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3. Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a severe developmental disorder spectrum

Author

Calame, Daniel G., Wong, Jovi Huixin, Panda, Puravi, Nguyen, Dat Tuan, Leong, Nancy C.P., Sangermano, Riccardo, Patankar, Sohil G., Abdel-Hamid, Mohamed S., AlAbdi, Lama, Safwat, Sylvia, Flannery, Kyle P., Dardas, Zain, Fatih, Jawid M., Murali, Chaya, Kannan, Varun, Lotze, Timothy E., Herman, Isabella, Ammouri, Farah, Rezich, Brianna, Efthymiou, Stephanie, Alavi, Shahryar, Murphy, David, Firoozfar, Zahra, Nasab, Mahya Ebrahimi, Bahreini, Amir, Ghasemi, Majid, Haridy, Nourelhoda A., Goldouzi, Hamid Reza, Eghbal, Fatemeh, Karimiani, Ehsan Ghayoor, Begtrup, Amber, Elloumi, Houda, Srinivasan, Varunvenkat M., Gowda, Vykuntaraju K., Du, Haowei, Jhangiani, Shalini N., Coban-Akdemir, Zeynep, Marafi, Dana, Rodan, Lance, Isikay, Sedat, Rosenfeld, Jill A., Ramanathan, Subhadra, Staton, Michael, Oberg, Kerby C., Clark, Robin D., Wenman, Catharina, Loughlin, Sam, Saad, Ramy, Ashraf, Tazeen, Male, Alison, Tadros, Shereen, Boostani, Reza, Abdel-Salam, Ghada M.H., Zaki, Maha, Mardi, Ali, Hashemi-Gorji, Farzad, Abdalla, Ebtesam, Manzini, M. Chiara, Pehlivan, Davut, Posey, Jennifer E., Gibbs, Richard A., Houlden, Henry, Alkuraya, Fowzan S., Bujakowska, Kinga, Maroofian, Reza, Lupski, James R., and Nguyen, Long Nam

Published
2024
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4. GestaltMatcher Database - A global reference for facial phenotypic variability in rare human diseases

