thomas M., Mao, Youying, Buerger, Florian, Majmundar, Amar J., Onuchic-Whitford, Ana C., Kolvenbach, Caroline M., Schierbaum, Luca, Schneider, Sophia, Halawi, Abdul A., Nakayama, Makiko, Mann, Nina, Connaughton, Dervla M., Klämbt, Verena, Wagner, Matias, Riedhammer, Korbinian M., Renders, Lutz, Katsura, Yoshichika, Thumkeo, Dean, Soliman, Neveen A., Mane, Shrikant, Lifton, Richard P., Shril, Shirlee, Khokha, Mustafa K., Hoefele, Julia, Goode, Bruce L., and Hildebrandt, Friedhelm

Published
2020
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27. 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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28. Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations

Author

Connaughton, Dervla M., Dai, Rufeng, Owen, Danielle J., Marquez, Jonathan, Mann, Nina, Graham-Paquin, Adda L., Nakayama, Makiko, Coyaud, Etienne, Laurent, Estelle M.N., St-Germain, Jonathan R., Blok, Lot Snijders, Vino, Arianna, Klämbt, Verena, Deutsch, Konstantin, Wu, Chen-Han Wilfred, Kolvenbach, Caroline M., Kause, Franziska, Ottlewski, Isabel, Schneider, Ronen, Kitzler, Thomas M., Majmundar, Amar J., Buerger, Florian, Onuchic-Whitford, Ana C., Youying, Mao, Kolb, Amy, Salmanullah, Daanya, Chen, Evan, van der Ven, Amelie T., Rao, Jia, Ityel, Hadas, Seltzsam, Steve, Rieke, Johanna M., Chen, Jing, Vivante, Asaf, Hwang, Daw-Yang, Kohl, Stefan, Dworschak, Gabriel C., Hermle, Tobias, Alders, Mariëlle, Bartolomaeus, Tobias, Bauer, Stuart B., Baum, Michelle A., Brilstra, Eva H., Challman, Thomas D., Zyskind, Jacob, Costin, Carrie E., Dipple, Katrina M., Duijkers, Floor A., Ferguson, Marcia, Fitzpatrick, David R., Fick, Roger, Glass, Ian A., Hulick, Peter J., Kline, Antonie D., Krey, Ilona, Kumar, Selvin, Lu, Weining, Marco, Elysa J., Wentzensen, Ingrid M., Mefford, Heather C., Platzer, Konrad, Povolotskaya, Inna S., Savatt, Juliann M., Shcherbakova, Natalia V., Senguttuvan, Prabha, Squire, Audrey E., Stein, Deborah R., Thiffault, Isabelle, Voinova, Victoria Y., Somers, Michael J.G., Ferguson, Michael A., Traum, Avram Z., Daouk, Ghaleb H., Daga, Ankana, Rodig, Nancy M., Terhal, Paulien A., van Binsbergen, Ellen, Eid, Loai A., Tasic, Velibor, Rasouly, Hila Milo, Lim, Tze Y., Ahram, Dina F., Gharavi, Ali G., Reutter, Heiko M., Rehm, Heidi L., MacArthur, Daniel G., Lek, Monkol, Laricchia, Kristen M., Lifton, Richard P., Xu, Hong, Mane, Shrikant M., Sanna-Cherchi, Simone, Sharrocks, Andrew D., Raught, Brian, Fisher, Simon E., Bouchard, Maxime, Khokha, Mustafa K., Shril, Shirlee, and Hildebrandt, Friedhelm

Published
2020
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29. Whole exome sequencing identified ATP6V1C2 as a novel candidate gene for recessive distal renal tubular acidosis

Author

Jobst-Schwan, Tilman, Klämbt, Verena, Tarsio, Maureen, Heneghan, John F., Majmundar, Amar J., Shril, Shirlee, Buerger, Florian, Ottlewski, Isabel, Shmukler, Boris E., Topaloglu, Rezan, Hashmi, Seema, Hafeez, Farkhanda, Emma, Francesco, Greco, Marcella, Laube, Guido F., Fathy, Hanan M., Pohl, Martin, Gellermann, Jutta, Milosevic, Danko, Baum, Michelle A., Mane, Shrikant, Lifton, Richard P., Kane, Patricia M., Alper, Seth L., and Hildebrandt, Friedhelm

