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1. Lessons from the CAGI‐4 Hopkins clinical panel challenge

Author

Chandonia, John‐Marc, Adhikari, Aashish, Carraro, Marco, Chhibber, Aparna, Cutting, Garry R, Fu, Yao, Gasparini, Alessandra, Jones, David T, Kramer, Andreas, Kundu, Kunal, Lam, Hugo YK, Leonardi, Emanuela, Moult, John, Pal, Lipika R, Searls, David B, Shah, Sohela, Sunyaev, Shamil, Tosatto, Silvio CE, Yin, Yizhou, and Buckley, Bethany A

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Clinical Sciences, Genetics, Clinical Research, 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, Computational Biology, Databases, Genetic, Genetic Predisposition to Disease, Genetic Testing, Humans, Phenotype, Sequence Analysis, DNA, CAGI, genetic testing, phenotype prediction, variant interpretation, Genetics & Heredity, Clinical sciences
Abstract

The CAGI-4 Hopkins clinical panel challenge was an attempt to assess state-of-the-art methods for clinical phenotype prediction from DNA sequence. Participants were provided with exonic sequences of 83 genes for 106 patients from the Johns Hopkins DNA Diagnostic Laboratory. Five groups participated in the challenge, predicting both the probability that each patient had each of the 14 possible classes of disease, as well as one or more causal variants. In cases where the Hopkins laboratory reported a variant, at least one predictor correctly identified the disease class in 36 of the 43 patients (84%). Even in cases where the Hopkins laboratory did not find a variant, at least one predictor correctly identified the class in 39 of the 63 patients (62%). Each prediction group correctly diagnosed at least one patient that was not successfully diagnosed by any other group. We discuss the causal variant predictions by different groups and their implications for further development of methods to assess variants of unknown significance. Our results suggest that clinically relevant variants may be missed when physicians order small panels targeted on a specific phenotype. We also quantify the false-positive rate of DNA-guided analysis in the absence of prior phenotypic indication.

Published
2017

2. Intrahepatic Cholestasis of Pregnancy (ICP) in U.S. Latinas and Chileans: Clinical features, Ancestry Analysis, and Admixture Mapping

Author

Bull, Laura N, Hu, Donglei, Shah, Sohela, Temple, Luisa, Silva, Karla, Huntsman, Scott, Melgar, Jennifer, Geiser, Mary T, Sanford, Ukina, Ortiz, Juan A, Lee, Richard H, Kusanovic, Juan P, Ziv, Elad, and Vargas, Juan E

Subjects
Reproductive Medicine, Biomedical and Clinical Sciences, Genetics, Biological Sciences, Prevention, Human Genome, Clinical Research, Adult, Alanine Transaminase, Aspartate Aminotransferases, Bile Acids and Salts, Bilirubin, Case-Control Studies, Chile, Cholestasis, Intrahepatic, Chromosomes, Human, Pair 2, Female, Genetic Predisposition to Disease, Hispanic or Latino, Humans, Polymorphism, Single Nucleotide, Pregnancy, Pregnancy Complications, Risk Factors, United States, Young Adult, gamma-Glutamyltransferase, General Science & Technology
Abstract

In the Americas, women with Indigenous American ancestry are at increased risk of intrahepatic cholestasis of pregnancy (ICP), relative to women of other ethnicities. We hypothesized that ancestry-related genetic factors contribute to this increased risk. We collected clinical and laboratory data, and performed biochemical assays on samples from U.S. Latinas and Chilean women, with and without ICP. The study sample included 198 women with ICP (90 from California, U.S., and 108 from Chile) and 174 pregnant control women (69 from California, U.S., and 105 from Chile). SNP genotyping was performed using Affymetrix arrays. We compared overall genetic ancestry between cases and controls, and used a genome-wide admixture mapping approach to screen for ICP susceptibility loci. We identified commonalities and differences in features of ICP between the 2 countries and determined that cases had a greater proportion of Indigenous American ancestry than did controls (p = 0.034). We performed admixture mapping, taking country of origin into account, and identified one locus for which Native American ancestry was associated with increased risk of ICP at a genome-wide level of significance (P = 3.1 x 10(-5), Pcorrected = 0.035). This locus has an odds ratio of 4.48 (95% CI: 2.21-9.06) for 2 versus zero Indigenous American chromosomes. This locus lies on chromosome 2, with a 10 Mb 95% confidence interval which does not contain any previously identified hereditary 'cholestasis genes.' Our results indicate that genetic factors contribute to the risk of developing ICP in the Americas, and support the utility of clinical and genetic studies of ethnically mixed populations for increasing our understanding of ICP.

Published
2015

3. Genetic Defects in Bile Acid Conjugation Cause Fat-Soluble Vitamin Deficiency

Author

Setchell, Kenneth DR, Heubi, James E, Shah, Sohela, Lavine, Joel E, Suskind, David, Al–Edreesi, Mohammed, Potter, Carol, Russell, David W, O'Connell, Nancy C, Wolfe, Brian, Jha, Pinky, Zhang, Wujuan, Bove, Kevin E, Knisely, Alex S, Hofmann, Alan F, Rosenthal, Philip, and Bull, Laura N

Subjects
Medical Biochemistry and Metabolomics, Biomedical and Clinical Sciences, Complementary and Integrative Health, Liver Disease, Nutrition, Clinical Research, Pediatric, Genetics, Digestive Diseases, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Acyltransferases, Avitaminosis, Bile Acids and Salts, Biopsy, Child, Child, Preschool, Coenzyme A Ligases, DNA, DNA Mutational Analysis, Fatty Acid Transport Proteins, Female, Genetic Predisposition to Disease, Homozygote, Humans, Infant, Liver, Male, Mass Spectrometry, Mutation, Missense, Chronic Liver Disease, Hepatic, Inherited, Nutrient, Clinical Sciences, Neurosciences, Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology, Clinical sciences, Nutrition and dietetics
Abstract

Background & aimsThe final step in bile acid synthesis involves conjugation with glycine and taurine, which promotes a high intraluminal micellar concentration to facilitate lipid absorption. We investigated the clinical, biochemical, molecular, and morphologic features of a genetic defect in bile acid conjugation in 10 pediatric patients with fat-soluble vitamin deficiency, some with growth failure or transient neonatal cholestatic hepatitis.MethodsWe identified the genetic defect that causes this disorder using mass spectrometry analysis of urine, bile, and serum samples and sequence analysis of the genes encoding bile acid-CoA:amino acid N-acyltransferase (BAAT) and bile acid-CoA ligase (SLC27A5).ResultsLevels of urinary bile acids were increased (432 ± 248 μmol/L) and predominantly excreted in unconjugated forms (79.4% ± 3.9%) and as sulfates and glucuronides. Glycine or taurine conjugates were absent in the urine, bile, and serum. Unconjugated bile acids accounted for 95.7% ± 5.8% of the bile acids in duodenal bile, with cholic acid accounting for 82.4% ± 5.5% of the total. Duodenal bile acid concentrations were 12.1 ± 5.9 mmol/L, which is too low for efficient lipid absorption. The biochemical profile was consistent with defective bile acid amidation. Molecular analysis of BAAT confirmed 4 different homozygous mutations in 8 patients tested.ConclusionsBased on a study of 10 pediatric patients, genetic defects that disrupt bile acid amidation cause fat-soluble vitamin deficiency and growth failure, indicating the importance of bile acid conjugation in lipid absorption. Some patients developed liver disease with features of a cholangiopathy. These findings indicate that patients with idiopathic neonatal cholestasis or later onset of unexplained fat-soluble vitamin deficiency should be screened for defects in bile acid conjugation.