Author

Hsieh, Tzung-Chien, primary, Lesmann, Hellen, additional, Hustinx, Alexander, additional, Moosa, Shahida, additional, Marchi, Elaine, additional, Martin, Maria del Pilar Caro, additional, Abdelrazek, Ibrahim, additional, Pantel, Jean Tori, additional, Klinkhammer, Hannah, additional, Hagen, Merle ten, additional, Thong, Meow-Keong, additional, Mazlan, Rifhan Azwani Binti, additional, Tae, Sok Kun, additional, Kamphans, Tom, additional, Meiswinkel, Wolfgang, additional, Li, Jing-Mei, additional, Javanmardi, Behnam, additional, Knaus, Alexej, additional, Uwineza, Annette, additional, Knopp, Cordula, additional, Tkemaladze, Tinatin, additional, Elbracht, Miriam, additional, Mattern, Larissa, additional, Jamra, Rami Abou, additional, Velmans, Clara, additional, Strehlow, Vincent, additional, Jacob, Maureen, additional, Peron, Angela, additional, Dias, Cristina, additional, Nunes, Beatriz, additional, Vilella, Thainá, additional, Pinheiro, Isabel, additional, Kim, Chong, additional, Melaragno, Maria, additional, Weiland, Hannah, additional, Kaptain, Sophia, additional, Chwiałkowska, Karolina , additional, Kwasniewski, Miroslaw, additional, Saad, Ramy, additional, Wiethoff, Sarah, additional, Goel, Himanshu, additional, Tang, Clara, additional, Hau, Anna, additional, Barakat, Tahsin Stefan, additional, Panek, Przemysław, additional, Nabil, Amira, additional, Suh, Julia, additional, Braun, Frederik, additional, Gomy, Israel, additional, Averdunk, Luisa, additional, Ekure, Ekanem, additional, Bergant, Gaber, additional, Peterlin, Borut, additional, Graziano, Claudio, additional, Gaboon, Nagwa, additional, Fiesco-Roa, Moisés, additional, Spinelli, Alessandro, additional, Wilpert, Nina-Maria, additional, Phowthongkum, Prasit, additional, Güzel, Nergis, additional, Haack, Tobias, additional, Bitar, Rana, additional, Tzschach, Andreas, additional, Rodriguez-Palmero, Agusti, additional, Brunet, Theresa, additional, Rudnik-Schöneborn, Sabine, additional, Contreras-Capetillo, Silvina, additional, Oberlack, Ava, additional, Samango-Sprouse, Carole, additional, Sadeghin, Teresa, additional, Olaya, Margaret, additional, Platzer, Konrad, additional, Borovikov, Artem, additional, Schnabel, Franziska, additional, Heuft, Lara, additional, Herrmann, Vera, additional, Oegema, Renske, additional, Elkhateeb, Nour, additional, Kumar, Sheetal, additional, Komlosi, Katalin, additional, Mohamed, Khoushoua, additional, Kalantari, Silvia, additional, Sirchia, Fabio, additional, Martinez-Monseny, Antonio, additional, Höller, Matthias, additional, Mohamed, Amal, additional, Lasa-Aranzasti, Amaia, additional, Sayer, John, additional, Ehmke, Nadja, additional, Danyel, Magdalena, additional, Sczakiel, Henrike, additional, Schwartzmann, Sarina, additional, Boschann, Felix, additional, Zhao, Max, additional, Adams, Ronja, additional, Einicke, Lara, additional, Horn, Denise, additional, Chew, Kee Seang, additional, Kam, Choy Chen, additional, Karakoyun, Miray, additional, Pode-Shakked, Ben, additional, Eliyahu, Aviva, additional, Rock, Rachel, additional, Carrion, Teresa, additional, Chorin, Odelia, additional, Zarate, Yuri, additional, Martinez, Marcello, additional, Karakaya, Mert, additional, Tung, Moon Ley, additional, Chandra, Bharatendu, additional, Lumaka, Aimé, additional, Shinawi, Marwan, additional, Blackburn, Patrick, additional, Wang, Tianyun, additional, Niehues, Tim, additional, Hu, Ping, additional, Waikel, Rebekah, additional, Hanchard, Suzanna Ledgister, additional, Elmakkawy, Gehad, additional, Safwat, Sylvia, additional, Ebstein, Frédéric, additional, Krüger, Elke, additional, Küry, Sébastien, additional, Bezieau, Stephane, additional, Arlt, Annabelle, additional, Marbach, Felix, additional, Li, Dong, additional, Dupuis, Lucie, additional, Mendoza-Londono, Roberto, additional, Houge, Sofia Douzgou, additional, Weis, Denisa, additional, Chung, Brian, additional, Mak, Christopher, additional, Elcioglu, Nursel, additional, Aykut, Ayca, additional, Şimşek-Kiper, Peli, additional, Bögershausen, Nina, additional, Wollnik, Bernd, additional, Bentzen, Heidi Beate, additional, Kurth, Ingo, additional, Netzer, Christian, additional, Jezela-Stanek, Aleksandra, additional, Devriendt, Koen, additional, Gripp, Karen, additional, Mücke, Martin, additional, Verloes, Alain, additional, Schaaf, Christian, additional, Nellåker, Christoffer, additional, Solomon, Benjamin, additional, Nöthen, Markus, additional, Abdalla, Ebtesam, additional, Lyon, Gholson, additional, Krawitz, Peter, additional, Kayserili, Hulya, additional, Toutouna, Louiza, additional, Schmidt, Axel, additional, Roth, Regina, additional, Wieczorek, Dagmar, additional, and Olinger, Eric, additional