Published
2020
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30. 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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32. Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma

Author

Bi, Mark, Zhao, Siming, Said, Jonathan W, Merino, Maria J, Adeniran, Adebowale J, Xie, Zuoquan, Nawaf, Cayce B, Choi, Jaehyuk, Belldegrun, Arie S, Pantuck, Allan J, Kluger, Harriet M, Bilgüvar, Kaya, Lifton, Richard P, and Shuch, Brian

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Human Genome, Cancer Genomics, Cancer, Biotechnology, Kidney Disease, Rare Diseases, Orphan Drug, 2.1 Biological and endogenous factors, Aged, Carcinoma, Renal Cell, Cell Dedifferentiation, DNA Mismatch Repair, DNA-Binding Proteins, Exome, Female, Genes, p53, Humans, Kidney Neoplasms, Loss of Heterozygosity, Male, Middle Aged, Mutation, Nuclear Proteins, Oncogenes, Polymorphism, Single Nucleotide, Prognosis, Transcription Factors, Tumor Suppressor Proteins, Ubiquitin Thiolesterase, kidney cancer, sarcomatoid, transformation, p53, dedifferentiation
Abstract

The presence of sarcomatoid features in clear cell renal cell carcinoma (ccRCC) confers a poor prognosis and is of unknown pathogenesis. We performed exome sequencing of matched normal-carcinomatous-sarcomatoid specimens from 21 subjects. Two tumors had hypermutation consistent with mismatch repair deficiency. In the remainder, sarcomatoid and carcinomatous elements shared 42% of somatic single-nucleotide variants (SSNVs). Sarcomatoid elements had a higher overall SSNV burden (mean 90 vs. 63 SSNVs, P = 4.0 × 10(-4)), increased frequency of nonsynonymous SSNVs in Pan-Cancer genes (mean 1.4 vs. 0.26, P = 0.002), and increased frequency of loss of heterozygosity (LOH) across the genome (median 913 vs. 460 Mb in LOH, P < 0.05), with significant recurrent LOH on chromosomes 1p, 9, 10, 14, 17p, 18, and 22. The most frequent SSNVs shared by carcinomatous and sarcomatoid elements were in known ccRCC genes including von Hippel-Lindau tumor suppressor (VHL), polybromo 1 (PBRM1), SET domain containing 2 (SETD2), phosphatase and tensin homolog (PTEN). Most interestingly, sarcomatoid elements acquired biallelic tumor protein p53 (TP53) mutations in 32% of tumors (P = 5.47 × 10(-17)); TP53 mutations were absent in carcinomatous elements in nonhypermutated tumors and rare in previously studied ccRCCs. Mutations in known cancer drivers AT-rich interaction domain 1A (ARID1A) and BRCA1 associated protein 1 (BAP1) were significantly mutated in sarcomatoid elements and were mutually exclusive with TP53 and each other. These findings provide evidence that sarcomatoid elements arise from dedifferentiation of carcinomatous ccRCCs and implicate specific genes in this process. These findings have implications for the treatment of patients with these poor-prognosis cancers.

Published
2016

33. Whole-exome sequencing of cervical carcinomas identifies activating ERBB2 and PIK3CA mutations as targets for combination therapy

