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51. Hajdu‐Cheney syndrome with atypical cardiovascular abnormalities.

Author

Ekure, Ekanem N., Sokunbi, Ogochukwu, Kruszka, Paul, Muenke, Maximilian, and Adeyemo, Adebowale A.

Abstract

Hajdu‐Cheney syndrome is an ultra‐rare autosomal dominant disorder caused by a heterozygous variant in NOTCH2 gene. Characteristic features include osteolysis, distinct facial appearance, skull deformity, joint laxity, osteoporosis, and short stature. Associated abnormalities are congenital heart disease, congenital defects of the kidney, and neurological problems. Here, we present the first reported case of an African child with a variant in NOTCH2 gene and features of Hajdu‐Cheney syndrome in whom we detected a congenital heart defect that has not been previously reported in association with the syndrome. To appropriately characterize this disease and document correct proportion of cardiovascular malformation associations, echocardiography is recommended for all cases of Hajdu Cheney syndrome. [ABSTRACT FROM AUTHOR]

Published
2023
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52. Heart

Author

Kruszka, Paul Stephen, primary and Olivieri, Laura, additional

Published
2015
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53. Case Study Contributors

Author

Applegate, Carolyn Dinsmore, Biesecker, Leslie G., Buchanan, Janet A., Carcao, Manuel, Christodoulou, John, Cohn, Iris, Cohn, Ronald Doron, Fahrner, Jill A., Finch, Amy, George-Hyslop, Peter St, Gulati, Ashima, Guthrie, Kelsey, Hamilton, Robert, Hamosh, Ada, Hegele, Robert A., Hitzler, Johann, Hoover-Fong, Julie, Kim, Alexander Y., Kruszka, Paul, Lillicrap, David, Lupski, James R., Mahmud, Farid, Malkin, David, Mallipatna, Ashwin, Martin, Donna, Miller, Kristen, Mu, Weiyi, Narod, Steven, Odame, Isaac, Ours, Christopher A., Pearson, Christopher, Peng, Xiao P., Raraigh, Karen, Rehm, Heidi L., Reuter, Miriam, Roifman, Maian, Roifman, Chaim M., Schatz, Krista, Shoubridge, Eric, Singh, Mandeep, Skuse, David, Thompson, Marisa Gilstrop, Tifft, Cynthia J., Toomey, Christopher B., Vorstman, Jacob A.S., Watnick, Terry J., Weksberg, Rosanna, Wolstencroft, Jeanne, Xiao, Changrui, and Ziegler, Shira G.

Published
2024
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55. Quantitative Craniofacial Analysis and Generation of Human Induced Pluripotent Stem Cells for Muenke Syndrome: A Case Report

Author

Kidwai, Fahad K., primary, Mui, Byron W. H., additional, Almpani, Konstantinia, additional, Jani, Priyam, additional, Keyvanfar, Cyrus, additional, Iqbal, Kulsum, additional, Paravastu, Sriram S., additional, Arora, Deepika, additional, Orzechowski, Pamela, additional, Merling, Randall K., additional, Mallon, Barbara, additional, Myneni, Vamsee D., additional, Ahmad, Moaz, additional, Kruszka, Paul, additional, Muenke, Maximilian, additional, Woodcock, Jeremiah, additional, Gilman, Jeffrey W., additional, Robey, Pamela G., additional, and Lee, Janice S., additional

Published
2021
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58. Mutations in SPECC1L, encoding sperm antigen with calponin homology and coiled-coil domains 1-like, are found in some cases of autosomal dominant Opitz G/BBB syndrome

Author

Kruszka, Paul, Li, Dong, Harr, Margaret H, Wilson, Nathan R, Swarr, Daniel, McCormick, Elizabeth M, Chiavacci, Rosetta M, Li, Mindy, Martinez, Ariel F, Hart, Rachel A, McDonald-McGinn, Donna M, Deardorff, Matthew A, Falk, Marni J, Allanson, Judith E, Hudson, Cindy, Johnson, John P, Saadi, Irfan, Hakonarson, Hakon, Muenke, Maximilian, and Zackai, Elaine H

Published
2015
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59. Phenotypic continuum between POLE‐related recessive disorders: A case report and literature review.