Published
2013

4. Strain background modifies phenotypes in the ATP8B1-deficient mouse.

Author

Shah, Sohela, Sanford, Ukina R, Vargas, Julie C, Xu, Hongmei, Groen, Annamiek, Paulusma, Coen C, Grenert, James P, Pawlikowska, Ludmila, Sen, Saunak, Elferink, Ronald PJ Oude, and Bull, Laura N

Subjects
Liver, Animals, Mice, Inbred Strains, Mice, Inbred C57BL, Animals, Newborn, Mice, Knockout, Humans, Mice, Cholestasis, Intrahepatic, Disease Models, Animal, Genetic Predisposition to Disease, Weight Gain, Bilirubin, Cholates, Cholesterol, Alkaline Phosphatase, Phospholipid Transfer Proteins, Survival Analysis, Species Specificity, Phenotype, Female, Male, Adenosine Triphosphatases, Inbred Strains, Inbred C57BL, Newborn, Knockout, Cholestasis, Intrahepatic, Disease Models, Animal, General Science & Technology
Abstract

BackgroundMutations in ATP8B1 (FIC1) underlie cases of cholestatic disease, ranging from chronic and progressive (progressive familial intrahepatic cholestasis) to intermittent (benign recurrent intrahepatic cholestasis). The ATP8B1-deficient mouse serves as an animal model of human ATP8B1 deficiency.Methodology/principal findingsWe investigated the effect of genetic background on phenotypes of ATP8B1-deficient and wild-type mice, using C57Bl/6 (B6), 129, and (B6-129) F1 strain backgrounds. B6 background resulted in greater abnormalities in ATP8B1-deficient mice than did 129 and/or F1 background. ATP8B1-deficient pups of B6 background gained less weight. In adult ATP8B1-deficient mice at baseline, those of B6 background had lower serum cholesterol levels, higher serum alkaline phosphatase levels, and larger livers. After challenge with cholate-supplemented diet, these mice exhibited higher serum alkaline phosphatase and bilirubin levels, greater weight loss and larger livers. ATP8B1-deficient phenotypes in mice of F1 and 129 backgrounds are usually similar, suggesting that susceptibility to manifestations of ATP8B1 deficiency may be recessive. We also detected differences in hepatobiliary phenotypes between wild-type mice of differing strains.Conclusions/significanceOur results indicate that the ATP8B1-deficient mouse in a B6 background may be a better model of human ATP8B1 deficiency and highlight the importance of informed background strain selection for mouse models of liver disease.

Published
2010

5. Supplementary Tables 1-4 from Common Variants at the 19p13.1 and ZNF365 Loci Are Associated with ER Subtypes of Breast Cancer and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author

Couch, Fergus J., primary, Gaudet, Mia M., primary, Antoniou, Antonis C., primary, Ramus, Susan J., primary, Kuchenbaecker, Karoline B., primary, Soucy, Penny, primary, Beesley, Jonathan, primary, Chen, Xiaoqing, primary, Wang, Xianshu, primary, Kirchhoff, Tomas, primary, McGuffog, Lesley, primary, Barrowdale, Daniel, primary, Lee, Andrew, primary, Healey, Sue, primary, Sinilnikova, Olga M., primary, Andrulis, Irene L., primary, Ozcelik, Hilmi, primary, Mulligan, Anna Marie, primary, Thomassen, Mads, primary, Gerdes, Anne-Marie, primary, Jensen, Uffe Birk, primary, Skytte, Anne-Bine, primary, Kruse, Torben A., primary, Caligo, Maria A., primary, von Wachenfeldt, Anna, primary, Barbany-Bustinza, Gisela, primary, Loman, Niklas, primary, Soller, Maria, primary, Ehrencrona, Hans, primary, Karlsson, Per, primary, Nathanson, Katherine L., primary, Rebbeck, Timothy R., primary, Domchek, Susan M., primary, Jakubowska, Ania, primary, Lubinski, Jan, primary, Jaworska, Katarzyna, primary, Durda, Katarzyna, primary, Złowocka, Elżbieta, primary, Huzarski, Tomasz, primary, Byrski, Tomasz, primary, Gronwald, Jacek, primary, Cybulski, Cezary, primary, Górski, Bohdan, primary, Osorio, Ana, primary, Durán, Mercedes, primary, Tejada, María Isabel, primary, Benitez, Javier, primary, Hamann, Ute, primary, Hogervorst, Frans B.L., primary, van Os, Theo A., primary, van Leeuwen, Flora E., primary, Meijers-Heijboer, Hanne E.J., primary, Wijnen, Juul, primary, Blok, Marinus J., primary, Kets, Marleen, primary, Hooning, Maartje J., primary, Oldenburg, Rogier A., primary, Ausems, Margreet G.E.M., primary, Peock, Susan, primary, Frost, Debra, primary, Ellis, Steve D., primary, Platte, Radka, primary, Fineberg, Elena, primary, Evans, D. Gareth, primary, Jacobs, Chris, primary, Eeles, Rosalind A., primary, Adlard, Julian, primary, Davidson, Rosemarie, primary, Eccles, Diana M., primary, Cole, Trevor, primary, Cook, Jackie, primary, Paterson, Joan, primary, Brewer, Carole, primary, Douglas, Fiona, primary, Hodgson, Shirley V., primary, Morrison, Patrick J., primary, Walker, Lisa, primary, Porteous, Mary E., primary, Kennedy, M. John, primary, Side, Lucy E., primary, Bove, Betsy, primary, Godwin, Andrew K., primary, Stoppa-Lyonnet, Dominique, primary, Fassy-Colcombet, Marion, primary, Castera, Laurent, primary, Cornelis, François, primary, Mazoyer, Sylvie, primary, Léoné, Mélanie, primary, Boutry-Kryza, Nadia, primary, Bressac-de Paillerets, Brigitte, primary, Caron, Olivier, primary, Pujol, Pascal, primary, Coupier, Isabelle, primary, Delnatte, Capucine, primary, Akloul, Linda, primary, Lynch, Henry T., primary, Snyder, Carrie L., primary, Buys, Saundra S., primary, Daly, Mary B., primary, Terry, MaryBeth, primary, Chung, Wendy K., primary, John, Esther M., primary, Miron, Alexander, primary, Southey, Melissa C., primary, Hopper, John L., primary, Goldgar, David E., primary, Singer, Christian F., primary, Rappaport, Christine, primary, Tea, Muy-Kheng M., primary, Fink-Retter, Anneliese, primary, Hansen, Thomas V.O., primary, Nielsen, Finn C., primary, Arason, Aðalgeir, primary, Vijai, Joseph, primary, Shah, Sohela, primary, Sarrel, Kara, primary, Robson, Mark E., primary, Piedmonte, Marion, primary, Phillips, Kelly, primary, Basil, Jack, primary, Rubinstein, Wendy S., primary, Boggess, John, primary, Wakeley, Katie, primary, Ewart-Toland, Amanda, primary, Montagna, Marco, primary, Agata, Simona, primary, Imyanitov, Evgeny N., primary, Isaacs, Claudine, primary, Janavicius, Ramunas, primary, Lazaro, Conxi, primary, Blanco, Ignacio, primary, Feliubadalo, Lidia, primary, Brunet, Joan, primary, Gayther, Simon A., primary, Pharoah, Paul P.D., primary, Odunsi, Kunle O., primary, Karlan, Beth Y., primary, Walsh, Christine S., primary, Olah, Edith, primary, Teo, Soo Hwang, primary, Ganz, Patricia A., primary, Beattie, Mary S., primary, van Rensburg, Elizabeth J., primary, Dorfling, Cecelia M., primary, Diez, Orland, primary, Kwong, Ava, primary, Schmutzler, Rita K., primary, Wappenschmidt, Barbara, primary, Engel, Christoph, primary, Meindl, Alfons, primary, Ditsch, Nina, primary, Arnold, Norbert, primary, Heidemann, Simone, primary, Niederacher, Dieter, primary, Preisler-Adams, Sabine, primary, Gadzicki, Dorothea, primary, Varon-Mateeva, Raymonda, primary, Deissler, Helmut, primary, Gehrig, Andrea, primary, Sutter, Christian, primary, Kast, Karin, primary, Fiebig, Britta, primary, Heinritz, Wolfram, primary, Caldes, Trinidad, primary, de la Hoya, Miguel, primary, Muranen, Taru A., primary, Nevanlinna, Heli, primary, Tischkowitz, Marc D., primary, Spurdle, Amanda B., primary, Neuhausen, Susan L., primary, Ding, Yuan Chun, primary, Lindor, Noralane M., primary, Fredericksen, Zachary, primary, Pankratz, V. Shane, primary, Peterlongo, Paolo, primary, Manoukian, Siranoush, primary, Peissel, Bernard, primary, Zaffaroni, Daniela, primary, Barile, Monica, primary, Bernard, Loris, primary, Viel, Alessandra, primary, Giannini, Giuseppe, primary, Varesco, Liliana, primary, Radice, Paolo, primary, Greene, Mark H., primary, Mai, Phuong L., primary, Easton, Douglas F., primary, Chenevix-Trench, Georgia, primary, Offit, Kenneth, primary, and Simard, Jacques, primary

