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1. Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance

Author

Durno, Carol, Ercan, Ayse Bahar, Bianchi, Vanessa, Edwards, Melissa, Aronson, Melyssa, Galati, Melissa, Atenafu, Eshetu G, Abebe-Campino, Gadi, Al-Battashi, Abeer, Alharbi, Musa, Azad, Vahid Fallah, Baris, Hagit N, Basel, Donald, Bedgood, Raymond, Bendel, Anne, Ben-Shachar, Shay, Blumenthal, Deborah T, Blundell, Maude, Bornhorst, Miriam, Bronsema, Annika, Cairney, Elizabeth, Rhode, Sara, Caspi, Shani, Chamdin, Aghiad, Chiaravalli, Stefano, Constantini, Shlomi, Crooks, Bruce, Das, Anirban, Dvir, Rina, Farah, Roula, Foulkes, William D, Frenkel, Zehavit, Gallinger, Bailey, Gardner, Sharon, Gass, David, Ghalibafian, Mithra, Gilpin, Catherine, Goldberg, Yael, Goudie, Catherine, Hamid, Syed Ahmer, Hampel, Heather, Hansford, Jordan R, Harlos, Craig, Hijiya, Nobuko, Hsu, Saunders, Kamihara, Junne, Kebudi, Rejin, Knipstein, Jeffrey, Koschmann, Carl, Kratz, Christian, Larouche, Valerie, Lassaletta, Alvaro, Lindhorst, Scott, Ling, Simon C, Link, Michael P, De Mola, Rebecca Loret, Luiten, Rebecca, Lurye, Michal, Maciaszek, Jamie L, MagimairajanIssai, Vanan, Maher, Ossama M, Massimino, Maura, McGee, Rose B, Mushtaq, Naureen, Mason, Gary, Newmark, Monica, Nicholas, Garth, Nichols, Kim E, Nicolaides, Theodore, Opocher, Enrico, Osborn, Michael, Oshrine, Benjamin, Pearlman, Rachel, Pettee, Daniel, Rapp, Jan, Rashid, Mohsin, Reddy, Alyssa, Reichman, Lara, Remke, Marc, Robbins, Gabriel, Roy, Sumita, Sabel, Magnus, Samuel, David, Scheers, Isabelle, Schneider, Kami Wolfe, Sen, Santanu, Stearns, Duncan, Sumerauer, David, Swallow, Carol, Taylor, Leslie, Thomas, Gregory, Toledano, Helen, Tomboc, Patrick, Van Damme, An, Winer, Ira, Yalon, Michal, Yen, Lee Yi, Zapotocky, Michal, Zelcer, Shayna, and Ziegler, David S

Subjects
Cancer, Brain Disorders, Clinical Research, Digestive Diseases, Prevention, Brain Cancer, Rare Diseases, Adolescent, Adult, Brain Neoplasms, Child, Child, Preschool, Colorectal Neoplasms, DNA Mismatch Repair, DNA Repair Enzymes, Early Detection of Cancer, Female, Follow-Up Studies, Humans, Male, Neoplastic Syndromes, Hereditary, Population Surveillance, Prognosis, Prospective Studies, Survival Rate, United States, Young Adult, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

PurposeConstitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals.Patients and methodsData were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation.ResultsA total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically (P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively (P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance (P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years.ConclusionSurveillance and early cancer detection are associated with improved OS for individuals with CMMRD.

Published
2021

3. Diagnostic utility of array‐based comparative genomic hybridization in a clinical setting

Author

Baris, Hagit N, Tan, Wen‐Hann, Kimonis, Virginia E, and Irons, Mira B

Subjects
Pediatric, Health Services, Human Genome, Biotechnology, Genetics, Clinical Research, 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, Case-Control Studies, Child, Child, Preschool, Chromosome Aberrations, Developmental Disabilities, Female, Genome, Human, Humans, Infant, Infant, Newborn, Intellectual Disability, Male, Nucleic Acid Hybridization, Oligonucleotide Array Sequence Analysis, chromosome aberrations, chromosome disorders, gene dosage, gene duplication, gene deletion, microarray comparative genomic hybridization, copy number variations, Clinical Sciences
Abstract

Array-based comparative genomic hybridization is a recently introduced technique for the detection of submicroscopic genomic imbalances (deletions or duplications) across the entire genome. To assess the potential utility of a widely available array-based comparative genomic hybridization platform that targets specific, clinically relevant, loci across the genome for cytogenetic diagnosis in a clinical setting, we reviewed the medical records of all 373 patients at Children's Hospital Boston who had normal chromosomal analysis and were tested with this targeted array-based comparative genomic hybridization over a 1-year period from November 1, 2004 to October 31, 2005. These patients were tested because of a suspicion of chromosomal abnormalities based on their clinical presentation. Thirty-six patients (9.7%) had abnormal array-based comparative genomic hybridization results. Twenty patients (5.4%) had potentially pathogenetic genomic imbalances and 16 patients (4.3%) had copy number variations that are not believed to be pathogenetic. Thirteen of 234 patients (5.6%) with mental retardation/global developmental delay, 10/114 patients (8.8%) with facial dysmorphism, 5/58 patients (8.6%) with multiple congenital anomalies, and 4/35 patients (11.4%) with both facial dysmorphism and multiple congenital anomalies had potentially pathogenetic genomic imbalances. Targeted array-based comparative genomic hybridization is a clinically available test that is useful in the evaluation of patients suspected of having chromosomal disorders. However, it is best used as an adjunct to chromosomal analysis when a clear genetic diagnosis is unavailable.