Author

Zammataro, Luca, Lopez, Salvatore, Bellone, Stefania, Pettinella, Francesca, Bonazzoli, Elena, Perrone, Emanuele, Zhao, Siming, Menderes, Gulden, Altwerger, Gary, Han, Chanhee, Zeybek, Burak, Bianchi, Anna, Manzano, Aranzazu, Manara, Paola, Cocco, Emiliano, Buza, Natalia, Hui, Pei, Wong, Serena, Ravaggi, Antonella, Bignotti, Eliana, Romani, Chiara, Todeschini, Paola, Zanotti, Laura, Odicino, Franco, Pecorelli, Sergio, Donzelli, Carla, Ardighieri, Laura, Angioli, Roberto, Raspagliesi, Francesco, Scambia, Giovanni, Choi, Jungmin, Dong, Weilai, Bilguvar, Kaya, Alexandrov, Ludmil B., Silasi, Dan-Arin, Huang, Gloria S., Ratner, Elena, Azodi, Masoud, Schwartz, Peter E., Pirazzoli, Valentina, Stiegler, Amy L., Boggon, Titus J., Lifton, Richard P., Schlessinger, Joseph, and Santin, Alessandro D.

Published
2019

37. Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome

Author

Boyden, Lynn M, Kam, Chen Y, Hernández-Martín, Angela, Zhou, Jing, Craiglow, Brittany G, Sidbury, Robert, Mathes, Erin F, Maguiness, Sheilagh M, Crumrine, Debra A, Williams, Mary L, Hu, Ronghua, Lifton, Richard P, Elias, Peter M, Green, Kathleen J, and Choate, Keith A

Subjects
Genetics, Pediatric, Biotechnology, Heart Disease, Congenital Structural Anomalies, Rare Diseases, Clinical Research, Cardiovascular, Aetiology, 2.1 Biological and endogenous factors, Skin, Amino Acid Sequence, Cardiomyopathies, Child, Child, Preschool, Connexin 43, Desmoplakins, Desmosomes, Female, Humans, Infant, Male, Molecular Sequence Data, Mutation, Missense, Myocardium, Protein Transport, Sequence Alignment, Skin Diseases, Genetic, Syndrome, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Disorders of keratinization (DOK) show marked genotypic and phenotypic heterogeneity. In most cases, disease is primarily cutaneous, and further clinical evaluation is therefore rarely pursued. We have identified subjects with a novel DOK featuring erythrokeratodermia and initially-asymptomatic, progressive, potentially fatal cardiomyopathy, a finding not previously associated with erythrokeratodermia. We show that de novo missense mutations clustered tightly within a single spectrin repeat of DSP cause this novel cardio-cutaneous disorder, which we term erythrokeratodermia-cardiomyopathy (EKC) syndrome. We demonstrate that DSP mutations in our EKC syndrome subjects affect localization of desmosomal proteins and connexin 43 in the skin, and result in desmosome aggregation, widening of intercellular spaces, and lipid secretory defects. DSP encodes desmoplakin, a primary component of desmosomes, intercellular adhesion junctions most abundant in the epidermis and heart. Though mutations in DSP are known to cause other disorders, our cohort features the unique clinical finding of severe whole-body erythrokeratodermia, with distinct effects on localization of desmosomal proteins and connexin 43. These findings add a severe, previously undescribed syndrome featuring erythrokeratodermia and cardiomyopathy to the spectrum of disease caused by mutation in DSP, and identify a specific region of the protein critical to the pathobiology of EKC syndrome and to DSP function in the heart and skin.

Published
2016

38. 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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39. 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

40. Frequent somatic reversion of KRT1 mutations in ichthyosis with confetti

Author

Choate, Keith A, Lu, Yin, Zhou, Jing, Elias, Peter M, Zaidi, Samir, Paller, Amy S, Farhi, Anita, Nelson-Williams, Carol, Crumrine, Debra, Milstone, Leonard M, and Lifton, Richard P