Published
2023
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6. Data from Common Variants at the 19p13.1 and ZNF365 Loci Are Associated with ER Subtypes of Breast Cancer and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author

Couch, Fergus J., primary, Gaudet, Mia M., primary, Antoniou, Antonis C., primary, Ramus, Susan J., primary, Kuchenbaecker, Karoline B., primary, Soucy, Penny, primary, Beesley, Jonathan, primary, Chen, Xiaoqing, primary, Wang, Xianshu, primary, Kirchhoff, Tomas, primary, McGuffog, Lesley, primary, Barrowdale, Daniel, primary, Lee, Andrew, primary, Healey, Sue, primary, Sinilnikova, Olga M., primary, Andrulis, Irene L., primary, Ozcelik, Hilmi, primary, Mulligan, Anna Marie, primary, Thomassen, Mads, primary, Gerdes, Anne-Marie, primary, Jensen, Uffe Birk, primary, Skytte, Anne-Bine, primary, Kruse, Torben A., primary, Caligo, Maria A., primary, von Wachenfeldt, Anna, primary, Barbany-Bustinza, Gisela, primary, Loman, Niklas, primary, Soller, Maria, primary, Ehrencrona, Hans, primary, Karlsson, Per, primary, Nathanson, Katherine L., primary, Rebbeck, Timothy R., primary, Domchek, Susan M., primary, Jakubowska, Ania, primary, Lubinski, Jan, primary, Jaworska, Katarzyna, primary, Durda, Katarzyna, primary, Złowocka, Elżbieta, primary, Huzarski, Tomasz, primary, Byrski, Tomasz, primary, Gronwald, Jacek, primary, Cybulski, Cezary, primary, Górski, Bohdan, primary, Osorio, Ana, primary, Durán, Mercedes, primary, Tejada, María Isabel, primary, Benitez, Javier, primary, Hamann, Ute, primary, Hogervorst, Frans B.L., primary, van Os, Theo A., primary, van Leeuwen, Flora E., primary, Meijers-Heijboer, Hanne E.J., primary, Wijnen, Juul, primary, Blok, Marinus J., primary, Kets, Marleen, primary, Hooning, Maartje J., primary, Oldenburg, Rogier A., primary, Ausems, Margreet G.E.M., primary, Peock, Susan, primary, Frost, Debra, primary, Ellis, Steve D., primary, Platte, Radka, primary, Fineberg, Elena, primary, Evans, D. Gareth, primary, Jacobs, Chris, primary, Eeles, Rosalind A., primary, Adlard, Julian, primary, Davidson, Rosemarie, primary, Eccles, Diana M., primary, Cole, Trevor, primary, Cook, Jackie, primary, Paterson, Joan, primary, Brewer, Carole, primary, Douglas, Fiona, primary, Hodgson, Shirley V., primary, Morrison, Patrick J., primary, Walker, Lisa, primary, Porteous, Mary E., primary, Kennedy, M. John, primary, Side, Lucy E., primary, Bove, Betsy, primary, Godwin, Andrew K., primary, Stoppa-Lyonnet, Dominique, primary, Fassy-Colcombet, Marion, primary, Castera, Laurent, primary, Cornelis, François, primary, Mazoyer, Sylvie, primary, Léoné, Mélanie, primary, Boutry-Kryza, Nadia, primary, Bressac-de Paillerets, Brigitte, primary, Caron, Olivier, primary, Pujol, Pascal, primary, Coupier, Isabelle, primary, Delnatte, Capucine, primary, Akloul, Linda, primary, Lynch, Henry T., primary, Snyder, Carrie L., primary, Buys, Saundra S., primary, Daly, Mary B., primary, Terry, MaryBeth, primary, Chung, Wendy K., primary, John, Esther M., primary, Miron, Alexander, primary, Southey, Melissa C., primary, Hopper, John L., primary, Goldgar, David E., primary, Singer, Christian F., primary, Rappaport, Christine, primary, Tea, Muy-Kheng M., primary, Fink-Retter, Anneliese, primary, Hansen, Thomas V.O., primary, Nielsen, Finn C., primary, Arason, Aðalgeir, primary, Vijai, Joseph, primary, Shah, Sohela, primary, Sarrel, Kara, primary, Robson, Mark E., primary, Piedmonte, Marion, primary, Phillips, Kelly, primary, Basil, Jack, primary, Rubinstein, Wendy S., primary, Boggess, John, primary, Wakeley, Katie, primary, Ewart-Toland, Amanda, primary, Montagna, Marco, primary, Agata, Simona, primary, Imyanitov, Evgeny N., primary, Isaacs, Claudine, primary, Janavicius, Ramunas, primary, Lazaro, Conxi, primary, Blanco, Ignacio, primary, Feliubadalo, Lidia, primary, Brunet, Joan, primary, Gayther, Simon A., primary, Pharoah, Paul P.D., primary, Odunsi, Kunle O., primary, Karlan, Beth Y., primary, Walsh, Christine S., primary, Olah, Edith, primary, Teo, Soo Hwang, primary, Ganz, Patricia A., primary, Beattie, Mary S., primary, van Rensburg, Elizabeth J., primary, Dorfling, Cecelia M., primary, Diez, Orland, primary, Kwong, Ava, primary, Schmutzler, Rita K., primary, Wappenschmidt, Barbara, primary, Engel, Christoph, primary, Meindl, Alfons, primary, Ditsch, Nina, primary, Arnold, Norbert, primary, Heidemann, Simone, primary, Niederacher, Dieter, primary, Preisler-Adams, Sabine, primary, Gadzicki, Dorothea, primary, Varon-Mateeva, Raymonda, primary, Deissler, Helmut, primary, Gehrig, Andrea, primary, Sutter, Christian, primary, Kast, Karin, primary, Fiebig, Britta, primary, Heinritz, Wolfram, primary, Caldes, Trinidad, primary, de la Hoya, Miguel, primary, Muranen, Taru A., primary, Nevanlinna, Heli, primary, Tischkowitz, Marc D., primary, Spurdle, Amanda B., primary, Neuhausen, Susan L., primary, Ding, Yuan Chun, primary, Lindor, Noralane M., primary, Fredericksen, Zachary, primary, Pankratz, V. Shane, primary, Peterlongo, Paolo, primary, Manoukian, Siranoush, primary, Peissel, Bernard, primary, Zaffaroni, Daniela, primary, Barile, Monica, primary, Bernard, Loris, primary, Viel, Alessandra, primary, Giannini, Giuseppe, primary, Varesco, Liliana, primary, Radice, Paolo, primary, Greene, Mark H., primary, Mai, Phuong L., primary, Easton, Douglas F., primary, Chenevix-Trench, Georgia, primary, Offit, Kenneth, primary, and Simard, Jacques, primary

Published
2023
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7. Working toward precision medicine: Predicting phenotypes from exomes in the Critical Assessment of Genome Interpretation (CAGI) challenges

Author

Daneshjou, Roxana, Wang, Yanran, Bromberg, Yana, Bovo, Samuele, Martelli, Pier L, Babbi, Giulia, Lena, Pietro Di, Casadio, Rita, Edwards, Matthew, Gifford, David, Jones, David T, Sundaram, Laksshman, Bhat, Rajendra Rana, Li, Xiaolin, Pal, Lipika R., Kundu, Kunal, Yin, Yizhou, Moult, John, Jiang, Yuxiang, Pejaver, Vikas, Pagel, Kymberleigh A., Li, Biao, Mooney, Sean D., Radivojac, Predrag, Shah, Sohela, Carraro, Marco, Gasparini, Alessandra, Leonardi, Emanuela, Giollo, Manuel, Ferrari, Carlo, Tosatto, Silvio C E, Bachar, Eran, Azaria, Johnathan R., Ofran, Yanay, Unger, Ron, Niroula, Abhishek, Vihinen, Mauno, Chang, Billy, Wang, Maggie H, Franke, Andre, Petersen, Britt-Sabina, Pirooznia, Mehdi, Zandi, Peter, McCombie, Richard, Potash, James B., Altman, Russ B., Klein, Teri E., Hoskins, Roger A., Repo, Susanna, Brenner, Steven E., and Morgan, Alexander A.