Published
2007

7. Prenatal microarray analysis in right aortic arch—a retrospective cohort study and review of the literature

Author

Maya, Idit, Singer, Amihood, Baris, Hagit N, Goldberg, Yael, Shalata, Adel, Khayat, Morad, Ben-Shachar, Shay, and Sagi-Dain, Lena

Abstract

To examine the risk for clinically significant chromosomal microarray analysis (CMA) findings in fetal right aortic arch (RAA). Data from all CMA analyses performed owing to isolated RAA reported to the Israeli Ministry of Health between January 2013 and September 2016 were evaluated retrospectively. Risk for abnormal CMA findings was compared with two control populations, based on both previously described 9272 pregnancies with normal ultrasound, and on a local cohort of 5541 pregnancies undergoing CMA testing owing to maternal request. In addition, Pubmed database search was conducted for original researches examining this issue. Of 94 CMA analyses performed owing to isolated RAA, six (6.4%) pathogenic findings were detected (47,XX?+?21; 45,X; two 22q11.2 microdeletions; 10p15.3 microdeletion and 16p11.2 duplication). Compared with control groups, an isolated RAA yielded a significantly increased relative risk for abnormal CMA results. Literature search yielded two additional retrospective studies describing microarray testing in RAA and encompassing 57 cases. The overall risk for clinically significant CMA findings was 6.62% (10/151). CMA testing is indicated in cases of prenatal isolated RAA, even in the era of advanced sonographic equipment, routine biochemical screening for Down syndrome and available non-invasive prenatal testing.

Published
2024
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9. Pathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder

Author

Friederich, Marisa W., Timal, Sharita, Powell, Christopher A., Dallabona, Cristina, Kurolap, Alina, Palacios-Zambrano, Sara, Bratkovic, Drago, Derks, Terry G. J., Bick, David, Bouman, Katelijne, Chatfield, Kathryn C., Damouny-Naoum, Nadine, Dishop, Megan K., Falik-Zaccai, Tzipora C., Fares, Fuad, Fedida, Ayalla, Ferrero, Ileana, Gallagher, Renata C., Garesse, Rafael, Gilberti, Micol, González, Cristina, Gowan, Katherine, Habib, Clair, Halligan, Rebecca K., Kalfon, Limor, Knight, Kaz, Lefeber, Dirk, Mamblona, Laura, Mandel, Hanna, Mory, Adi, Ottoson, John, Paperna, Tamar, Pruijn, Ger J. M., Rebelo-Guiomar, Pedro F., Saada, Ann, Sainz, Jr., Bruno, Salvemini, Hayley, Schoots, Mirthe H., Smeitink, Jan A., Szukszto, Maciej J., ter Horst, Hendrik J., van den Brandt, Frans, van Spronsen, Francjan J., Veltman, Joris A., Wartchow, Eric, Wintjes, Liesbeth T., Zohar, Yaniv, Fernández-Moreno, Miguel A., Baris, Hagit N., Donnini, Claudia, Minczuk, Michal, Rodenburg, Richard J., and Van Hove, Johan L. K.

Published
2018
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12. PI(3,4)P2-mediated cytokinetic abscission prevents early senescence and cataract formation

Author

Gulluni, Federico, primary, Prever, Lorenzo, additional, Li, Huayi, additional, Krafcikova, Petra, additional, Corrado, Ilaria, additional, Lo, Wen-Ting, additional, Margaria, Jean Piero, additional, Chen, Anlu, additional, De Santis, Maria Chiara, additional, Cnudde, Sophie J., additional, Fogerty, Joseph, additional, Yuan, Alex, additional, Massarotti, Alberto, additional, Sarijalo, Nasrin Torabi, additional, Vadas, Oscar, additional, Williams, Roger L., additional, Thelen, Marcus, additional, Powell, David R., additional, Schueler, Markus, additional, Wiesener, Michael S., additional, Balla, Tamas, additional, Baris, Hagit N., additional, Tiosano, Dov, additional, McDermott, Brian M., additional, Perkins, Brian D., additional, Ghigo, Alessandra, additional, Martini, Miriam, additional, Haucke, Volker, additional, Boura, Evzen, additional, Merlo, Giorgio Roberto, additional, Buchner, David A., additional, and Hirsch, Emilio, additional

Published
2021
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14. Non-syndromic retinitis pigmentosa due to mutations in the mucopolysaccharidosis type IIIC gene, heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT)

Author

Haer-Wigman, Lonneke, Newman, Hadas, Leibu, Rina, Bax, Nathalie M., Baris, Hagit N, Rizel, Leah, Banin, Eyal, Massarweh, Amir, Roosing, Susanne, Lefeber, Dirk J., Zonneveld-Vrieling, Marijke N., Isakov, Ofer, Shomron, Noam, Sharon, Dror, Den Hollander, Anneke I., Hoyng, Carel B., Cremers, Frans P.M., and Ben-Yosef, Tamar

Published
2015
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16. Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance

Author

UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, Durno, Carol, Ercan, Ayse Bahar, Bianchi, Vanessa, Edwards, Melissa, Aronson, Melyssa, Galati, Melissa, Atenafu, Eshetu G., Abebe-Campino, Gadi, Al-Battashi, Abeer, Alharbi, Musa, Azad, Vahid Fallah, Baris, Hagit N., Basel, Donald, Bedgood, Raymond, Bendel, Anne, Ben-Shachar, Shay, Blumenthal, Deborah T., Blundell, Maude, Bornhorst, Miriam, Bronsema, Annika, Cairney, Elizabeth, Rhode, Sara, Caspi, Shani, Chamdin, Aghiad, Chiaravalli, Stefano, Constantini, Shlomi, Crooks, Bruce, Das, Anirban, Dvir, Rina, Farah, Roula, Foulkes, William D., Frenkel, Zehavit, Gallinger, Bailey, Gardner, Sharon, Gass, David, Ghalibafian, Mithra, Gilpin, Catherine, Goldberg, Yael, Goudie, Catherine, Hamid, Syed Ahmer, Hampel, Heather, Hansford, Jordan R., Harlos, Craig, Hijiya, Nobuko, Hsu, Saunders, Kamihara, Junne, Kebudi, Rejin, Knipstein, Jeffrey, Koschmann, Carl, Kratz, Christian, Larouche, Valerie, Lassaletta, Alvaro, Lindhorst, Scott, Ling, Simon C., Link, Michael P., Loret De Mola, Rebecca, Luiten, Rebecca, Lurye, Michal, Maciaszek, Jamie L., MagimairajanIssai, Vanan, Maher, Ossama M., Massimino, Maura, McGee, Rose B., Mushtaq, Naureen, Mason, Gary, Newmark, Monica, Nicholas, Garth, Nichols, Kim E., Nicolaides, Theodore, Opocher, Enrico, Osborn, Michael, Oshrine, Benjamin, Pearlman, Rachel, Pettee, Daniel, Rapp, Jan, Rashid, Mohsin, Reddy, Alyssa, Reichman, Lara, Remke, Marc, Robbins, Gabriel, Roy, Sumita, Sabel, Magnus, Samuel, David, Scheers, Isabelle, Schneider, Kami Wolfe, Sen, Santanu, Stearns, Duncan, Sumerauer, David, Swallow, Carol, Taylor, Leslie, Thomas, Gregory, Toledano, Helen, Tomboc, Patrick, Van Damme, An, Winer, Ira, Yalon, Michal, Yen, Lee Yi, Zapotocky, Michal, Zelcer, Shayna, Ziegler, David S., Zimmermann, Stefanie, Hawkins, Cynthia, Malkin, David, Bouffet, Eric, Villani, Anita, Tabori, Uri, UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, Durno, Carol, Ercan, Ayse Bahar, Bianchi, Vanessa, Edwards, Melissa, Aronson, Melyssa, Galati, Melissa, Atenafu, Eshetu G., Abebe-Campino, Gadi, Al-Battashi, Abeer, Alharbi, Musa, Azad, Vahid Fallah, Baris, Hagit N., Basel, Donald, Bedgood, Raymond, Bendel, Anne, Ben-Shachar, Shay, Blumenthal, Deborah T., Blundell, Maude, Bornhorst, Miriam, Bronsema, Annika, Cairney, Elizabeth, Rhode, Sara, Caspi, Shani, Chamdin, Aghiad, Chiaravalli, Stefano, Constantini, Shlomi, Crooks, Bruce, Das, Anirban, Dvir, Rina, Farah, Roula, Foulkes, William D., Frenkel, Zehavit, Gallinger, Bailey, Gardner, Sharon, Gass, David, Ghalibafian, Mithra, Gilpin, Catherine, Goldberg, Yael, Goudie, Catherine, Hamid, Syed Ahmer, Hampel, Heather, Hansford, Jordan R., Harlos, Craig, Hijiya, Nobuko, Hsu, Saunders, Kamihara, Junne, Kebudi, Rejin, Knipstein, Jeffrey, Koschmann, Carl, Kratz, Christian, Larouche, Valerie, Lassaletta, Alvaro, Lindhorst, Scott, Ling, Simon C., Link, Michael P., Loret De Mola, Rebecca, Luiten, Rebecca, Lurye, Michal, Maciaszek, Jamie L., MagimairajanIssai, Vanan, Maher, Ossama M., Massimino, Maura, McGee, Rose B., Mushtaq, Naureen, Mason, Gary, Newmark, Monica, Nicholas, Garth, Nichols, Kim E., Nicolaides, Theodore, Opocher, Enrico, Osborn, Michael, Oshrine, Benjamin, Pearlman, Rachel, Pettee, Daniel, Rapp, Jan, Rashid, Mohsin, Reddy, Alyssa, Reichman, Lara, Remke, Marc, Robbins, Gabriel, Roy, Sumita, Sabel, Magnus, Samuel, David, Scheers, Isabelle, Schneider, Kami Wolfe, Sen, Santanu, Stearns, Duncan, Sumerauer, David, Swallow, Carol, Taylor, Leslie, Thomas, Gregory, Toledano, Helen, Tomboc, Patrick, Van Damme, An, Winer, Ira, Yalon, Michal, Yen, Lee Yi, Zapotocky, Michal, Zelcer, Shayna, Ziegler, David S., Zimmermann, Stefanie, Hawkins, Cynthia, Malkin, David, Bouffet, Eric, Villani, Anita, and Tabori, Uri

Abstract

Purpose: Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. Patients and methods: Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation. Results: A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically (P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively (P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance (P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. Conclusion: Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.