Author

Roberts, Maegan E., Nimrichter, Sarah, Marshall, Megan L., Flynn, Elizabeth K., Person, Rick, Hruska, Kathleen S., Kruszka, Paul, and Juusola, Jane

Abstract

POLE is a pleiotropic gene with phenotypic expression of pathogenic variants depending on the type of variant, impact on the protein, and mode of inheritance. Heterozygous missense variants located within the exonuclease domain have been shown to result in polymerase proofreading‐associated polyposis (PPAP) which is characterized by an increased risk for colon polyps and colorectal cancer. Biallelic variants resulting in markedly reduced amounts of normal protein have been reported in two separate recessive pediatric syndromes: facial dysmorphism, immunodeficiency, livedo, and short stature as well as intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenital, and genital anomalies. Here we report two siblings identified to have POLE c.1686 + 32C > G in trans with POLE p.(Glu709*) via exome sequencing. A detailed review of the reported phenotypes in these two siblings and from available literature revealed that individuals with biallelic POLE pathogenic variants resulting in partial loss‐of‐function present with a similar phenotype: short stature and facial dysmorphism with or without immunodeficiency. These data suggest a phenotypic continuum between the previously reported POLE‐related recessive disorders. [ABSTRACT FROM AUTHOR]

Published
2022
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60. The human inactive X chromosome modulates expression of the active X chromosome

Author

San Roman, Adrianna K., primary, Godfrey, Alexander K., additional, Skaletsky, Helen, additional, Bellott, Daniel W., additional, Groff, Abigail F., additional, Harris, Hannah L., additional, Blanton, Laura V., additional, Hughes, Jennifer F., additional, Brown, Laura, additional, Phou, Sidaly, additional, Buscetta, Ashley, additional, Kruszka, Paul, additional, Banks, Nicole, additional, Dutra, Amalia, additional, Pak, Evgenia, additional, Lasutschinkow, Patricia C., additional, Keen, Colleen, additional, Davis, Shanlee M., additional, Tartaglia, Nicole R., additional, Samango-Sprouse, Carole, additional, Muenke, Maximilian, additional, and Page, David C., additional

Published
2021
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62. De Novo Variants in CNOT1, a Central Component of the CCR4-NOT Complex Involved in Gene Expression and RNA and Protein Stability, Cause Neurodevelopmental Delay.

Author

UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, Vissers, Lisenka E L M, Kalvakuri, Sreehari, de Boer, Elke, Geuer, Sinje, Oud, Machteld, van Outersterp, Inge, Kwint, Michael, Witmond, Melde, Kersten, Simone, Polla, Daniel L, Weijers, Dilys, Begtrup, Amber, McWalter, Kirsty, Ruiz, Anna, Gabau, Elisabeth, Morton, Jenny E V, Griffith, Christopher, Weiss, Karin, Gamble, Candace, Bartley, James, Vernon, Hilary J, Brunet, Kendra, Ruivenkamp, Claudia, Kant, Sarina G, Kruszka, Paul, Larson, Austin, Afenjar, Alexandra, Billette de Villemeur, Thierry, Nugent, Kimberly, DDD Study, Raymond, F Lucy, Venselaar, Hanka, Demurger, Florence, Soler-Alfonso, Claudia, Li, Dong, Bhoj, Elizabeth, Hayes, Ian, Hamilton, Nina Powell, Ahmad, Ayesha, Fisher, Rachel, van den Born, Myrthe, Willems, Marjolaine, Sorlin, Arthur, Delanne, Julian, Moutton, Sebastien, Christophe, Philippe, Mau-Them, Frederic Tran, Vitobello, Antonio, Goel, Himanshu, Massingham, Lauren, Phornphutkul, Chanika, Schwab, Jennifer, Keren, Boris, Charles, Perrine, Vreeburg, Maaike, De Simone, Lenika, Hoganson, George, Iascone, Maria, Milani, Donatella, Evenepoel, Lucie, Revencu, Nicole, Ward, D Isum, Burns, Kaitlyn, Krantz, Ian, Raible, Sarah E, Murrell, Jill R, Wood, Kathleen, Cho, Megan T, van Bokhoven, Hans, Muenke, Maximilian, Kleefstra, Tjitske, Bodmer, Rolf, de Brouwer, Arjan P M, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, Vissers, Lisenka E L M, Kalvakuri, Sreehari, de Boer, Elke, Geuer, Sinje, Oud, Machteld, van Outersterp, Inge, Kwint, Michael, Witmond, Melde, Kersten, Simone, Polla, Daniel L, Weijers, Dilys, Begtrup, Amber, McWalter, Kirsty, Ruiz, Anna, Gabau, Elisabeth, Morton, Jenny E V, Griffith, Christopher, Weiss, Karin, Gamble, Candace, Bartley, James, Vernon, Hilary J, Brunet, Kendra, Ruivenkamp, Claudia, Kant, Sarina G, Kruszka, Paul, Larson, Austin, Afenjar, Alexandra, Billette de Villemeur, Thierry, Nugent, Kimberly, DDD Study, Raymond, F Lucy, Venselaar, Hanka, Demurger, Florence, Soler-Alfonso, Claudia, Li, Dong, Bhoj, Elizabeth, Hayes, Ian, Hamilton, Nina Powell, Ahmad, Ayesha, Fisher, Rachel, van den Born, Myrthe, Willems, Marjolaine, Sorlin, Arthur, Delanne, Julian, Moutton, Sebastien, Christophe, Philippe, Mau-Them, Frederic Tran, Vitobello, Antonio, Goel, Himanshu, Massingham, Lauren, Phornphutkul, Chanika, Schwab, Jennifer, Keren, Boris, Charles, Perrine, Vreeburg, Maaike, De Simone, Lenika, Hoganson, George, Iascone, Maria, Milani, Donatella, Evenepoel, Lucie, Revencu, Nicole, Ward, D Isum, Burns, Kaitlyn, Krantz, Ian, Raible, Sarah E, Murrell, Jill R, Wood, Kathleen, Cho, Megan T, van Bokhoven, Hans, Muenke, Maximilian, Kleefstra, Tjitske, Bodmer, Rolf, and de Brouwer, Arjan P M