Published
2017
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11. Rare variants in XRCC2 as breast cancer susceptibility alleles

Author

Hilbers, Florentine S, Wijnen, Juul T, Hoogerbrugge, Nicoline, Oosterwijk, Jan C, Collee, Margriet J, Peterlongo, Paolo, Radice, Paolo, Manoukian, Siranoush, Feroce, Irene, Capra, Fabio, Couch, Fergus J, Wang, Xianshu, Guidugli, Lucia, Offit, Kenneth, Shah, Sohela, Campbell, Ian G, Thompson, Ella R, James, Paul A, Trainer, Alison H, Gracia, Javier, Benitez, Javier, van Asperen, Christi J, and Devilee, Peter

Published
2012
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12. Better bioinformatics will help labs manage genetic testing

Author

Shah, Sohela

Subjects
Genetic testing -- Information management, Biomedical laboratories -- Information management, Medical informatics -- Usage, Company systems management, Business, Health care industry
Abstract

With the increasing complexity of genomic tests, clinical labs are under pressure to expand their bioinformatics capabilities and pipelines while scaling their operations for increasing testing volume and fast turnaround [...]

Published
2017

14. Evaluating the association of multiple single nucleotide polymorphisms with response to gemcitabine and platinum combination chemotherapy in urothelial carcinoma of the bladder

Author

Alanee, Shaheen, primary, Shah, Sohela, additional, Zabor, Emily, additional, Vijai, Joseph, additional, Ostrovnaya, Irina, additional, Garcia-Grossman, Ilana, additional, Pendse, Deepa, additional, Littman, Jason, additional, Regazzi, Ashley, additional, Offit, Kenneth, additional, and Bajorin, Dean, additional

Published
2017
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15. Genome Sequencing of Multiple Primary Tumors Reveals a Novel PALB2 Variant

Author

Schrader, Kasmintan A., primary, Stratton, Kelly L., additional, Murali, Rajmohan, additional, Laitman, Yael, additional, Cavallone, Luca, additional, Offit, Lily, additional, Wen, Yong Hannah, additional, Thomas, Tinu, additional, Shah, Sohela, additional, Rau-Murthy, Rohini, additional, Manschreck, Christopher, additional, Salo-Mullen, Erin, additional, Otegbeye, Ebun, additional, Corines, Marina, additional, Zhang, Liying, additional, Norton, Larry, additional, Hudis, Clifford, additional, Klein, Robert J., additional, Kauff, Noah D., additional, Robson, Mark, additional, Stadler, Zsofia K., additional, Haber, Daniel A., additional, Lipkin, Steven M., additional, Friedman, Eitan, additional, Foulkes, William D., additional, Altshuler, David, additional, Vijai, Joseph, additional, and Offit, Kenneth, additional

Published
2016
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16. Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk

Author

Gaudet, Mia M., Kuchenbaecker, Karoline B., Vijai, Joseph, Klein, Robert J., Kirchhoff, Tomas, McGuffog, Lesley, Barrowdale, Daniel, Dunning, Alison M., Lee, Andrew, Dennis, Joe, Healey, Sue, Dicks, Ed, Soucy, Penny, Sinilnikova, Olga M., Pankratz, Vernon S., Wang, Xianshu, Eldridge, Ronald C., Tessier, Daniel C., Vincent, Daniel, Bacot, Francois, Hogervorst, Frans B. L., Peock, Susan, Stoppa-Lyonnet, Dominique, Peterlongo, Paolo, Schmutzler, Rita K., Nathanson, Katherine L., Piedmonte, Marion, Singer, Christian F., Thomassen, Mads, Hansen, Thomas v. O., Neuhausen, Susan L., Blanco, Ignacio, Greene, Mark H., Garber, Judith, Weitzel, Jeffrey N., Andrulis, Irene L., Goldgar, David E., D'Andrea, Emma, Caldes, Trinidad, Nevanlinna, Heli, Osorio, Ana, van Rensburg, Elizabeth J., Arason, Adalgeir, Rennert, Gad, van den Ouweland, Ans M. W., van der Hout, Annemarie H., Kets, Carolien M., Aalfs, Cora M., Wijnen, Juul T., Ausems, Margreet G. E. M., Frost, Debra, Ellis, Steve, Fineberg, Elena, Platte, Radka, Evans, D. Gareth, Jacobs, Chris, Adlard, Julian, Tischkowitz, Marc, Porteous, Mary E., Damiola, Francesca, Golmard, Lisa, Barjhoux, Laure, Longy, Michel, Belotti, Muriel, Ferrer, Sandra Fert, Mazoyer, Sylvie, Spurdle, Amanda B., Manoukian, Siranoush, Barile, Monica, Genuardi, Maurizio, Arnold, Norbert, Meindl, Alfons, Sutter, Christian, Wappenschmidt, Barbara, Domchek, Susan M., Pfeiler, Georg, Friedman, Eitan, Jensen, Uffe Birk, Robson, Mark, Shah, Sohela, Lazaro, Conxi, Mai, Phuong L., Benitez, Javier, Southey, Melissa C., Schmidt, Marjanka K., Fasching, Peter A., Peto, Julian, Humphreys, Manjeet K., Wang, Qin, Michailidou, Kyriaki, Sawyer, Elinor J., Burwinkel, Barbara, Guénel, Pascal, Bojesen, Stig E., Milne, Roger L., Brenner, Hermann, Lochmann, Magdalena, Aittomäki, Kristiina, Dörk, Thilo, Margolin, Sara, Mannermaa, Arto, Lambrechts, Diether, Chang-Claude, Jenny, Radice, Paolo, Giles, Graham G., Haiman, Christopher A., Winqvist, Robert, Devillee, Peter, García-Closas, Montserrat, Schoof, Nils, Hooning, Maartje J., Cox, Angela, Pharoah, Paul D. P., Jakubowska, Anna, Orr, Nick, González-Neira, Anna, Pita, Guillermo, Alonso, M. Rosario, Hall, Per, Couch, Fergus J., Simard, Jacques, Altshuler, David, Easton, Douglas F., Chenevix-Trench, Georgia, Antoniou, Antonis C., Offit, Kenneth, and Tobias, Ed

Subjects
skin and connective tissue diseases, QH426
Abstract

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80–0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.

Published
2013

19. A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia

Author

Shah, Sohela, primary, Schrader, Kasmintan A, additional, Waanders, Esmé, additional, Timms, Andrew E, additional, Vijai, Joseph, additional, Miething, Cornelius, additional, Wechsler, Jeremy, additional, Yang, Jun, additional, Hayes, James, additional, Klein, Robert J, additional, Zhang, Jinghui, additional, Wei, Lei, additional, Wu, Gang, additional, Rusch, Michael, additional, Nagahawatte, Panduka, additional, Ma, Jing, additional, Chen, Shann-Ching, additional, Song, Guangchun, additional, Cheng, Jinjun, additional, Meyers, Paul, additional, Bhojwani, Deepa, additional, Jhanwar, Suresh, additional, Maslak, Peter, additional, Fleisher, Martin, additional, Littman, Jason, additional, Offit, Lily, additional, Rau-Murthy, Rohini, additional, Fleischut, Megan Harlan, additional, Corines, Marina, additional, Murali, Rajmohan, additional, Gao, Xiaoni, additional, Manschreck, Christopher, additional, Kitzing, Thomas, additional, Murty, Vundavalli V, additional, Raimondi, Susana C, additional, Kuiper, Roland P, additional, Simons, Annet, additional, Schiffman, Joshua D, additional, Onel, Kenan, additional, Plon, Sharon E, additional, Wheeler, David A, additional, Ritter, Deborah, additional, Ziegler, David S, additional, Tucker, Kathy, additional, Sutton, Rosemary, additional, Chenevix-Trench, Georgia, additional, Li, Jun, additional, Huntsman, David G, additional, Hansford, Samantha, additional, Senz, Janine, additional, Walsh, Tom, additional, Lee, Ming, additional, Hahn, Christopher N, additional, Roberts, Kathryn G, additional, King, Mary-Claire, additional, Lo, Sarah M, additional, Levine, Ross L, additional, Viale, Agnes, additional, Socci, Nicholas D, additional, Nathanson, Katherine L, additional, Scott, Hamish S, additional, Daly, Mark, additional, Lipkin, Steven M, additional, Lowe, Scott W, additional, Downing, James R, additional, Altshuler, David, additional, Sandlund, John T, additional, Horwitz, Marshall S, additional, Mullighan, Charles G, additional, and Offit, Kenneth, additional

Published
2013
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20. Assessment of SLX4 Mutations in Hereditary Breast Cancers

Author

Shah, Sohela, primary, Kim, Yonghwan, additional, Ostrovnaya, Irina, additional, Murali, Rajmohan, additional, Schrader, Kasmintan A., additional, Lach, Francis P., additional, Sarrel, Kara, additional, Rau-Murthy, Rohini, additional, Hansen, Nichole, additional, Zhang, Liyng, additional, Kirchhoff, Tomas, additional, Stadler, Zsofia, additional, Robson, Mark, additional, Vijai, Joseph, additional, Offit, Kenneth, additional, and Smogorzewska, Agata, additional

Published
2013
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21. Genome sequencing of multiple primary tumors to reveal underlying germline cancer susceptibility.