Published
2021

17. Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance

Author

UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique, Durno, Carol, Ercan, Ayse Bahar, Bianchi, Vanessa, Edwards, Melissa, Aronson, Melyssa, Galati, Melissa, Atenafu, Eshetu G., Abebe-Campino, Gadi, Al-Battashi, Abeer, Alharbi, Musa, Azad, Vahid Fallah, Baris, Hagit N., Basel, Donald, Bedgood, Raymond, Bendel, Anne, Ben-Shachar, Shay, Blumenthal, Deborah T., Blundell, Maude, Bornhorst, Miriam, Bronsema, Annika, Cairney, Elizabeth, Rhode, Sara, Caspi, Shani, Chamdin, Aghiad, Chiaravalli, Stefano, Constantini, Shlomi, Crooks, Bruce, Das, Anirban, Dvir, Rina, Farah, Roula, Foulkes, William D., Frenkel, Zehavit, Gallinger, Bailey, Gardner, Sharon, Gass, David, Ghalibafian, Mithra, Gilpin, Catherine, Goldberg, Yael, Goudie, Catherine, Hamid, Syed Ahmer, Hampel, Heather, Hansford, Jordan R., Harlos, Craig, Hijiya, Nobuko, Hsu, Saunders, Kamihara, Junne, Kebudi, Rejin, Knipstein, Jeffrey, Koschmann, Carl, Kratz, Christian, Larouche, Valerie, Lassaletta, Alvaro, Lindhorst, Scott, Ling, Simon C., Link, Michael P., Loret De Mola, Rebecca, Luiten, Rebecca, Lurye, Michal, Maciaszek, Jamie L., MagimairajanIssai, Vanan, Maher, Ossama M., Massimino, Maura, McGee, Rose B., Mushtaq, Naureen, Mason, Gary, Newmark, Monica, Nicholas, Garth, Nichols, Kim E., Nicolaides, Theodore, Opocher, Enrico, Osborn, Michael, Oshrine, Benjamin, Pearlman, Rachel, Pettee, Daniel, Rapp, Jan, Rashid, Mohsin, Reddy, Alyssa, Reichman, Lara, Remke, Marc, Robbins, Gabriel, Roy, Sumita, Sabel, Magnus, Samuel, David, Scheers, Isabelle, Schneider, Kami Wolfe, Sen, Santanu, Stearns, Duncan, Sumerauer, David, Swallow, Carol, Taylor, Leslie, Thomas, Gregory, Toledano, Helen, Tomboc, Patrick, Van Damme, An, Winer, Ira, Yalon, Michal, Yen, Lee Yi, Zapotocky, Michal, Zelcer, Shayna, Ziegler, David S., Zimmermann, Stefanie, Hawkins, Cynthia, Malkin, David, Bouffet, Eric, Villani, Anita, Tabori, Uri, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique, Durno, Carol, Ercan, Ayse Bahar, Bianchi, Vanessa, Edwards, Melissa, Aronson, Melyssa, Galati, Melissa, Atenafu, Eshetu G., Abebe-Campino, Gadi, Al-Battashi, Abeer, Alharbi, Musa, Azad, Vahid Fallah, Baris, Hagit N., Basel, Donald, Bedgood, Raymond, Bendel, Anne, Ben-Shachar, Shay, Blumenthal, Deborah T., Blundell, Maude, Bornhorst, Miriam, Bronsema, Annika, Cairney, Elizabeth, Rhode, Sara, Caspi, Shani, Chamdin, Aghiad, Chiaravalli, Stefano, Constantini, Shlomi, Crooks, Bruce, Das, Anirban, Dvir, Rina, Farah, Roula, Foulkes, William D., Frenkel, Zehavit, Gallinger, Bailey, Gardner, Sharon, Gass, David, Ghalibafian, Mithra, Gilpin, Catherine, Goldberg, Yael, Goudie, Catherine, Hamid, Syed Ahmer, Hampel, Heather, Hansford, Jordan R., Harlos, Craig, Hijiya, Nobuko, Hsu, Saunders, Kamihara, Junne, Kebudi, Rejin, Knipstein, Jeffrey, Koschmann, Carl, Kratz, Christian, Larouche, Valerie, Lassaletta, Alvaro, Lindhorst, Scott, Ling, Simon C., Link, Michael P., Loret De Mola, Rebecca, Luiten, Rebecca, Lurye, Michal, Maciaszek, Jamie L., MagimairajanIssai, Vanan, Maher, Ossama M., Massimino, Maura, McGee, Rose B., Mushtaq, Naureen, Mason, Gary, Newmark, Monica, Nicholas, Garth, Nichols, Kim E., Nicolaides, Theodore, Opocher, Enrico, Osborn, Michael, Oshrine, Benjamin, Pearlman, Rachel, Pettee, Daniel, Rapp, Jan, Rashid, Mohsin, Reddy, Alyssa, Reichman, Lara, Remke, Marc, Robbins, Gabriel, Roy, Sumita, Sabel, Magnus, Samuel, David, Scheers, Isabelle, Schneider, Kami Wolfe, Sen, Santanu, Stearns, Duncan, Sumerauer, David, Swallow, Carol, Taylor, Leslie, Thomas, Gregory, Toledano, Helen, Tomboc, Patrick, Van Damme, An, Winer, Ira, Yalon, Michal, Yen, Lee Yi, Zapotocky, Michal, Zelcer, Shayna, Ziegler, David S., Zimmermann, Stefanie, Hawkins, Cynthia, Malkin, David, Bouffet, Eric, Villani, Anita, and Tabori, Uri

Abstract

Purpose: Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. Patients and methods: Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation. Results: A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically (P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively (P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance (P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. Conclusion: Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.

Published
2021

25. Mutations in PIK3C2A cause syndromic short stature, skeletal abnormalities, and cataracts associated with ciliary dysfunction

Author

Tiosano, Dov, Baris, Hagit N., Chen, Anlu, Hitzert, Marrit M., Schueler, Markus, Gulluni, Federico, Roepman, R., Pfundt, R.P., Aslanyan, M.G., Buchner, David A., Tiosano, Dov, Baris, Hagit N., Chen, Anlu, Hitzert, Marrit M., Schueler, Markus, Gulluni, Federico, Roepman, R., Pfundt, R.P., Aslanyan, M.G., and Buchner, David A.

Abstract

Contains fulltext : 204035.pdf (publisher's version ) (Open Access)

Published
2019

26. Safety, efficacy, and authorization of eliglustat as a first-line therapy in Gaucher disease type 1

Author

Mistry, Pramod K., Balwani, Manisha, Baris, Hagit N., Turkia, Hadhami Ben, Burrow, T. Andrew, Charrow, Joel, Cox, Gerald F., Danda, Sumita, Dragosky, Marta, Drelichman, Guillermo, El-Beshlawy, Amal, Fraga, Cristina, Freisens, Selena, Gaemers, Sebastiaan, Hadjiev, Evgueniy, Kishnani, Priya S., Lukina, Elena, Maison-Blanche, Pierre, Martins, Ana Maria, Pastores, Gregory, Petakov, Milan, Peterschmitt, M. Judith, Rosenbaum, Hanna, Rosenbloom, Barry, Underhill, Lisa H., and Cox, Timothy M.