Published
2024
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5. GestaltMatcher Database - A global reference for facial phenotypic variability in rare human diseases

Author

Hsieh, Tzung-Chien, Lesmann, Hellen, Hustinx, Alexander, Moosa, Shahida, Marchi, Elaine, Martin, Maria Del Pilar Caro, Abdelrazek, Ibrahim, Pantel, Jean Tori, Klinkhammer, Hannah, Hagen, Merle Ten, Thong, Meow-Keong, Mazlan, Rifhan Azwani Binti, Tae, Sok Kun, Kamphans, Tom, Meiswinkel, Wolfgang, Javanmardi, Behnam, Knaus, Alexej, Uwineza, Annette, Knopp, Cordula, Tkemaladze, Tinatin, Elbracht, Miriam, Mattern, Larissa, Jamra, Rami Abou, Velmans, Clara, Strehlow, Vincent, Jacob, Maureen, Peron, Angela, Dias, Cristina, Nunes, Beatriz, Vilella, Thainá, Pinheiro, Isabel, Kim, Chong, Melaragno, Maria, Weiland, Hannah, Kaptain, Sophia, Chwiałkowska, Karolina, Kwasniewski, Miroslaw, Saad, Ramy, Wiethoff, Sarah, Goel, Himanshu, Tang, Clara, Hau, Anna, Barakat, Tahsin Stefan, Panek, Przemysław, Nabil, Amira, Suh, Julia, Braun, Frederik, Gomy, Israel, Averdunk, Luisa, Ekure, Ekanem, Bergant, Gaber, Peterlin, Borut, Graziano, Claudio, Gaboon, Nagwa, Fiesco-Roa, Moisés, Spinelli, Alessandro, Wilpert, Nina-Maria, Phowthongkum, Prasit, Güzel, Nergis, Haack, Tobias, Bitar, Rana, Tzschach, Andreas, Rodriguez-Palmero, Agusti, Brunet, Theresa, Rudnik-Schöneborn, Sabine, Contreras-Capetillo, Silvina, Oberlack, Ava, Samango-Sprouse, Carole, Sadeghin, Teresa, Olaya, Margaret, Platzer, Konrad, Borovikov, Artem, Schnabel, Franziska, Heuft, Lara, Herrmann, Vera, Elkhateeb, Nour, Kumar, Sheetal, Komlosi, Katalin, Mohamed, Khoushoua, Kalantari, Silvia, Sirchia, Fabio, Martinez-Monseny, Antonio, Höller, Matthias, Mohamed, Amal, Lasa-Aranzasti, Amaia, Sayer, John, Ehmke, Nadja, Danyel, Magdalena, Sczakiel, Henrike, Schwartzmann, Sarina, Boschann, Felix, Zhao, Max, Adams, Ronja, Einicke, Lara, Chew, Kee Seang, Kam, Choy Chen, Karakoyun, Miray, Pode-Shakked, Ben, Eliyahu, Aviva, Rock, Rachel, Carrion, Teresa, Chorin, Odelia, Zarate, Yuri, Martinez, Marcello, Karakaya, Mert, Tung, Moon Ley, Chandra, Bharatendu, Lumaka, Aimé, Shinawi, Marwan, Blackburn, Patrick, Wang, Tianyun, Niehues, Tim, Hu, Ping, Waikel, Rebekah, Hanchard, Suzanna Ledgister, Elmakkawy, Gehad, Safwat, Sylvia, Ebstein, Frédéric, Krüger, Elke, Küry, Sébastien, Bezieau, Stephane, Arlt, Annabelle, Marbach, Felix, Li, Dong, Dupuis, Lucie, Mendoza-Londono, Roberto, Houge, Sofia Douzgou, Weis, Denisa, Mak, Christopher, Elcioglu, Nursel, Aykut, Ayca, Şimşek-Kiper, Peli, Bögershausen, Nina, Wollnik, Bernd, Bentzen, Heidi