Author

Schrader, Kasmintan A., primary, Stratton, Kelly Lynn, additional, Murali, Rajmohan, additional, Laitman, Yael, additional, Cavallone, Luca, additional, Offit, Lily, additional, Wen, Yong Hannah, additional, Shah, Sohela, additional, Rau-Murthy, Rohini, additional, Manschreck, Christopher, additional, Otegbeye, Ebunoluwa, additional, Corines, Marina, additional, Kauff, Noah D., additional, Klein, Robert J., additional, Robson, Mark E., additional, Stadler, Zsofia Kinga, additional, Friedman, Eitan, additional, Foulkes, William, additional, Vijai, Joseph, additional, and Offit, Kenneth, additional

Published
2013
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22. Association of germ-line single nucleotide polymorphisms (SNPs) with pathologic response to neoadjuvant cisplatin-based chemotherapy in patients with resectable non-small cell lung cancers.

Author

Chaft, Jamie E., primary, Shah, Sohela, additional, Drill, Esther N., additional, Sima, Camelia S., additional, Joseph, Vijai, additional, Dutra-Clarke, Ana Virginia Calogeras, additional, Littman, Jason, additional, Kris, Mark G., additional, Travis, William D., additional, Rizvi, Naiyer A., additional, and Offit, Kenneth, additional

Published
2013
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25. Susceptibility Loci Associated with Specific and Shared Subtypes of Lymphoid Malignancies

Author

Vijai, Joseph, primary, Kirchhoff, Tomas, additional, Schrader, Kasmintan A., additional, Brown, Jennifer, additional, Dutra-Clarke, Ana Virginia, additional, Manschreck, Christopher, additional, Hansen, Nichole, additional, Rau-Murthy, Rohini, additional, Sarrel, Kara, additional, Przybylo, Jennifer, additional, Shah, Sohela, additional, Cheguri, Srujana, additional, Stadler, Zsofia, additional, Zhang, Liying, additional, Paltiel, Ora, additional, Ben-Yehuda, Dina, additional, Viale, Agnes, additional, Portlock, Carol, additional, Straus, David, additional, Lipkin, Steven M., additional, Lacher, Mortimer, additional, Robson, Mark, additional, Klein, Robert J., additional, Zelenetz, Andrew, additional, and Offit, Kenneth, additional

Published
2013
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27. Rare De Novo Germline Copy-Number Variation in Testicular Cancer

Author

Stadler, Zsofia K., primary, Esposito, Diane, additional, Shah, Sohela, additional, Vijai, Joseph, additional, Yamrom, Boris, additional, Levy, Dan, additional, Lee, Yoon-ha, additional, Kendall, Jude, additional, Leotta, Anthony, additional, Ronemus, Michael, additional, Hansen, Nichole, additional, Sarrel, Kara, additional, Rau-Murthy, Rohini, additional, Schrader, Kasmintan, additional, Kauff, Noah, additional, Klein, Robert J., additional, Lipkin, Steven M., additional, Murali, Rajmohan, additional, Robson, Mark, additional, Sheinfeld, Joel, additional, Feldman, Darren, additional, Bosl, George, additional, Norton, Larry, additional, Wigler, Michael, additional, and Offit, Kenneth, additional

Published
2012
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28. Abstract 2600: SLX4 mutation in hereditary breast cancer

Author

Shah, Sohela, primary, Lach, Frank, additional, Kim, Yonghwan, additional, Sarrel, Kara, additional, Rau-Murthy, Rohini, additional, Hansen, Nichole, additional, Rendleman, Justin, additional, Kirchhoff, Tomas, additional, Joseph, Vijai, additional, Offit, Kenneth, additional, and Smogorzewska, Agata, additional

Published
2012
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29. Common Variants at the 19p13.1 and ZNF365 Loci Are Associated with ER Subtypes of Breast Cancer and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author