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Clinical Sciences, Genetics, Pediatric, Skin, Adult, Age of Onset, Amino Acid Sequence, Cell Line, Tumor, Cell Nucleus, Child, Child, Preschool, Chromosomes, Human, Pair 12, Cytoskeleton, Frameshift Mutation, Humans, Ichthyosis, Intermediate Filaments, Keratin-1, Keratinocytes, Loss of Heterozygosity, Male, Molecular Sequence Data, Mosaicism, Phenotype, Polymorphism, Single Nucleotide, Protein Transport, Transfection, Medical and Health Sciences, Immunology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Widespread reversion of genetic disease is rare; however, such events are particularly evident in some skin disorders in which normal clones develop on a background of affected skin. We previously demonstrated that mutations in keratin 10 (KRT10) cause ichthyosis with confetti (IWC), a severe dominant disorder that is characterized by progressive development of hundreds of normal skin spots via revertant mosaicism. Here, we report on a clinical and histological IWC subtype in which affected subjects have red, scaly skin at birth, experience worsening palmoplantar keratoderma in childhood, and develop hundreds of normal skin spots, beginning at around 20 years of age, that increase in size and number over time. We identified a causal de novo mutation in keratin 1 (KRT1). Similar to IWC-causing KRT10 mutations, this mutation in KRT1 resulted in a C-terminal frameshift, replacing 22 C-terminal amino acids with an alternate 30-residue peptide. Mutant KRT1 caused partial collapse of the cytoplasmic intermediate filament network and mislocalized to the nucleus. As with KRT10 mutations causing IWC, reversion of KRT1 mutations occurred via mitotic recombination. Because reversion is not observed with other disease-causing keratin mutations, the results of this study implicate KRT1 and KRT10 C-terminal frameshift mutations in the high frequency of revertant mosaicism in IWC.

Published
2015

41. 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

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, and Lupski, James R.

Published
2019
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43. Monogenic causes of chronic kidney disease in adults

Author

Connaughton, Dervla M., Kennedy, Claire, Shril, Shirlee, Mann, Nina, Murray, Susan L., Williams, Patrick A., Conlon, Eoin, Nakayama, Makiko, van der Ven, Amelie T., Ityel, Hadas, Kause, Franziska, Kolvenbach, Caroline M., Dai, Rufeng, Vivante, Asaf, Braun, Daniela A., Schneider, Ronen, Kitzler, Thomas M., Moloney, Brona, Moran, Conor P., Smyth, John S., Kennedy, Alan, Benson, Katherine, Stapleton, Caragh, Denton, Mark, Magee, Colm, O’Seaghdha, Conall M., Plant, William D., Griffin, Matthew D., Awan, Atif, Sweeney, Clodagh, Mane, Shrikant M., Lifton, Richard P., Griffin, Brenda, Leavey, Sean, Casserly, Liam, de Freitas, Declan G., Holian, John, Dorman, Anthony, Doyle, Brendan, Lavin, Peter J., Little, Mark A., Conlon, Peter J., and Hildebrandt, Friedhelm

Published
2019
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44. Mutations in Chromatin Modifier and Ephrin Signaling Genes in Vein of Galen Malformation

Author

Duran, Daniel, Zeng, Xue, Jin, Sheng Chih, Choi, Jungmin, Nelson-Williams, Carol, Yatsula, Bogdan, Gaillard, Jonathan, Furey, Charuta Gavankar, Lu, Qiongshi, Timberlake, Andrew T., Dong, Weilai, Sorscher, Michelle A., Loring, Erin, Klein, Jennifer, Allocco, August, Hunt, Ava, Conine, Sierra, Karimy, Jason K., Youngblood, Mark W., Zhang, Jinwei, DiLuna, Michael L., Matouk, Charles C., Mane, Shrikant, Tikhonova, Irina R., Castaldi, Christopher, López-Giráldez, Francesc, Knight, James, Haider, Shozeb, Soban, Mariya, Alper, Seth L., Komiyama, Masaki, Ducruet, Andrew F., Zabramski, Joseph M., Dardik, Alan, Walcott, Brian P., Stapleton, Christopher J., Aagaard-Kienitz, Beverly, Rodesch, Georges, Jackson, Eric, Smith, Edward R., Orbach, Darren B., Berenstein, Alejandro, Bilguvar, Kaya, Vikkula, Miikka, Gunel, Murat, Lifton, Richard P., and Kahle, Kristopher T.