Abstract

CNOT1 is a member of the CCR4-NOT complex, which is a master regulator, orchestrating gene expression, RNA deadenylation, and protein ubiquitination. We report on 39 individuals with heterozygous de novo CNOT1 variants, including missense, splice site, and nonsense variants, who present with a clinical spectrum of intellectual disability, motor delay, speech delay, seizures, hypotonia, and behavioral problems. To link CNOT1 dysfunction to the neurodevelopmental phenotype observed, we generated variant-specific Drosophila models, which showed learning and memory defects upon CNOT1 knockdown. Introduction of human wild-type CNOT1 was able to rescue this phenotype, whereas mutants could not or only partially, supporting our hypothesis that CNOT1 impairment results in neurodevelopmental delay. Furthermore, the genetic interaction with autism-spectrum genes, such as ASH1L, DYRK1A, MED13, and SHANK3, was impaired in our Drosophila models. Molecular characterization of CNOT1 variants revealed normal CNOT1 expression levels, with both mutant and wild-type alleles expressed at similar levels. Analysis of protein-protein interactions with other members indicated that the CCR4-NOT complex remained intact. An integrated omics approach of patient-derived genomics and transcriptomics data suggested only minimal effects on endonucleolytic nonsense-mediated mRNA decay components, suggesting that de novo CNOT1 variants are likely haploinsufficient hypomorph or neomorph, rather than dominant negative. In summary, we provide strong evidence that de novo CNOT1 variants cause neurodevelopmental delay with a wide range of additional co-morbidities. Whereas the underlying pathophysiological mechanism warrants further analysis, our data demonstrate an essential and central role of the CCR4-NOT complex in human brain development.

Published
2020

63. Circle of Willis anomalies in Turner syndrome: Absent A1 segment of the anterior cerebral artery

Author

Massachusetts Institute of Technology. Department of Biology, Kruszka, Paul, Buscetta, Ashley, Acosta, Maria T., Banks, Nicole, Addissie, Yonit A., Toro, Camilo, Luby, Marie, Latour, Lawrence, Vezina, Gilbert, Page, David C, Muenke, Maximilian, Massachusetts Institute of Technology. Department of Biology, Kruszka, Paul, Buscetta, Ashley, Acosta, Maria T., Banks, Nicole, Addissie, Yonit A., Toro, Camilo, Luby, Marie, Latour, Lawrence, Vezina, Gilbert, Page, David C, and Muenke, Maximilian

Abstract

Purpose: Turner syndrome (TS) is the most common sex chromosome disorder in women and is associated with a higher than expected death rate secondary to cerebrovascular disease, including stroke. This study evaluates the cerebral vascular anatomy of individuals with TS. Methods: Twenty-one women with TS had brain magnetic resonance angiography (MRA). These MRAs were evaluated in a blinded manner with a control group of 25 men and 25 women who had MRA imaging for multiple indications including migraine headaches, psychiatric disorders, and seizures. Results: Twenty-nine percent of women with TS were missing an A1 segment of the anterior cerebral artery (ACA) compared to 0% in the control group (p <.001). There were no other significant differences in the circle of Willis (COW) in women with TS compared with the control group. A complete COW was found in 3 of 21 (14%) of women with TS and 12 of 47 (26%) controls (p =.36). Conclusion: Women with TS have a significantly different intracranial vascular anatomy, specifically the absence of the A1 segment of the ACA when compared to male and female controls. More research in brain imaging in women with TS and stroke and other cerebrovascular diseases is needed to determine the clinical significance of this anomaly., National Human Genome Research Institute (Grant 1U01HG007587-01A1)

Published
2020

65. Exome Sequencing and Congenital Heart Disease in Sub-Saharan Africa

Author

Ekure, Ekanem N., primary, Adeyemo, Adebowale, additional, Liu, Hanhan, additional, Sokunbi, Ogochukwu, additional, Kalu, Nnenna, additional, Martinez, Ariel F., additional, Owosela, Babajide, additional, Tekendo-Ngongang, Cedrik, additional, Addissie, Yonit A., additional, Olusegun-Joseph, Akinsanya, additional, Ikebudu, Desmond, additional, Berger, Seth I., additional, Muenke, Maximilian, additional, Han, Zhe, additional, and Kruszka, Paul, additional