Published
2018
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27. Addendum to Letter to the Editor: Safety, efficacy, and authorization of eliglustat as a first-line therapy in Gaucher disease type 1

Author

Mistry, Pramod K., primary, Balwani, Manisha, additional, Baris, Hagit N., additional, Turkia, Hadhami Ben, additional, Burrow, T. Andrew, additional, Charrow, Joel, additional, Cox, Gerald F., additional, Danda, Sumita, additional, Dragosky, Marta, additional, Drelichman, Guillermo, additional, El-Beshlawy, Amal, additional, Fraga, Cristina, additional, Freisens, Selena, additional, Gaemers, Sebastiaan, additional, Hadjiev, Evgueniy, additional, Kishnani, Priya S., additional, Lukina, Elena, additional, Maison-Blanche, Pierre, additional, Martins, Ana Maria, additional, Pastores, Gregory, additional, Petakov, Milan, additional, Peterschmitt, M. Judith, additional, Rosenbaum, Hanna, additional, Rosenbloom, Barry, additional, Underhill, Lisa H., additional, and Cox, Timothy M., additional

Published
2019
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28. Mutations in PIK3C2A cause syndromic short stature, skeletal abnormalities, and cataracts associated with ciliary dysfunction

Author

Tiosano, Dov, primary, Baris, Hagit N., additional, Chen, Anlu, additional, Hitzert, Marrit M., additional, Schueler, Markus, additional, Gulluni, Federico, additional, Wiesener, Antje, additional, Bergua, Antonio, additional, Mory, Adi, additional, Copeland, Brett, additional, Gleeson, Joseph G., additional, Rump, Patrick, additional, van Meer, Hester, additional, Sival, Deborah A., additional, Haucke, Volker, additional, Kriwinsky, Josh, additional, Knaup, Karl X., additional, Reis, André, additional, Hauer, Nadine N., additional, Hirsch, Emilio, additional, Roepman, Ronald, additional, Pfundt, Rolph, additional, Thiel, Christian T., additional, Wiesener, Michael S., additional, Aslanyan, Mariam G., additional, and Buchner, David A., additional

Published
2019
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29. Pathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder

Author

Medical Research Council (UK), University of Colorado, Fondazione Telethon, Instituto de Salud Carlos III, Federación Española de Enfermedades Raras, Fundação para a Ciência e a Tecnologia (Portugal), Friederich, Marisa W., Timal, Sharita, Powell, Christopher A., Dallabona, Cristina, Kurolap, Alina, Palacios-Zambrano, Sara, Bratkovic, Drago, Derks, Terry G. J., Bick, David, Bouman, Katelijne, Chatfield, Kathryn C., Damouny-Naoum, Nadine, Dishop, Megan K., Falik-Zaccai, Tzipora C., Fares, Fuad, Fedida, Ayalla, Ferrero, Ileana, Gallagher, Renata C., Garesse, Rafael, Gilberti, Micol, Gónzalez, Cristina, Gowan, Katherine, Habib, Clair, Halligan, Rebecca K., Kalfon, Limor, Knight, Kaz, Lefeber, Dirk, Mamblona, Laura, Mandel, Hanna, Mory, Adi, Ottoson, John, Paperma, Tamar, Prujin, Ger J. M., Rebelo-Guiomar, Pedro F., Saada, Ann, Sainz, Bruno Jr., Salvemini, Hayley, Schoots, Mirthe H., Smeitink, Jan A., Szukszto, Maciej J., Horst, Hendrik J. ter, Brandt, Frans van den, Spronsen, Francjan J. van, Veltman, Joris A., Wartchow, Eric, Wintjes, Liesbeth T., Zohar, Yaniv, Fernández-Moreno, Miguel Ángel, Baris, Hagit N., Donnini, Claudia, Minczuk, Michal, Rodenburg, Richard J., Van Hove, Johan L.K., Medical Research Council (UK), University of Colorado, Fondazione Telethon, Instituto de Salud Carlos III, Federación Española de Enfermedades Raras, Fundação para a Ciência e a Tecnologia (Portugal), Friederich, Marisa W., Timal, Sharita, Powell, Christopher A., Dallabona, Cristina, Kurolap, Alina, Palacios-Zambrano, Sara, Bratkovic, Drago, Derks, Terry G. J., Bick, David, Bouman, Katelijne, Chatfield, Kathryn C., Damouny-Naoum, Nadine, Dishop, Megan K., Falik-Zaccai, Tzipora C., Fares, Fuad, Fedida, Ayalla, Ferrero, Ileana, Gallagher, Renata C., Garesse, Rafael, Gilberti, Micol, Gónzalez, Cristina, Gowan, Katherine, Habib, Clair, Halligan, Rebecca K., Kalfon, Limor, Knight, Kaz, Lefeber, Dirk, Mamblona, Laura, Mandel, Hanna, Mory, Adi, Ottoson, John, Paperma, Tamar, Prujin, Ger J. M., Rebelo-Guiomar, Pedro F., Saada, Ann, Sainz, Bruno Jr., Salvemini, Hayley, Schoots, Mirthe H., Smeitink, Jan A., Szukszto, Maciej J., Horst, Hendrik J. ter, Brandt, Frans van den, Spronsen, Francjan J. van, Veltman, Joris A., Wartchow, Eric, Wintjes, Liesbeth T., Zohar, Yaniv, Fernández-Moreno, Miguel Ángel, Baris, Hagit N., Donnini, Claudia, Minczuk, Michal, Rodenburg, Richard J., and Van Hove, Johan L.K.

Abstract

Mitochondrial protein synthesis requires charging mt-tRNAs with their cognate amino acids by mitochondrial aminoacyl-tRNA synthetases, with the exception of glutaminyl mt-tRNA (mt-tRNAGln). mt-tRNAGln is indirectly charged by a transamidation reaction involving the GatCAB aminoacyl-tRNA amidotransferase complex. Defects involving the mitochondrial protein synthesis machinery cause a broad spectrum of disorders, with often fatal outcome. Here, we describe nine patients from five families with genetic defects in a GatCAB complex subunit, including QRSL1, GATB, and GATC, each showing a lethal metabolic cardiomyopathy syndrome. Functional studies reveal combined respiratory chain enzyme deficiencies and mitochondrial dysfunction. Aminoacylation of mt-tRNAGln and mitochondrial protein translation are deficient in patients' fibroblasts cultured in the absence of glutamine but restore in high glutamine. Lentiviral rescue experiments and modeling in S. cerevisiae homologs confirm pathogenicity. Our study completes a decade of investigations on mitochondrial aminoacylation disorders, starting with DARS2 and ending with the GatCAB complex.