Couch, Fergus J., primary, Gaudet, Mia M., additional, Antoniou, Antonis C., additional, Ramus, Susan J., additional, Kuchenbaecker, Karoline B., additional, Soucy, Penny, additional, Beesley, Jonathan, additional, Chen, Xiaoqing, additional, Wang, Xianshu, additional, Kirchhoff, Tomas, additional, McGuffog, Lesley, additional, Barrowdale, Daniel, additional, Lee, Andrew, additional, Healey, Sue, additional, Sinilnikova, Olga M., additional, Andrulis, Irene L., additional, Ozcelik, Hilmi, additional, Mulligan, Anna Marie, additional, Thomassen, Mads, additional, Gerdes, Anne-Marie, additional, Jensen, Uffe Birk, additional, Skytte, Anne-Bine, additional, Kruse, Torben A., additional, Caligo, Maria A., additional, von Wachenfeldt, Anna, additional, Barbany-Bustinza, Gisela, additional, Loman, Niklas, additional, Soller, Maria, additional, Ehrencrona, Hans, additional, Karlsson, Per, additional, Nathanson, Katherine L., additional, Rebbeck, Timothy R., additional, Domchek, Susan M., additional, Jakubowska, Ania, additional, Lubinski, Jan, additional, Jaworska, Katarzyna, additional, Durda, Katarzyna, additional, Złowocka, Elżbieta, additional, Huzarski, Tomasz, additional, Byrski, Tomasz, additional, Gronwald, Jacek, additional, Cybulski, Cezary, additional, Górski, Bohdan, additional, Osorio, Ana, additional, Durán, Mercedes, additional, Tejada, María Isabel, additional, Benitez, Javier, additional, Hamann, Ute, additional, Hogervorst, Frans B.L., additional, van Os, Theo A., additional, van Leeuwen, Flora E., additional, Meijers-Heijboer, Hanne E.J., additional, Wijnen, Juul, additional, Blok, Marinus J., additional, Kets, Marleen, additional, Hooning, Maartje J., additional, Oldenburg, Rogier A., additional, Ausems, Margreet G.E.M., additional, Peock, Susan, additional, Frost, Debra, additional, Ellis, Steve D., additional, Platte, Radka, additional, Fineberg, Elena, additional, Evans, D. Gareth, additional, Jacobs, Chris, additional, Eeles, Rosalind A., additional, Adlard, Julian, additional, Davidson, Rosemarie, additional, Eccles, Diana M., additional, Cole, Trevor, additional, Cook, Jackie, additional, Paterson, Joan, additional, Brewer, Carole, additional, Douglas, Fiona, additional, Hodgson, Shirley V., additional, Morrison, Patrick J., additional, Walker, Lisa, additional, Porteous, Mary E., additional, Kennedy, M. John, additional, Side, Lucy E., additional, Bove, Betsy, additional, Godwin, Andrew K., additional, Stoppa-Lyonnet, Dominique, additional, Fassy-Colcombet, Marion, additional, Castera, Laurent, additional, Cornelis, François, additional, Mazoyer, Sylvie, additional, Léoné, Mélanie, additional, Boutry-Kryza, Nadia, additional, Bressac-de Paillerets, Brigitte, additional, Caron, Olivier, additional, Pujol, Pascal, additional, Coupier, Isabelle, additional, Delnatte, Capucine, additional, Akloul, Linda, additional, Lynch, Henry T., additional, Snyder, Carrie L., additional, Buys, Saundra S., additional, Daly, Mary B., additional, Terry, MaryBeth, additional, Chung, Wendy K., additional, John, Esther M., additional, Miron, Alexander, additional, Southey, Melissa C., additional, Hopper, John L., additional, Goldgar, David E., additional, Singer, Christian F., additional, Rappaport, Christine, additional, Tea, Muy-Kheng M., additional, Fink-Retter, Anneliese, additional, Hansen, Thomas V.O., additional, Nielsen, Finn C., additional, Arason, Aðalgeir, additional, Vijai, Joseph, additional, Shah, Sohela, additional, Sarrel, Kara, additional, Robson, Mark E., additional, Piedmonte, Marion, additional, Phillips, Kelly, additional, Basil, Jack, additional, Rubinstein, Wendy S., additional, Boggess, John, additional, Wakeley, Katie, additional, Ewart-Toland, Amanda, additional, Montagna, Marco, additional, Agata, Simona, additional, Imyanitov, Evgeny N., additional, Isaacs, Claudine, additional, Janavicius, Ramunas, additional, Lazaro, Conxi, additional, Blanco, Ignacio, additional, Feliubadalo, Lidia, additional, Brunet, Joan, additional, Gayther, Simon A., additional, Pharoah, Paul P.D., additional, Odunsi, Kunle O., additional, Karlan, Beth Y., additional, Walsh, Christine S., additional, Olah, Edith, additional, Teo, Soo Hwang, additional, Ganz, Patricia A., additional, Beattie, Mary S., additional, van Rensburg, Elizabeth J., additional, Dorfling, Cecelia M., additional, Diez, Orland, additional, Kwong, Ava, additional, Schmutzler, Rita K., additional, Wappenschmidt, Barbara, additional, Engel, Christoph, additional, Meindl, Alfons, additional, Ditsch, Nina, additional, Arnold, Norbert, additional, Heidemann, Simone, additional, Niederacher, Dieter, additional, Preisler-Adams, Sabine, additional, Gadzicki, Dorothea, additional, Varon-Mateeva, Raymonda, additional, Deissler, Helmut, additional, Gehrig, Andrea, additional, Sutter, Christian, additional, Kast, Karin, additional, Fiebig, Britta, additional, Heinritz, Wolfram, additional, Caldes, Trinidad, additional, de la Hoya, Miguel, additional, Muranen, Taru A., additional, Nevanlinna, Heli, additional, Tischkowitz, Marc D., additional, Spurdle, Amanda B., additional, Neuhausen, Susan L., additional, Ding, Yuan Chun, additional, Lindor, Noralane M., additional, Fredericksen, Zachary, additional, Pankratz, V. Shane, additional, Peterlongo, Paolo, additional, Manoukian, Siranoush, additional, Peissel, Bernard, additional, Zaffaroni, Daniela, additional, Barile, Monica, additional, Bernard, Loris, additional, Viel, Alessandra, additional, Giannini, Giuseppe, additional, Varesco, Liliana, additional, Radice, Paolo, additional, Greene, Mark H., additional, Mai, Phuong L., additional, Easton, Douglas F., additional, Chenevix-Trench, Georgia, additional, Offit, Kenneth, additional, and Simard, Jacques, additional

Published
2012
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30. Babesia microti Primarily Invades Mature Erythrocytes in Mice

Author

Borggraefe, Ingo, primary, Yuan, Jie, additional, Telford, Sam R., additional, Menon, Sanjay, additional, Hunter, Rouette, additional, Shah, Sohela, additional, Spielman, Andrew, additional, Gelfand, Jeffrey A., additional, Wortis, Henry H., additional, and Vannier, Edouard, additional

Published
2006
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31. Prevalence of HOXB13 mutation in a population of Ashkenazi Jewish men treated for prostate cancer.

Author

Alanee, Shaheen, Shah, Sohela, Vijai, Joseph, Schrader, Kasmintan, Hamilton, Robert, Rau-Murthy, Rohini, Sarrel, Kara, Manschreck, Christopher, Eastham, James, and Offit, Kenneth

Abstract

We performed a retrospective analysis of germline DNA samples from Ashkenazi Jewish men and a comparison group of non-Ashkenazi men treated for prostate cancer at our institution to determine the prevalence of HOXB13 G84E mutation in prostate cancer patients of Ashkenazi Jewish heritage, an ethnic group common to the New York City area. Patients were genotyped for G84E using a TaqMan assay (Applied Biosystems). Positive cases were confirmed using Sanger sequencing. Median age at prostate cancer diagnosis was 68 years for 889 Ashkenazi Jewish patients, 64 years for 920 non-Ashkenazi Jewish patients. The median follow up was 9 years for Ashkenazi Jewish patients and 8.8 years for non-Ashkenazi Jewish patients. Only 4 patients were found to be heterozygous carriers of G84E. They were all of non-Ashkenazi Jewish ancestry and were diagnosed at 70, 66, 78, and 49 years of age. Two of them presented with high-risk prostate cancer. The prevalence of G84E in the non-Ashkenazi sample was 0.4 %. HOXB13 G84E mutation was not observed in prostate cancer patients of Ashkenazi Jewish ancestry treated at our institution. Screening for G84E, therefore, may be unnecessary in Ashkenazi Jewish men if these results are validated by other studies. [ABSTRACT FROM AUTHOR]

Published
2013
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32. Assessment of SLX4 Mutations in Hereditary Breast Cancers.

Author

Shah, Sohela, Kim, Yonghwan, Ostrovnaya, Irina, Murali, Rajmohan, Schrader, Kasmintan A., Lach, Francis P., Sarrel, Kara, Rau-Murthy, Rohini, Hansen, Nichole, Zhang, Liyng, Kirchhoff, Tomas, Stadler, Zsofia, Robson, Mark, Vijai, Joseph, Offit, Kenneth, and Smogorzewska, Agata

Subjects
*BREAST cancer, *GENETIC mutation, *GENETIC disorders, *DNA repair, *ENDONUCLEASES, *DNA topoisomerase I, *ADP-ribosyltransferases
Abstract

Background: SLX4 encodes a DNA repair protein that regulates three structure-specific endonucleases and is necessary for resistance to DNA crosslinking agents, topoisomerase I and poly (ADP-ribose) polymerase (PARP) inhibitors. Recent studies have reported mutations in SLX4 in a new subtype of Fanconi anemia (FA), FA-P. Monoallelic defects in several FA genes are known to confer susceptibility to breast and ovarian cancers. Methods and Results: To determine if SLX4 is involved in breast cancer susceptibility, we sequenced the entire SLX4 coding region in 738 (270 Jewish and 468 non-Jewish) breast cancer patients with 2 or more family members affected by breast cancer and no known BRCA1 or BRCA2 mutations. We found a novel nonsense (c.2469G>A, p.W823*) mutation in one patient. In addition, we also found 51 missense variants [13 novel, 23 rare (MAF<0.1%), and 15 common (MAF>1%)], of which 22 (5 novel and 17 rare) were predicted to be damaging by Polyphen2 (score = 0.65–1). We performed functional complementation studies using p.W823* and 5 SLX4 variants (4 novel and 1 rare) cDNAs in a human SLX4-null fibroblast cell line, RA3331. While wild type SLX4 and all the other variants fully rescued the sensitivity to mitomycin C (MMC), campthothecin (CPT), and PARP inhibitor (Olaparib) the p.W823* SLX4 mutant failed to do so. Conclusion: Loss-of-function mutations in SLX4 may contribute to the development of breast cancer in very rare cases. [ABSTRACT FROM AUTHOR]

Published
2013
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33. Babesia microtiPrimarily Invades Mature Erythrocytes in Mice

Author

Borggraefe, Ingo, Yuan, Jie, Telford, Sam R., Menon, Sanjay, Hunter, Rouette, Shah, Sohela, Spielman, Andrew, Gelfand, Jeffrey A., Wortis, Henry H., and Vannier, Edouard