Published
2019
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45. Mutations in PERP Cause Dominant and Recessive Keratoderma

Author

Duchatelet, Sabine, Boyden, Lynn M., Ishida-Yamamoto, Akemi, Zhou, Jing, Guibbal, Laure, Hu, Ronghua, Lim, Young H., Bole-Feysot, Christine, Nitschké, Patrick, Santos-Simarro, Fernando, de Lucas, Raul, Milstone, Leonard M., Gildenstern, Vanessa, Helfrich, Yolanda R., Attardi, Laura D., Lifton, Richard P., Choate, Keith A., and Hovnanian, Alain

Published
2019
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46. 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, Shril, Shirlee, Buerger, Florian, Deutsch, Konstantin, Yousef, Kirollos, Frank, Camille N., Onuchic-Whitford, Ana C., Kitzler, Thomas M., Mao, Youying, Klämbt, Verena, Zahoor, Muhammad Y., Lemberg, Katharina, Majmundar, Amar J., Mansour, Bshara, Saida, Ken, Seltzsam, Steve, Kolvenbach, Caroline M., Merz, Lea Maria, Mertens, Nils D., Hermle, Tobias, Mann, Nina, Pantel, Dalia, Halawi, Abdul A., Bao, Aaron, Schierbaum, Luca, Schneider, Sophia, Salmanullah, Daanya, Ben-Dov, Iddo Z., Sagiv, Itamar, Eid, Loai A., Awad, Hazem Subhi H., Al Saffar, Muna, Soliman, Neveen A., Nabhan, Marwa M., Kari, Jameela A., El Desoky, Sherif, Shalaby, Mohamed A., Ooda, Said, Fathy, Hanan M., Mane, Shrikant, Lifton, Richard P., Somers, Michael J.G., and Hildebrandt, Friedhelm

Published
2025
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47. Mutational landscape of primary, metastatic, and recurrent ovarian cancer reveals c-MYC gains as potential target for BET inhibitor

Author

Li, Charles, Bonazzoli, Elena, Bellone, Stefania, Choi, Jungmin, Dong, Weilai, Menderes, Gulden, Altwerger, Gary, Han, Chanhee, Manzano, Aranzazu, Bianchi, Anna, Pettinella, Francesca, Manara, Paola, Lopez, Salvatore, Yadav, Ghanshyam, Riccio, Francesco, Zammataro, Luca, Zeybek, Burak, Yang-Hartwich, Yang, Buza, Natalia, Hui, Pei, Wong, Serena, Ravaggi, Antonella, Bignotti, Eliana, Romani, Chiara, Todeschini, Paola, Zanotti, Laura, Zizioli, Valentina, Odicino, Franco, Pecorelli, Sergio, Ardighieri, Laura, Silasi, Dan-Arin, Litkouhi, Babak, Ratner, Elena, Azodi, Masoud, Huang, Gloria S., Schwartz, Peter E., Lifton, Richard P., Schlessinger, Joseph, and Santin, Alessandro D.

Published
2019

48. Increased Frequency of De Novo Copy Number Variants in Congenital Heart Disease by Integrative Analysis of Single Nucleotide Polymorphism Array and Exome Sequence Data

Author

Glessner, Joseph T, Bick, Alexander G, Ito, Kaoru, Homsy, Jason, Rodriguez-Murillo, Laura, Fromer, Menachem, Mazaika, Erica, Vardarajan, Badri, Italia, Michael, Leipzig, Jeremy, DePalma, Steven R, Golhar, Ryan, Sanders, Stephan J, Yamrom, Boris, Ronemus, Michael, Iossifov, Ivan, Willsey, A Jeremy, State, Matthew W, Kaltman, Jonathan R, White, Peter S, Shen, Yufeng, Warburton, Dorothy, Brueckner, Martina, Seidman, Christine, Goldmuntz, Elizabeth, Gelb, Bruce D, Lifton, Richard, Seidman, Jonathan, Hakonarson, Hakon, and Chung, Wendy K