Published
2021
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68. Rubinstein–Taybi syndrome in diverse populations

Author

Tekendo‐Ngongang, Cedrik, primary, Owosela, Babajide, additional, Fleischer, Nicole, additional, Addissie, Yonit A., additional, Malonga, Bryan, additional, Badoe, Ebenezer, additional, Gupta, Neerja, additional, Moresco, Angélica, additional, Huckstadt, Victoria, additional, Ashaat, Engy A., additional, Hussen, Dalia Farouk, additional, Luk, Ho‐Ming, additional, Lo, Ivan F. M., additional, Hon‐Yin Chung, Brian, additional, Fung, Jasmine L. F., additional, Moretti‐Ferreira, Danilo, additional, Batista, Letícia Cassimiro, additional, Lotz‐Esquivel, Stephanie, additional, Saborio‐Rocafort, Manuel, additional, Badilla‐Porras, Ramses, additional, Penon Portmann, Monica, additional, Jones, Kelly L., additional, Abdul‐Rahman, Omar A., additional, Uwineza, Annette, additional, Prijoles, Eloise J., additional, Ifeorah, Ifeanyi Kanayo, additional, Llamos Paneque, Arianne, additional, Sirisena, Nirmala D., additional, Dowsett, Leah, additional, Lee, Sansan, additional, Cappuccio, Gerarda, additional, Kitchin, Carolyn Sian, additional, Diaz‐Kuan, Alicia, additional, Thong, Meow‐Keong, additional, Obregon, María Gabriela, additional, Mutesa, Leon, additional, Dissanayake, Vajira H. W., additional, El Ruby, Mona O., additional, Brunetti‐Pierri, Nicola, additional, Ekure, Ekanem Nsikak, additional, Stevenson, Roger E., additional, Muenke, Maximilian, additional, and Kruszka, Paul, additional

Published
2020
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71. De Novo Variants in CNOT1, a Central Component of the CCR4-NOT Complex Involved in Gene Expression and RNA and Protein Stability, Cause Neurodevelopmental Delay

Author

Vissers, Lisenka E.L.M., primary, Kalvakuri, Sreehari, additional, de Boer, Elke, additional, Geuer, Sinje, additional, Oud, Machteld, additional, van Outersterp, Inge, additional, Kwint, Michael, additional, Witmond, Melde, additional, Kersten, Simone, additional, Polla, Daniel L., additional, Weijers, Dilys, additional, Begtrup, Amber, additional, McWalter, Kirsty, additional, Ruiz, Anna, additional, Gabau, Elisabeth, additional, Morton, Jenny E.V., additional, Griffith, Christopher, additional, Weiss, Karin, additional, Gamble, Candace, additional, Bartley, James, additional, Vernon, Hilary J., additional, Brunet, Kendra, additional, Ruivenkamp, Claudia, additional, Kant, Sarina G., additional, Kruszka, Paul, additional, Larson, Austin, additional, Afenjar, Alexandra, additional, Billette de Villemeur, Thierry, additional, Nugent, Kimberly, additional, Raymond, F. Lucy, additional, Venselaar, Hanka, additional, Demurger, Florence, additional, Soler-Alfonso, Claudia, additional, Li, Dong, additional, Bhoj, Elizabeth, additional, Hayes, Ian, additional, Hamilton, Nina Powell, additional, Ahmad, Ayesha, additional, Fisher, Rachel, additional, van den Born, Myrthe, additional, Willems, Marjolaine, additional, Sorlin, Arthur, additional, Delanne, Julian, additional, Moutton, Sebastien, additional, Christophe, Philippe, additional, Mau-Them, Frederic Tran, additional, Vitobello, Antonio, additional, Goel, Himanshu, additional, Massingham, Lauren, additional, Phornphutkul, Chanika, additional, Schwab, Jennifer, additional, Keren, Boris, additional, Charles, Perrine, additional, Vreeburg, Maaike, additional, De Simone, Lenika, additional, Hoganson, George, additional, Iascone, Maria, additional, Milani, Donatella, additional, Evenepoel, Lucie, additional, Revencu, Nicole, additional, Ward, D. Isum, additional, Burns, Kaitlyn, additional, Krantz, Ian, additional, Raible, Sarah E., additional, Murrell, Jill R., additional, Wood, Kathleen, additional, Cho, Megan T., additional, van Bokhoven, Hans, additional, Muenke, Maximilian, additional, Kleefstra, Tjitske, additional, Bodmer, Rolf, additional, and de Brouwer, Arjan P.M., additional

Published
2020
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74. Congenital heart disease in school children in Lagos, Nigeria: Prevalence and the diagnostic gap