Published
2018

30. Rambam Health Care Campus Research Day Organizing Committee

Author

Blazer, Shraga, Giladi, Hadar Zigdon, Avraham, Karen B., Skorecki, Karl, Beyar, Rafael, Paul, Mical, Koppel, Fidi, Bitterman, Roni, Neuberger, Ami, Ghanem-Zoubi, Nesrin, Stern, Anat, Dickstein, Yaakov, Zbu-Zayyad, Hiba, Mussini, Cristina, Leibovici, Leonard, Yahav, Dafna, Yehudai-Reshef, Shlomit, Sabah, Rawan, Fridman-Dror, Anna, Gabay, Tal, Turgeman, Shira, Zuckerman, Tsila, Cohen-Vaizer, Mauricio, Fridman, Eran, Dakhlallah, Shifaa, Federman, Moria, Khamaysi, Iyad, Ben Hemo, Dalit, Bhattacharya, Udayan, Kinaneh, Safa, Ilan, Neta, Vlodavsky, Israel, Abassi, Zaid, Shinnawi, Rami, Shaheen, Naim, Huber, Irit, Shiti, Assad, Arbel, Gil, Gepstein, Amira, Tijsen, Anke, Borggrefe, Marin, Gepstein, Lior, Solt, Ido, Caspi, Or, Beloosesky, Ron, Weiner, Zeev, Avdor, Eyal, Rechtman, Hilla Korach, Hreish, Maysaa, Fried, Carmit, Gerassy-Vainberg, Shiran, Azzam, Zaher S., Kashi, Yechezkel, Berger, Gidon, Duek, Ori Samuel, Ben Naftali, Yeela, Ullmann, Yehuda, Ullman, Yehuda, Kuperman, Pora, Bosak, Noam, Granovsky, Yelena, Granot, Michal, Bahouth, Hany, Fadel, Shiri, Ben-Lulu, Hen, Marco, Avihu, Buxbaum, Chen, Sprecher, Elliot, Yarnitsky, David, Gelber, Pazit Shachar, Halil, Adnan, Gorelik, Yuri, Hag, Eisa, Hananya, Tomer, Leiba, Ronit, Half, Elizabeth, Fares, Basem, Perets, Ruth, Kurolap, Alina, Naoum, Nadine Damouny, Palacios-Zambrano, Sara, Mory, Adi, Paperna, Tamar, Garesse, Rafael, Mandel, Hanna, Zohar, Yaniv, Fernández-Moreno, Miguel A., Feldman, Hagit Baris, Ofir, Ayala, Pollack, Shirley, Eisenstein, Israel, Tzur, Shay, Magen, Daniella, Beck-Razi, Nira, Gaitini, Diana, Besser, Ziva, Halevi, Dorit, Javitt, Marcia, Horowitz, Netanel, Giryes, Sami, Nasser, Roni, Sharon, Rivka, Azoulay, David, Doppelt, Ofri, Cohen, Gal, Book, Reut, Elimelech, Rina, Tamari, Tal, Zigdon, Hadar, Hochberg, Irit, Alon, Raviv, Yom-Tov, Elad, Lauterbach, Roy, Matanes, Emad, Ben David, Chen, Mor, Omer, Linder, Revital, Cohen-Halbertal, Adi, Zipori, Yaniv, Ginsberg, Yuval, Ilan, Lena, Kabha, Ahmad, Zussman, Eyal, Amiel, Gilad, Mabariki, Therese Shehadeh, Sabo, Edmond, Kremer, Ran, Haverfeld, Ori, Sarig, Galit, Blich, Miry, Oron, Hodaya, Darawsha, Wisam, Suleiman, Mahmoud, Boulos, Monther, Luko, Liel, Parush, Avi, Lowenstein, Lior, Haklai, Ziona, Mendelovic, Joseph, Lavie, Gil, Mustafa-Mikhail, Susana, Amit, Amnon, Weiss, Karin, Steinberg, Maya, Hershkovitz, Tova, Ekhilevitch, Nina, Baris, Hagit N., Dabajah, Hanin, Gruenwald, Ilan, Aharoni, Saar, Tal, Raanan, Appel, Boaz, Ghannam-Shahbari, Dima, Jacob, Eyal, Kakun, Reli Rachel, Wasserman, Tanya, Korsensky, Lina, Sternfeld, Ofir, Kagan, Juliana, Bublik, Debora Rosa, Aviel-Ronen, Sarit, Levanon, Keren, Larisch, Sarit, Oren, Moshe, Hershkovitz, Dov, Zur, Gil, Litvin, Maria, Berkovich, Eyal, Andreus, Maisa, Beck, Nira, Na’ara, Shorook, Amit, Moran, Billan, Salem, Shinnawi, Shadi, Gil, Ziv, Amir, Moran, Yehieli-Cohen, Ravit, Masarwa, Omar, Ginini, Lana, Milman, Neta, and Namora, Khalil

Subjects
Guest Lecturers, Oral Presentations, Selected Abstracts from Rambam Research Day, Supplement
Published
2019

32. No Overt Clinical Immunodeficiency Despite Immune Biological Abnormalities in Patients With Constitutional Mismatch Repair Deficiency

Author

Tesch, Victoria K., primary, IJspeert, Hanna, additional, Raicht, Andrea, additional, Rueda, Daniel, additional, Dominguez-Pinilla, Nerea, additional, Allende, Luis M., additional, Colas, Chrystelle, additional, Rosenbaum, Thorsten, additional, Ilencikova, Denisa, additional, Baris, Hagit N., additional, Nathrath, Michaela H. M., additional, Suerink, Manon, additional, Januszkiewicz-Lewandowska, Danuta, additional, Ragab, Iman, additional, Azizi, Amedeo A., additional, Wenzel, Soeren S., additional, Zschocke, Johannes, additional, Schwinger, Wolfgang, additional, Kloor, Matthias, additional, Blattmann, Claudia, additional, Brugieres, Laurence, additional, van der Burg, Mirjam, additional, Wimmer, Katharina, additional, and Seidel, Markus G., additional