Subjects
Human Genome, Pediatric, Congenital Structural Anomalies, Genetics, Cardiovascular, Heart Disease, Aetiology, 2.1 Biological and endogenous factors, Case-Control Studies, Cohort Studies, DNA Copy Number Variations, Exome, Gene Frequency, Gene Regulatory Networks, Heart Defects, Congenital, Humans, Molecular Sequence Data, Polymorphism, Single Nucleotide, DNA copy number variations, genomics, microarray analysis, polymorphism, single nucleotide, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Cardiovascular System & Hematology
Abstract

RationaleCongenital heart disease (CHD) is among the most common birth defects. Most cases are of unknown pathogenesis.ObjectiveTo determine the contribution of de novo copy number variants (CNVs) in the pathogenesis of sporadic CHD.Methods and resultsWe studied 538 CHD trios using genome-wide dense single nucleotide polymorphism arrays and whole exome sequencing. Results were experimentally validated using digital droplet polymerase chain reaction. We compared validated CNVs in CHD cases with CNVs in 1301 healthy control trios. The 2 complementary high-resolution technologies identified 63 validated de novo CNVs in 51 CHD cases. A significant increase in CNV burden was observed when comparing CHD trios with healthy trios, using either single nucleotide polymorphism array (P=7×10(-5); odds ratio, 4.6) or whole exome sequencing data (P=6×10(-4); odds ratio, 3.5) and remained after removing 16% of de novo CNV loci previously reported as pathogenic (P=0.02; odds ratio, 2.7). We observed recurrent de novo CNVs on 15q11.2 encompassing CYFIP1, NIPA1, and NIPA2 and single de novo CNVs encompassing DUSP1, JUN, JUP, MED15, MED9, PTPRE SREBF1, TOP2A, and ZEB2, genes that interact with established CHD proteins NKX2-5 and GATA4. Integrating de novo variants in whole exome sequencing and CNV data suggests that ETS1 is the pathogenic gene altered by 11q24.2-q25 deletions in Jacobsen syndrome and that CTBP2 is the pathogenic gene in 10q subtelomeric deletions.ConclusionsWe demonstrate a significantly increased frequency of rare de novo CNVs in CHD patients compared with healthy controls and suggest several novel genetic loci for CHD.

Published
2014

49. Mutations of ADAMTS9 Cause Nephronophthisis-Related Ciliopathy

Author

Choi, Yo Jun, Halbritter, Jan, Braun, Daniela A., Schueler, Markus, Schapiro, David, Rim, John Hoon, Nandadasa, Sumeda, Choi, Won-il, Widmeier, Eugen, Shril, Shirlee, Körber, Friederike, Sethi, Sidharth K., Lifton, Richard P., Beck, Bodo B., Apte, Suneel S., Gee, Heon Yung, and Hildebrandt, Friedhelm

Published
2019
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50. A novel SMARCC1 BAFopathy implicates neural progenitor epigenetic dysregulation in human hydrocephalus

Author

Singh, Amrita K, primary, Allington, Garrett, additional, Viviano, Stephen, additional, McGee, Stephen, additional, Kiziltug, Emre, additional, Ma, Shaojie, additional, Zhao, Shujuan, additional, Mekbib, Kedous Y, additional, Shohfi, John P, additional, Duy, Phan Q, additional, DeSpenza, Tyrone, additional, Furey, Charuta G, additional, Reeves, Benjamin C, additional, Smith, Hannah, additional, Sousa, André M M, additional, Cherskov, Adriana, additional, Allocco, August, additional, Nelson-Williams, Carol, additional, Haider, Shozeb, additional, Rizvi, Syed R A, additional, Alper, Seth L, additional, Sestan, Nenad, additional, Shimelis, Hermela, additional, Walsh, Lauren K, additional, Lifton, Richard P, additional, Moreno-De-Luca, Andres, additional, Jin, Sheng Chih, additional, Kruszka, Paul, additional, Deniz, Engin, additional, and Kahle, Kristopher T, additional

Published
2023
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