Author

Ekure, Ekanem N., primary, Sokunbi, Ogochukwu, additional, Kalu, Nnenna, additional, Olusegun‐Joseph, Akinsanya, additional, Kushimo, Oyewole, additional, Amadi, Casmir, additional, Hassan, Olayinka, additional, Ikebudu, Desmond, additional, Onyia, Sophia, additional, Onwudiwe, Chinonso, additional, Nwankwo, Victor, additional, Akinwunmi, Remi, additional, Awusa, Fukpode, additional, Akere, Zainab, additional, Dele‐Salawu, Olaolu, additional, Ajayi, Elizabeth, additional, Ale, Olagoke, additional, Muoneke, Dorothy, additional, Muenke, Maximillian, additional, Kruszka, Paul, additional, Beaton, Andrea, additional, Sable, Craig, additional, and Adeyemo, Adebowale, additional

Published
2020
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77. PRDM15 loss of function links NOTCH and WNT/PCP signaling to patterning defects in holoprosencephaly

Author

Mzoughi, Slim, primary, Di Tullio, Federico, additional, Low, Diana H. P., additional, Motofeanu, Corina-Mihaela, additional, Ong, Sheena L. M., additional, Wollmann, Heike, additional, Wun, Cheng Mun, additional, Kruszka, Paul, additional, Muenke, Maximilian, additional, Hildebrandt, Friedhelm, additional, Dunn, N. Ray, additional, Messerschmidt, Daniel M., additional, and Guccione, Ernesto, additional

Published
2020
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78. Turner syndrome in diverse populations

Author

Kruszka, Paul, primary, Addissie, Yonit A., additional, Tekendo‐Ngongang, Cedrik, additional, Jones, Kelly L., additional, Savage, Sarah K., additional, Gupta, Neerja, additional, Sirisena, Nirmala D., additional, Dissanayake, Vajira H. W., additional, Paththinige, C. Sampath, additional, Aravena, Teresa, additional, Nampoothiri, Sheela, additional, Yesodharan, Dhanya, additional, Girisha, Katta M., additional, Patil, Siddaramappa Jagdish, additional, Jamuar, Saumya Shekhar, additional, Goh, Jasmine Chew‐Yin, additional, Utari, Agustini, additional, Sihombing, Nydia, additional, Mishra, Rupesh, additional, Chitrakar, Neer Shoba, additional, Iriele, Brenda C., additional, Lulseged, Ezana, additional, Megarbane, Andre, additional, Uwineza, Annette, additional, Oyenusi, Elizabeth Eberechi, additional, Olopade, Oluwarotimi Bolaji, additional, Fasanmade, Olufemi Adetola, additional, Duenas‐Roque, Milagros M., additional, Thong, Meow‐Keong, additional, Tung, Joanna Y. L., additional, Mok, Gary T. K., additional, Fleischer, Nicole, additional, Rwegerera, Godfrey M., additional, Herreros, María Beatriz, additional, Watts, Johnathan, additional, Fieggen, Karen, additional, Huckstadt, Victoria, additional, Moresco, Angélica, additional, Obregon, María Gabriela, additional, Hussen, Dalia Farouk, additional, Ashaat, Neveen A., additional, Ashaat, Engy A., additional, Chung, Brian H. Y., additional, Badoe, Eben, additional, Faradz, Sultana M. H., additional, El Ruby, Mona O., additional, Shotelersuk, Vorasuk, additional, Wonkam, Ambroise, additional, Ekure, Ekanem Nsikak, additional, Phadke, Shubha R., additional, Richieri‐Costa, Antonio, additional, and Muenke, Maximilian, additional

Published
2019
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80. Phenotype delineation of ZNF462 related syndrome

Author

Kruszka, Paul, Hu, Tommy, Hong, Sungkook, Signer, Rebecca, Cogne, Benjamin, Isidor, Betrand, Mazzola, Sarah E., Giltay, Jacques C., van Gassen, Koen L. I., England, Eleina M., Pais, Lynn, Ockeloen, Charlotte W., Sanchez-Lara, Pedro A., Kinning, Esther, Adams, Darius J., Treat, Kayla, Torres-Martinez, Wilfredo, Bedeschi, Maria F., Iascone, Maria, Blaney, Stephanie, Bell, Oliver, Tan, Tiong Y., Delrue, Marie-Ange, Jurgens, Julie, Barry, Brenda J., Engle, Elizabeth C., Savage, Sarah K., Fleischer, Nicole, Martinez-Agosto, Julian A., Boycott, Kym, Zackai, Elaine H., Muenke, Maximilian, Kruszka, Paul, Hu, Tommy, Hong, Sungkook, Signer, Rebecca, Cogne, Benjamin, Isidor, Betrand, Mazzola, Sarah E., Giltay, Jacques C., van Gassen, Koen L. I., England, Eleina M., Pais, Lynn, Ockeloen, Charlotte W., Sanchez-Lara, Pedro A., Kinning, Esther, Adams, Darius J., Treat, Kayla, Torres-Martinez, Wilfredo, Bedeschi, Maria F., Iascone, Maria, Blaney, Stephanie, Bell, Oliver, Tan, Tiong Y., Delrue, Marie-Ange, Jurgens, Julie, Barry, Brenda J., Engle, Elizabeth C., Savage, Sarah K., Fleischer, Nicole, Martinez-Agosto, Julian A., Boycott, Kym, Zackai, Elaine H., and Muenke, Maximilian