Published
2018
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33. Establishing the role of PLVAP in protein-losing enteropathy: a homozygous missense variant leads to an attenuated phenotype

Author

Kurolap, Alina, primary, Eshach-Adiv, Orly, additional, Gonzaga-Jauregui, Claudia, additional, Dolnikov, Katya, additional, Mory, Adi, additional, Paperna, Tamar, additional, Hershkovitz, Tova, additional, Overton, John D, additional, Kaplan, Marielle, additional, Glaser, Fabian, additional, Zohar, Yaniv, additional, Shuldiner, Alan R, additional, Berger, Gidon, additional, and Baris, Hagit N, additional

Published
2018
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35. Mutations in the mitochondrial ribosomal protein MRPS22 lead to primary ovarian insufficiency

Author

Chen, Anlu, primary, Tiosano, Dov, additional, Guran, Tulay, additional, Baris, Hagit N, additional, Bayram, Yavuz, additional, Mory, Adi, additional, Shapiro-Kulnane, Laura, additional, Hodges, Craig A, additional, Akdemir, Zeynep C, additional, Turan, Serap, additional, Jhangiani, Shalini N, additional, van den Akker, Focco, additional, Hoppel, Charles L, additional, Salz, Helen K, additional, Lupski, James R, additional, and Buchner, David A, additional

Published
2018
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36. Loss of CD55 in Eculizumab-Responsive Protein-Losing Enteropathy

Author

Kurolap, Alina, primary, Eshach-Adiv, Orly, additional, Hershkovitz, Tova, additional, Paperna, Tamar, additional, Mory, Adi, additional, Oz-Levi, Danit, additional, Zohar, Yaniv, additional, Mandel, Hanna, additional, Chezar, Judith, additional, Azoulay, David, additional, Peleg, Sarit, additional, Half, Elizabeth E., additional, Yahalom, Vered, additional, Finkel, Lilach, additional, Weissbrod, Omer, additional, Geiger, Dan, additional, Tabib, Adi, additional, Shaoul, Ron, additional, Magen, Daniella, additional, Bonstein, Lilach, additional, Mevorach, Dror, additional, and Baris, Hagit N., additional

Published
2017
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37. Gaucher Disease: The Metabolic Defect, Pathophysiology, Phenotypes And Natural History

Author

Baris, Hagit N., Cohen, Ian J., and Mistry, Pramod K.

Subjects
Gaucher Disease, Glucosylceramidase, Humans, Article
Abstract

Gaucher disease (GD), a prototype lysosomal storage disorder, results from inherited deficiency of lysosomal glucocerebrosidase due to biallelic mutations in GBA. The result is widespread accumulation of macrophages engorged with predominantly lysosomal glucocerebroside. A complex multisystem phenotype arises involving the liver, spleen, bone marrow and occasionally the lungs in type 1 Gaucher disease; in neuronopathic fulminant type 2 and chronic type 3 disease there is in addition progressive neurodegenerative disease. Manifestations of Gaucher disease type 1 (GD1) include hepatosplenomegaly, cytopenia, a complex pattern of bone involvement with avascular osteonecrosis (AVN), osteoporosis, fractures and lytic lesions. Enzyme replacement therapy became the standard of care in 1991, and this has transformed the natural history of GD1. This article reviews the clinical phenotypes of GD, diagnosis, pathophysiology and its natural history. A subsequent chapter discusses the treatment options.

Published
2014

39. Loss of Glycine Transporter 1 Causes a Subtype of Glycine Encephalopathy with Arthrogryposis and Mildly Elevated Cerebrospinal Fluid Glycine

Author

Kurolap, Alina, primary, Armbruster, Anja, additional, Hershkovitz, Tova, additional, Hauf, Katharina, additional, Mory, Adi, additional, Paperna, Tamar, additional, Hannappel, Ewald, additional, Tal, Galit, additional, Nijem, Yusif, additional, Sella, Ella, additional, Mahajnah, Muhammad, additional, Ilivitzki, Anat, additional, Hershkovitz, Dov, additional, Ekhilevitch, Nina, additional, Mandel, Hanna, additional, Eulenburg, Volker, additional, and Baris, Hagit N., additional

Published
2016
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40. Is one diagnosis the whole story? patients with double diagnoses

Author

Kurolap, Alina, primary, Orenstein, Naama, additional, Kedar, Inbal, additional, Weisz Hubshman, Monika, additional, Tiosano, Dov, additional, Mory, Adi, additional, Levi, Zohar, additional, Marom, Daphna, additional, Cohen, Lior, additional, Ekhilevich, Nina, additional, Douglas, Jessica, additional, Nowak, Catherine Bearce, additional, Tan, Wen-Hann, additional, and Baris, Hagit N., additional

Published
2016
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41. VarElect: the phenotype-based variation prioritizer of the GeneCards Suite

Author

Stelzer, Gil, primary, Plaschkes, Inbar, additional, Oz-Levi, Danit, additional, Alkelai, Anna, additional, Olender, Tsviya, additional, Zimmerman, Shahar, additional, Twik, Michal, additional, Belinky, Frida, additional, Fishilevich, Simon, additional, Nudel, Ron, additional, Guan-Golan, Yaron, additional, Warshawsky, David, additional, Dahary, Dvir, additional, Kohn, Asher, additional, Mazor, Yaron, additional, Kaplan, Sergey, additional, Iny Stein, Tsippi, additional, Baris, Hagit N., additional, Rappaport, Noa, additional, Safran, Marilyn, additional, and Lancet, Doron, additional