Abstract

ABSTRACTBabesia microtiis a tick-borne red blood cell parasite that causes babesiosis in people. Its most common vertebrate reservoir is the white-footed mouse. To determine whether B. microtiinvades reticulocytes, as does the canine pathogen B. gibsoni, we infected the susceptible inbred mouse strains C.B-17.scid and DBA/2 with a clinical isolate of B. microti. Staining of fixed permeabilized red blood cells with 4′,6′-diamidino-2-phenylindole or YOYO-1, a sensitive nucleic acid stain, revealed parasite nuclei as large bright dots. Flow cytometric analysis indicated that parasite DNA is primarily found in mature erythrocytes that expressed Babesiaantigens but not the transferrin receptor CD71. In contrast, CD71-positive reticulocytes rarely contained Babesianuclei and failed to express Babesiaantigens. Accordingly, the frequency of YOYO-1-positive, CD71-negative cells strongly correlated with parasitemia, defined as the frequency of infected red blood cells assessed on Giemsa-stained blood smears. Importantly, the absolute numbers generated by the two techniques were similar. Parasitemia was modest and transient in DBA/2 mice but intense and sustained in C.B-17.scid mice. In both strains, parasitemia preceded reticulocytosis, but reticulocytes remained refractory to B. microti. In immunocompetent C.B-17 mice, reticulocytosis developed early, despite a marginal and short-lived parasitemia. Likewise, an early reticulocytosis developed in resistant BALB/cBy and B10.D2 mice. These studies establish that B. microtihas a tropism for mature erythrocytes. Although reticulocytes are rarely infected, the delayed reticulocytosis in susceptible strains may result from parasite or host activities to limit renewal of the mature erythrocyte pool, thereby preventing an overwhelming parasitemia.

Published
2006
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34. Common Variants at the 19p13.1 and ZNF365 Loci Are Associated with ER Subtypes of Breast Cancer and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author

Cornelis, Franco̧is, Peterlongo, Paolo, Tejada, María Isabel, Karlsson, Per, Hansen, Thomas V.O., Domchek, Susan M., Sutter, Christian, Godwin, Andrew K., Janavicius, Ramunas, Thomassen, Mads, Kirchhoff, Tomas, Lindor, Noralane M., Van Rensburg, Elizabeth J., Ewart-Toland, Amanda, Agata, Simona, McGuffog, Lesley, Coupier, Isabelle, Evans, D. Gareth, Andrulis, Irene L., Zołwocka, Elzbieta, Fineberg, Elena, Peissel, Bernard, Engel, Christoph, Kennedy, M. John, Meijers-Heijboer, Hanne E.J., Ehrencrona, Hans, Niederacher, Dieter, Porteous, Mary E., Eccles, Diana M., Caligo, Maria A., Rubinstein, Wendy S., Ganz, Patricia A., Huzarski, Tomasz, Tea, Muy Kheng M., Kruse, Torben A., Imyanitov, Evgeny N., Chenevix-Trench, Georgia, Kwong, Ava, Simard, Jacques, Healey, Sue, Varesco, Liliana, Von Wachenfeldt, Anna, Teo, Soo Hwang, Terry, Mary Beth, Buys, Saundra S., Wang, Xianshu, Caron, Olivier, Barile, Monica, Caldes, Trinidad, Beattie, Mary S., Brewer, Carole, Gerdes, Anne Marie, Spurdle, Amanda B., Sarrel, Kara, Miron, Alexander, Mai, Phuong L., Sinilnikova, Olga M., Peock, Susan, Lazaro, Conxi, Byrski, Tomasz, Fredericksen, Zachary, Wakeley, Katie, Brunet, Joan, Van Leeuwen, Flora E., Stoppa-Lyonnet, Dominique, Durań, Mercedes, Couch, Fergus J., Varon-Mateeva, Raymonda, Castera, Laurent, Giannini, Giuseppe, Chung, Wendy K., Lubinski, Jan, Heinritz, Wolfram, Muranen, Taru A., Bernard, Loris, Preisler-Adams, Sabine, Arnold, Norbert, Lynch, Henry T., Kets, Marleen, Diez, Orland, Platte, Radka, Karlan, Beth Y., Loman, Niklas, Daly, Mary B., Chen, Xiaoqing, Odunsi, Kunle O., Snyder, Carrie L., Douglas, Fiona, Hopper, John L., Radice, Paolo, Dorfling, Cecelia M., Arason, Aoalgeir, Jacobs, Chris, Basil, Jack, Piedmonte, Marion, Viel, Alessandra, Jaworska, Katarzyna, Pujol, Pascal, Mulligan, Anna Marie, Jensen, Uffe Birk, Fassy-Colcombet, Marion, Rebbeck, Timothy R., Gehrig, Andrea, Goŕski, Bohdan, Rappaport, Christine, Osorio, Ana, Benitez, Javier, Ditsch, Nina, Kast, Karin, Paterson, Joan, Nevanlinna, Heli, Southey, Melissa C., Goldgar, David E., Manoukian, Siranoush, Bove, Betsy, Boutry-Kryza, Nadia, Durda, Katarzyna, Heidemann, Simone, Kuchenbaecker, Karoline B., Walsh, Christine S., Deissler, Helmut, Meindl, Alfons, Van Os, Theo A., Ozcelik, Hilmi, Phillips, Kelly, Wijnen, Juul, Delnatte, Capucine, Gaudet, Mia M., Morrison, Patrick J., Fink-Retter, Anneliese, De La Hoya, Miguel, Bressac-de Paillerets, Brigitte, Leóne, Meĺanie, Zaffaroni, Daniela, Hodgson, Shirley V., Nielsen, Finn C., Mazoyer, Sylvie, Walker, Lisa, Ausems, Margreet G.E.M., Eeles, Rosalind A., Robson, Mark E., Side, Lucy E., Pharoah, Paul P.D., Antoniou, Antonis C., Lee, Andrew, Greene, Mark H., Adlard, Julian, Gadzicki, Dorothea, Fiebig, Britta, Singer, Christian F., Blok, Marinus J., Soucy, Penny, Easton, Douglas F., Gayther, Simon A., Barrowdale, Daniel, Beesley, Jonathan, Ding, Yuan Chun, Jakubowska, Ania, Davidson, Rosemarie, Schmutzler, Rita K., Boggess, John, Skytte, Anne Bine, Olah, Edith, Hogervorst, Frans B.L., Montagna, Marco, Ramus, Susan J., Vijai, Joseph, Barbany-Bustinza, Gisela, Tischkowitz, Marc D., Offit, Kenneth, Oldenburg, Rogier A., Neuhausen, Susan L., Ellis, Steve D., Cole, Trevor, Cook, Jackie, Pankratz, V. Shane, Soller, Maria, Blanco, Ignacio, Isaacs, Claudine, Frost, Debra, Feliubadalo, Lidia, Akloul, Linda, Shah, Sohela, Hamann, Ute, John, Esther M., Cybulski, Cezary, Wappenschmidt, Barbara, Nathanson, Katherine, Hooning, Maartje J., and Gronwald, Jacek

Subjects
endocrine system diseases, skin and connective tissue diseases, 3. Good health
Abstract

Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).

35. The Challenge of Genetic Variants.

Author

Joecker, Anika and Shah, Sohela

Abstract

The article discusses the challenges posed by genetic variant interpretation and the need for automation. It mentions the importance of next-generation sequencing (NGS) as well as exome- or genome-sequencing tests in understanding mysterious diseases and the challenges in variant interpretation pipeline involving the review of literature, review of public databases and review of evidence by geneticists and the role of automation in addressing the bottleneck in the analysis of NGS test results.

Published
2016

36. CCBE1 Mutation in Two Siblings, One Manifesting Lymphedema-Cholestasis Syndrome, and the Other, Fetal Hydrops.

Author

Shah, Sohela, Conlin, Laura K., Gomez, Luis, Aagenaes, Øystein, Eiklid, Kristin, Knisely, A. S., Mennuti, Michael T., Matthews, Randolph P., Spinner, Nancy B., and Bull, Laura N.