Published
2019

81. Phenotype delineation of ZNF462 related syndrome

Author

Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Kruszka, Paul, Hu, Tommy, Hong, Sungkook, Signer, Rebecca, Cogne, Benjamin, Isidor, Betrand, Mazzola, Sarah E., Giltay, Jacques C., van Gassen, Koen L. I., England, Eleina M., Pais, Lynn, Ockeloen, Charlotte W., Sanchez-Lara, Pedro A., Kinning, Esther, Adams, Darius J., Treat, Kayla, Torres-Martinez, Wilfredo, Bedeschi, Maria F., Iascone, Maria, Blaney, Stephanie, Bell, Oliver, Tan, Tiong Y., Delrue, Marie-Ange, Jurgens, Julie, Barry, Brenda J., Engle, Elizabeth C., Savage, Sarah K., Fleischer, Nicole, Martinez-Agosto, Julian A., Boycott, Kym, Zackai, Elaine H., Muenke, Maximilian, Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Kruszka, Paul, Hu, Tommy, Hong, Sungkook, Signer, Rebecca, Cogne, Benjamin, Isidor, Betrand, Mazzola, Sarah E., Giltay, Jacques C., van Gassen, Koen L. I., England, Eleina M., Pais, Lynn, Ockeloen, Charlotte W., Sanchez-Lara, Pedro A., Kinning, Esther, Adams, Darius J., Treat, Kayla, Torres-Martinez, Wilfredo, Bedeschi, Maria F., Iascone, Maria, Blaney, Stephanie, Bell, Oliver, Tan, Tiong Y., Delrue, Marie-Ange, Jurgens, Julie, Barry, Brenda J., Engle, Elizabeth C., Savage, Sarah K., Fleischer, Nicole, Martinez-Agosto, Julian A., Boycott, Kym, Zackai, Elaine H., and Muenke, Maximilian

Published
2019

82. Cohesin complex-associated holoprosencephaly

Author

Karabey, Hülya Kayserili (ORCID 0000-0003-0376-499X & YÖK ID 7945), Kruszka, Paul; Berger, Seth I.; Casa, Valentina; Dekker, Mike R.; Gaesser, Jenna; Weiss, Karin; Martinez, Ariel F.; Murdock, David R.; Louie, Raymond J.; Prijoles, Eloise J.; Lichty, Angie W.; Brouwer, Oebele F.; Zonneveld-Huijssoon, Evelien; Stephan, Mark J.; Hogue, Jacob; Hu, Ping; Tanima-Nagai, Momoko; Everson, Joshua L.; Prasad, Chitra; Cereda, Anna; Iascone, Maria; Schreiber, Allison; Zurcher, Vickie; Corsten-Janssen, Nicole; Escobar, Luis; Clegg, Nancy J.; Delgado, Mauricio R.; Hajirnis, Omkar; Balasubramanian, Meena; Deardorff, Matthew; Poot, Raymond A.; Wendt, Kerstin S.; Lipinski, Robert J.; Muenke, Maximilian, School of Medicine, Department of Medical Genetics, Karabey, Hülya Kayserili (ORCID 0000-0003-0376-499X & YÖK ID 7945), Kruszka, Paul; Berger, Seth I.; Casa, Valentina; Dekker, Mike R.; Gaesser, Jenna; Weiss, Karin; Martinez, Ariel F.; Murdock, David R.; Louie, Raymond J.; Prijoles, Eloise J.; Lichty, Angie W.; Brouwer, Oebele F.; Zonneveld-Huijssoon, Evelien; Stephan, Mark J.; Hogue, Jacob; Hu, Ping; Tanima-Nagai, Momoko; Everson, Joshua L.; Prasad, Chitra; Cereda, Anna; Iascone, Maria; Schreiber, Allison; Zurcher, Vickie; Corsten-Janssen, Nicole; Escobar, Luis; Clegg, Nancy J.; Delgado, Mauricio R.; Hajirnis, Omkar; Balasubramanian, Meena; Deardorff, Matthew; Poot, Raymond A.; Wendt, Kerstin S.; Lipinski, Robert J.; Muenke, Maximilian, School of Medicine, and Department of Medical Genetics