Published
2016
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43. Gastrointestinal Findings in the Largest Series of Patients With Hereditary Biallelic Mismatch Repair Deficiency Syndrome: Report from the International Consortium

Author

Aronson, Melyssa, primary, Gallinger, Steven, additional, Cohen, Zane, additional, Cohen, Shlomi, additional, Dvir, Rina, additional, Elhasid, Ronit, additional, Baris, Hagit N, additional, Kariv, Revital, additional, Druker, Harriet, additional, Chan, Helen, additional, Ling, Simon C, additional, Kortan, Paul, additional, Holter, Spring, additional, Semotiuk, Kara, additional, Malkin, David, additional, Farah, Roula, additional, Sayad, Alain, additional, Heald, Brandie, additional, Kalady, Matthew F, additional, Penney, Lynette S, additional, Rideout, Andrea L, additional, Rashid, Mohsin, additional, Hasadsri, Linda, additional, Pichurin, Pavel, additional, Riegert-Johnson, Douglas, additional, Campbell, Brittany, additional, Bakry, Doua, additional, Al-Rimawi, Hala, additional, Alharbi, Qasim Kholaif, additional, Alharbi, Musa, additional, Shamvil, Ashraf, additional, Tabori, Uri, additional, and Durno, Carol, additional

Published
2016
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45. Constitutional mismatch repair deficiency and Lynch syndrome among consecutive Arab Bedouins with colorectal cancer in Israel.

Author

Abu Freha, Naim, Leibovici Weissman, Yaara, Fich, Alexander, Barnes Kedar, Inbal, Halpern, Marisa, Sztarkier, Ignacio, Behar, Doron M., Arbib Sneh, Orly, Vilkin, Alex, Baris, Hagit N., Gingold, Rachel, Lejbkowicz, Flavio, Niv, Yaron, Goldberg, Yael, and Levi, Zohar

Abstract

We assessed the molecular characteristics and the frequency of mutations in mismatch-repair genes among Bedouin patients with colorectal cancer (CRC) in Israel. Bedouin patients with a diagnosis of CRC at a major hospital in the southern part of Israel were deemed eligible for this study. The primary screening method was immunohistochemical staining for mismatch-repair proteins (MLH1, MSH2, MSH6, and PMS2). For subjects with abnormal immunohistochemical staining, we performed microsatellite instability (MSI) analyses, and for tumors with a loss of MLH1 expression we also performed BRAF testing. In MSI high cases we searched further for germline mutations. Of the 24 patients enrolled, four subjects (16.7%) had MSI high tumors: one subject was found to harbor a biallelic PMS2 mutation, one subject had Lynch syndrome (LS) with MSH6 mutation and two subjects had a loss of MLH1/PMS2 proteins/ BRAF /normal MLH1 sequence. Ten patients (41.7%) were younger than 50 at the time of diagnosis and none had first degree relatives with CRC. In conclusion, in this cohort of 24 consecutive Arab Bedouins with CRC, one patient was found to harbor a constitutional mismatch repair deficiency, one patient had LS with MSH6 mutation, and two patients had unresolved loss of MLH1/PMS2 proteins/ BRAF phenotype. [ABSTRACT FROM AUTHOR]

Published
2018
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46. Constitutional Mismatch Repair Deficiency in Israel: High Proportion of Founder Mutations in MMR Genes and Consanguinity

Author

Baris, Hagit N., primary, Barnes-Kedar, Inbal, additional, Toledano, Helen, additional, Halpern, Marisa, additional, Hershkovitz, Dov, additional, Lossos, Alexander, additional, Lerer, Israela, additional, Peretz, Tamar, additional, Kariv, Revital, additional, Cohen, Shlomi, additional, Half, Elizabeth E., additional, Magal, Nurit, additional, Drasinover, Valerie, additional, Wimmer, Katharina, additional, Goldberg, Yael, additional, Bercovich, Dani, additional, and Levi, Zohar, additional

Published
2015
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48. Establishing the role of PLVAPin protein-losing enteropathy: a homozygous missense variant leads to an attenuated phenotype

Author

Kurolap, Alina, Eshach-Adiv, Orly, Gonzaga-Jauregui, Claudia, Dolnikov, Katya, Mory, Adi, Paperna, Tamar, Hershkovitz, Tova, Overton, John D, Kaplan, Marielle, Glaser, Fabian, Zohar, Yaniv, Shuldiner, Alan R, Berger, Gidon, and Baris, Hagit N

Abstract

BackgroundIntestinal integrity is essential for proper nutrient absorption and tissue homeostasis, with damage leading to enteric protein loss, that is, protein-losing enteropathy (PLE). Recently, homozygous nonsense variants in the plasmalemma vesicle-associated protein gene (PLVAP) were reported in two patients with severe congenital PLE. PLVAP is the building block of endothelial cell (EC) fenestral diaphragms; its importance in barrier function is supported by mouse models of Plvap deficiency.ObjectiveTo genetically diagnose two first-degree cousins once removed, who presented with PLE at ages 22 and 2.5 years.MethodsFamily-based whole exome sequencing was performed based on an autosomal recessive inheritance model. In silicoanalyses were used to predict variant impact on protein structure and function.ResultsWe identified a rare homozygous variant (NM_031310.2:c.101T>C;p.Leu34Pro) in PLVAP, which co-segregated with the disease. Leu34 is predicted to be located in a highly conserved, hydrophobic, α-helical region within the protein’s transmembrane domain, suggesting Leu34Pro is likely to disrupt protein function and/or structure. Electron microscopy and PLVAP immunohistochemistry demonstrated apparently normal diaphragm morphology, predicted to be functionally affected.ConclusionsBiallelic missense variants in PLVAPcan cause an attenuated form of the PLE and hypertriglyceridaemia syndrome. Our findings support the role of PLVAP in the pathophysiology of PLE, expand the phenotypic and mutation spectrums and underscore PLVAP’s importance in EC barrier function in the gut.

Published
2018
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