Subjects
*LYMPHEDEMA, *CHOLESTASIS, *GENETIC mutation, *EDEMA, *FETAL diseases, *PREGNANCY complications, *PHENOTYPES
Abstract

Background:Lymphedema-cholestasis syndrome (LCS; Aagenaes syndrome) is a rare autosomal recessive disorder, characterized by 1) neonatal intrahepatic cholestasis, often lessening and becoming intermittent with age, and 2) severe chronic lymphedema, mainly lower limb. LCS was originally described in a Norwegian kindred in which a locus, LCS1, was mapped to a 6.6cM region on chromosome 15. Mutations in CCBE1 on chromosome 18 have been reported in some cases of lymphatic dysplasia, but not in LCS. Methods:Consanguineous parents of Mexican ancestry had a child with LCS who did not exhibit extended homozygosity in the LCS1 region. A subsequent pregnancy was electively terminated due to fetal hydrops. We performed whole-genome single nucleotide polymorphism genotyping to identify regions of homozygosity in these siblings, and sequenced promising candidate genes. Results:Both siblings harbored a homozygous mutation in CCBE1, c.398 T>C, predicted to result in the missense change p.L133P. Regions containing known ‘cholestasis genes’ did not demonstrate homozygosity in the LCS patient. Conclusions:Mutations in CCBE1 may yield a phenotype not only of lymphatic dysplasia, but also of LCS or fetal hydrops; however, the possibility that the sibling with LCS also carries a homozygous mutation in an unidentified gene influencing cholestasis cannot be excluded. [ABSTRACT FROM AUTHOR]

Published
2013
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37. Working towards precision medicine: predicting phenotypes from exomes in the Critical Assessment of Genome Interpretation (CAGI) challenges

Author

Predrag Radivojac, Yanran Wang, Kunal Kundu, Maggie Haitian Wang, Laksshman Sundaram, Pier Luigi Martelli, Sohela Shah, Steven E. Brenner, Emanuela Leonardi, Yuxiang Jiang, Roxana Daneshjou, Mehdi Pirooznia, Marco Carraro, Rita Casadio, Biao Li, Giulia Babbi, Peter P. Zandi, John Moult, Silvio C. E. Tosatto, Andre Franke, Yanay Ofran, James B. Potash, David T. Jones, Mauno Vihinen, Billy Chang, Sean D. Mooney, Pietro Di Lena, Roger A. Hoskins, Russ B. Altman, David K. Gifford, Rajendra Rana Bhat, Kymberleigh A. Pagel, Carlo Ferrari, Yana Bromberg, Susanna Repo, Britt-Sabina Petersen, Xiaolin Li, Yizhou Yin, Alexander A. Morgan, Teri E. Klein, Lipika R. Pal, Ron Unger, Samuele Bovo, Abhishek Niroula, Richard W. McCombie, Vikas Pejaver, Eran Bachar, Matthew D. Edwards, Alessandra Gasparini, Johnathan Roy Azaria, Manuel Giollo, Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Daneshjou, Roxana, Wang, Yanran, Bromberg, Yana, Bovo, Samuele, Martelli, Pier L, Babbi, Giulia, Pietro Di, Lena, Casadio, Rita, Edwards, Matthew, Gifford, David, Jones, David T, Sundaram, Laksshman, Bhat, Rajendra Rana, Xiaolin, Li, Pal, Lipika R., Kundu, Kunal, Yin, Yizhou, Moult, John, Jiang, Yuxiang, Pejaver, Vika, Pagel, Kymberleigh A., Biao, Li, Mooney, Sean D., Radivojac, Predrag, Shah, Sohela, Carraro, Marco, Gasparini, Alessandra, Leonardi, Emanuela, Giollo, Manuel, Ferrari, Carlo, Tosatto, Silvio C E, Bachar, Eran, Azaria, Johnathan R., Ofran, Yanay, Unger, Ron, Niroula, Abhishek, Vihinen, Mauno, Chang, Billy, Wang, Maggie H, Franke, Andre, Petersen, Britt-Sabina, Pirooznia, Mehdi, Zandi, Peter, Mccombie, Richard, Potash, James B., Altman, Russ B., Klein, Teri E., Hoskins, Roger A., Repo, Susanna, Brenner, Steven E., and Morgan, Alexander A.

Subjects
0301 basic medicine, Bipolar Disorder, Pharmacogenomic Variants, Information Dissemination, Disease, Biology, Bioinformatics, Genome, Whole Exome Sequencing, Article, 03 medical and health sciences, 0302 clinical medicine, Genetic, Crohn Disease, bipolar disorder, Crohn's disease, exomes, machine learning, phenotype prediction, warfarin, Genetics, Genetics (clinical), Databases, Genetic, Exome Sequencing, Humans, Genetic Predisposition to Disease, Precision Medicine, Exome, Exome sequencing, Interpretation (philosophy), Computational Biology, Precision medicine, Data science, Phenotype, 030104 developmental biology, Pharmacogenomic Variant, Warfarin, exome, 030217 neurology & neurosurgery, Human
Abstract

Precision medicine aims to predict a patient's disease risk and best therapeutic options by using that individual's genetic sequencing data. The Critical Assessment of Genome Interpretation (CAGI) is a community experiment consisting of genotype–phenotype prediction challenges; participants build models, undergo assessment, and share key findings. For CAGI 4, three challenges involved using exome-sequencing data: Crohn's disease, bipolar disorder, and warfarin dosing. Previous CAGI challenges included prior versions of the Crohn's disease challenge. Here, we discuss the range of techniques used for phenotype prediction as well as the methods used for assessing predictive models. Additionally, we outline some of the difficulties associated with making predictions and evaluating them. The lessons learned from the exome challenges can be applied to both research and clinical efforts to improve phenotype prediction from genotype. In addition, these challenges serve as a vehicle for sharing clinical and research exome data in a secure manner with scientists who have a broad range of expertise, contributing to a collaborative effort to advance our understanding of genotype–phenotype relationships.

Published
2017

39. Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk.

Author

Gaudet MM, Kuchenbaecker KB, Vijai J, Klein RJ, Kirchhoff T, McGuffog L, Barrowdale D, Dunning AM, Lee A, Dennis J, Healey S, Dicks E, Soucy P, Sinilnikova OM, Pankratz VS, Wang X, Eldridge RC, Tessier DC, Vincent D, Bacot F, Hogervorst FB, Peock S, Stoppa-Lyonnet D, Peterlongo P, Schmutzler RK, Nathanson KL, Piedmonte M, Singer CF, Thomassen M, Hansen Tv, Neuhausen SL, Blanco I, Greene MH, Garber J, Weitzel JN, Andrulis IL, Goldgar DE, D'Andrea E, Caldes T, Nevanlinna H, Osorio A, van Rensburg EJ, Arason A, Rennert G, van den Ouweland AM, van der Hout AH, Kets CM, Aalfs CM, Wijnen JT, Ausems MG, Frost D, Ellis S, Fineberg E, Platte R, Evans DG, Jacobs C, Adlard J, Tischkowitz M, Porteous ME, Damiola F, Golmard L, Barjhoux L, Longy M, Belotti M, Ferrer SF, Mazoyer S, Spurdle AB, Manoukian S, Barile M, Genuardi M, Arnold N, Meindl A, Sutter C, Wappenschmidt B, Domchek SM, Pfeiler G, Friedman E, Jensen UB, Robson M, Shah S, Lazaro C, Mai PL, Benitez J, Southey MC, Schmidt MK, Fasching PA, Peto J, Humphreys MK, Wang Q, Michailidou K, Sawyer EJ, Burwinkel B, Guénel P, Bojesen SE, Milne RL, Brenner H, Lochmann M, Aittomäki K, Dörk T, Margolin S, Mannermaa A, Lambrechts D, Chang-Claude J, Radice P, Giles GG, Haiman CA, Winqvist R, Devillee P, García-Closas M, Schoof N, Hooning MJ, Cox A, Pharoah PD, Jakubowska A, Orr N, González-Neira A, Pita G, Alonso MR, Hall P, Couch FJ, Simard J, Altshuler D, Easton DF, Chenevix-Trench G, Antoniou AC, and Offit K

Subjects
Adult, Aged, Alleles, BRCA1 Protein genetics, Breast Neoplasms pathology, Female, Genetic Predisposition to Disease, Genotype, Heterozygote, Humans, Middle Aged, Mutation, Polymorphism, Single Nucleotide, Risk Factors, BRCA2 Protein genetics, Breast Neoplasms genetics, Chromosomes, Human, Pair 6 genetics, Genome-Wide Association Study
Abstract

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9 × 10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer., Competing Interests: The authors have declared that no competing interests exist.

Published
2013
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