Abstract

Marked by incomplete division of the embryonic forebrain, holoprosencephaly is one of the most common human developmental disorders. Despite decades of phenotype-driven research, 80-90% of aneuploidy-negative holoprosencephaly individuals with a probable genetic aetiology do not have a genetic diagnosis. Here we report holoprosencephaly associated with variants in the two X-linked cohesin complex genes, STAG2 and SMC1A, with loss-of-function variants in 10 individuals and a missense variant in one. Additionally, we report four individuals with variants in the cohesin complex genes that are not X-linked, SMC3 and RAD21. Using whole mount in situ hybridization, we show that STAG2 and SMC1A are expressed in the prosencephalic neural folds during primary neurulation in the mouse, consistent with forebrain morphogenesis and holoprosencephaly pathogenesis. Finally, we found that shRNA knockdown of STAG2 and SMC1A causes aberrant expression of HPE-associated genes ZIC2, GLI2, SMAD3 and FGFR1 in human neural stem cells. These findings show the cohesin complex as an important regulator of median forebrain development and X-linked inheritance patterns in holoprosencephaly., National Human Genome Research Institute Intramural Research Program; Dutch Cancer Society (KWF); Netherlands Organisation of Scientific Research (NWO); National Institute of Environmental Health Sciences of the National Institutes of Health

Published
2019

87. Phenotype delineation of ZNF462 related syndrome

Author

Kruszka, Paul, primary, Hu, Tommy, additional, Hong, Sungkook, additional, Signer, Rebecca, additional, Cogné, Benjamin, additional, Isidor, Betrand, additional, Mazzola, Sarah E., additional, Giltay, Jacques C., additional, Gassen, Koen L. I., additional, England, Eleina M., additional, Pais, Lynn, additional, Ockeloen, Charlotte W., additional, Sanchez‐Lara, Pedro A., additional, Kinning, Esther, additional, Adams, Darius J., additional, Treat, Kayla, additional, Torres‐Martinez, Wilfredo, additional, Bedeschi, Maria F., additional, Iascone, Maria, additional, Blaney, Stephanie, additional, Bell, Oliver, additional, Tan, Tiong Y., additional, Delrue, Marie‐Ange, additional, Jurgens, Julie, additional, Barry, Brenda J., additional, Engle, Elizabeth C., additional, Savage, Sarah K., additional, Fleischer, Nicole, additional, Martinez‐Agosto, Julian A., additional, Boycott, Kym, additional, Zackai, Elaine H., additional, and Muenke, Maximilian, additional

Published
2019
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88. Cohesin complex-associated holoprosencephaly

Author

Kruszka, Paul, primary, Berger, Seth I, primary, Casa, Valentina, primary, Dekker, Mike R, primary, Gaesser, Jenna, primary, Weiss, Karin, primary, Martinez, Ariel F, primary, Murdock, David R, primary, Louie, Raymond J, primary, Prijoles, Eloise J, primary, Lichty, Angie W, primary, Brouwer, Oebele F, primary, Zonneveld-Huijssoon, Evelien, primary, Stephan, Mark J, primary, Hogue, Jacob, primary, Hu, Ping, primary, Tanima-Nagai, Momoko, primary, Everson, Joshua L, primary, Prasad, Chitra, primary, Cereda, Anna, primary, Iascone, Maria, primary, Schreiber, Allison, primary, Zurcher, Vickie, primary, Corsten-Janssen, Nicole, primary, Escobar, Luis, primary, Clegg, Nancy J, primary, Delgado, Mauricio R, primary, Hajirnis, Omkar, primary, Balasubramanian, Meena, primary, Kayserili, Hülya, primary, Deardorff, Matthew, primary, Poot, Raymond A, primary, Wendt, Kerstin S, primary, Lipinski, Robert J, primary, and Muenke, Maximilian, primary

Published
2019
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92. Echocardiographic screening of 4107 Nigerian school children for rheumatic heart disease

Author

Ekure, Ekanem N., primary, Amadi, Casmir, additional, Sokunbi, Ogochukwu, additional, Kalu, Nnenna, additional, Olusegun‐Joseph, Akinsanya, additional, Kushimo, Oyewole, additional, Hassan, Olayinka, additional, Ikebudu, Desmond, additional, Onyia, Sophia, additional, Onwudiwe, Chinonso, additional, Nwankwo, Victor, additional, Akinwunmi, Remi, additional, Awusa, Fukpode, additional, Akere, Zainab, additional, Dele‐Salawu, Olaolu, additional, Ajayi, Elizabeth, additional, Ale, Olagoke, additional, Muoneke, Dorothy, additional, Muenke, Maximillian, additional, Kruszka, Paul, additional, Beaton, Andrea, additional, Sable, Craig, additional, and Adeyemo, Adebowale, additional

Published
2019
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94. Identifying environmental risk factors and gene–environment interactions in holoprosencephaly.

Author

Addissie, Yonit A., Troia, Angela, Wong, Zoe C., Everson, Joshua L., Kozel, Beth A., Muenke, Maximilian, Lipinski, Robert J., Malecki, Kristen M.C., and Kruszka, Paul

Abstract

Background: Holoprosencephaly is the most common malformation of the forebrain (1 in 250 embryos) with severe consequences for fetal and child development. This study evaluates nongenetic factors associated with holoprosencephaly risk, severity, and gene–environment interactions. Methods: For this retrospective case control study, we developed an online questionnaire focusing on exposures to common and rare toxins/toxicants before and during pregnancy, nutritional factors, maternal health history, and demographic factors. Patients with holoprosencephaly were primarily ascertained from our ongoing genetic and clinical studies of holoprosencephaly. Controls included children with Williams‐Beuren syndrome (WBS) ascertained through online advertisements in a WBD support group and fliers. Results: Difference in odds of exposures between cases and controls as well as within cases with varying holoprosencephaly severity were studied. Cases included children born with holoprosencephaly (n = 92) and the control group consisted of children with WBS (n = 56). Pregnancy associated risk associated with holoprosencephaly included maternal pregestational diabetes (9.2% of cases and 0 controls, p =.02), higher alcohol consumption (adjusted odds ratio [aOR], 1.73; 95% CI, 0.88–15.71), and exposure to consumer products such as aerosols or sprays including hair sprays (aOR, 2.46; 95% CI, 0.89–7.19). Significant gene–environment interactions were identified including for consumption of cheese (p <.05) and espresso drinks (p =.03). Conclusion: The study identifies modifiable risk factors and gene–environment interactions that should be considered in future prevention of holoprosencephaly. Studies with larger HPE cohorts will be needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Published
2021
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95. Noonan syndrome on the African Continent.

Author

Tekendo‐Ngongang, Cedrik and Kruszka, Paul

Abstract

Background: Noonan syndrome is a common genetic syndrome caused by pathogenic variants in genes in the Ras/MAPK signaling pathway. The medical literature has an abundance of studies on Noonan syndrome, but few are from the African continent. Methods: The medical literature was searched for studies on Noonan syndrome from the African continent and these reports were added to our experience in Africa. Facial analysis was reviewed from two previous reports from our group using a support vector machine (SVM) algorithm and an analysis using the Face2Gene convolutional neural network technology. Results: Individuals with Noonan syndrome from reports in African populations have the classic phenotype characteristics including typical minor facial anomalies such as widely spaced eyes (31–100%), short stature (71–100%), and congenital heart disease with pulmonary stenosis found in 24–100% of patients. Similarly, the genotypes are similar with the majority of variants occurring in the gene PTPN11 (72%) and 36% of these variants occurred in the amino acid residue Asn308, which is most commonly found in other populations. The two separate facial analysis algorithms successfully discriminated Africans with NS from unaffected matched individuals with area under the curve (AUC) of the receiver operator characteristic of 0.94 (SVM) and 0.979 for the Face2Gene research methodology. Conclusion: Few studies characterizing Noonan syndrome in Africans have been conducted, highlighting the need for more genetic and genomic research in African populations. Available clinical data, genotypes, and facial analysis technology data show that individuals of African descent with NS can be efficiently diagnosed using available standards. [ABSTRACT FROM AUTHOR]

Published
2020
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97. Turner syndrome in diverse populations.

Author

Kruszka, Paul, Addissie, Yonit A., Tekendo‐Ngongang, Cedrik, Jones, Kelly L., Savage, Sarah K., Gupta, Neerja, Sirisena, Nirmala D., Dissanayake, Vajira H. W., Paththinige, C. Sampath, Aravena, Teresa, Nampoothiri, Sheela, Yesodharan, Dhanya, Girisha, Katta M., Patil, Siddaramappa Jagdish, Jamuar, Saumya Shekhar, Goh, Jasmine Chew‐Yin, Utari, Agustini, Sihombing, Nydia, Mishra, Rupesh, and Chitrakar, Neer Shoba

Abstract

Turner syndrome (TS) is a common multiple congenital anomaly syndrome resulting from complete or partial absence of the second X chromosome. In this study, we explore the phenotype of TS in diverse populations using clinical examination and facial analysis technology. Clinical data from 78 individuals and images from 108 individuals with TS from 19 different countries were analyzed. Individuals were grouped into categories of African descent (African), Asian, Latin American, Caucasian (European descent), and Middle Eastern. The most common phenotype features across all population groups were short stature (86%), cubitus valgus (76%), and low posterior hairline 70%. Two facial analysis technology experiments were conducted: TS versus general population and TS versus Noonan syndrome. Across all ethnicities, facial analysis was accurate in diagnosing TS from frontal facial images as measured by the area under the curve (AUC). An AUC of 0.903 (p <.001) was found for TS versus general population controls and 0.925 (p <.001) for TS versus individuals with Noonan syndrome. In summary, we present consistent clinical findings from global populations with TS and additionally demonstrate that facial analysis technology can accurately distinguish TS from the general population and Noonan syndrome. [ABSTRACT FROM AUTHOR]

Published
2020
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