Beate, Kurth, Ingo, Netzer, Christian, Jezela-Stanek, Aleksandra, Devriendt, Koen, Gripp, Karen, Mücke, Martin, Verloes, Alain, Schaaf, Christian, Nellåker, Christoffer, Solomon, Benjamin, Nöthen, Markus, Abdalla, Ebtesam, Lyon, Gholson, Krawitz, Peter, Kayserili, Hulya, Toutouna, Louiza, Schmidt, Axel, Roth, Regina, Wieczorek, Dagmar, Olinger, Eric, Hsieh, Tzung-Chien, Lesmann, Hellen, Hustinx, Alexander, Moosa, Shahida, Marchi, Elaine, Martin, Maria Del Pilar Caro, Abdelrazek, Ibrahim, Pantel, Jean Tori, Klinkhammer, Hannah, Hagen, Merle Ten, Thong, Meow-Keong, Mazlan, Rifhan Azwani Binti, Tae, Sok Kun, Kamphans, Tom, Meiswinkel, Wolfgang, Javanmardi, Behnam, Knaus, Alexej, Uwineza, Annette, Knopp, Cordula, Tkemaladze, Tinatin, Elbracht, Miriam, Mattern, Larissa, Jamra, Rami Abou, Velmans, Clara, Strehlow, Vincent, Jacob, Maureen, Peron, Angela, Dias, Cristina, Nunes, Beatriz, Vilella, Thainá, Pinheiro, Isabel, Kim, Chong, Melaragno, Maria, Weiland, Hannah, Kaptain, Sophia, Chwiałkowska, Karolina, Kwasniewski, Miroslaw, Saad, Ramy, Wiethoff, Sarah, Goel, Himanshu, Tang, Clara, Hau, Anna, Barakat, Tahsin Stefan, Panek, Przemysław, Nabil, Amira, Suh, Julia, Braun, Frederik, Gomy, Israel, Averdunk, Luisa, Ekure, Ekanem, Bergant, Gaber, Peterlin, Borut, Graziano, Claudio, Gaboon, Nagwa, Fiesco-Roa, Moisés, Spinelli, Alessandro, Wilpert, Nina-Maria, Phowthongkum, Prasit, Güzel, Nergis, Haack, Tobias, Bitar, Rana, Tzschach, Andreas, Rodriguez-Palmero, Agusti, Brunet, Theresa, Rudnik-Schöneborn, Sabine, Contreras-Capetillo, Silvina, Oberlack, Ava, Samango-Sprouse, Carole, Sadeghin, Teresa, Olaya, Margaret, Platzer, Konrad, Borovikov, Artem, Schnabel, Franziska, Heuft, Lara, Herrmann, Vera, Elkhateeb, Nour, Kumar, Sheetal, Komlosi, Katalin, Mohamed, Khoushoua, Kalantari, Silvia, Sirchia, Fabio, Martinez-Monseny, Antonio, Höller, Matthias, Mohamed, Amal, Lasa-Aranzasti, Amaia, Sayer, John, Ehmke, Nadja, Danyel, Magdalena, Sczakiel, Henrike, Schwartzmann, Sarina, Boschann, Felix, Zhao, Max, Adams, Ronja, Einicke, Lara, Chew, Kee Seang, Kam, Choy Chen, Karakoyun, Miray, Pode-Shakked, Ben, Eliyahu, Aviva, Rock, Rachel, Carrion, Teresa, Chorin, Odelia, Zarate, Yuri, Martinez, Marcello, Karakaya, Mert, Tung, Moon Ley, Chandra, Bharatendu, Lumaka, Aimé, Shinawi, Marwan, Blackburn, Patrick, Wang, Tianyun, Niehues, Tim, Hu, Ping, Waikel, Rebekah, Hanchard, Suzanna Ledgister, Elmakkawy, Gehad, Safwat, Sylvia, Ebstein, Frédéric, Krüger, Elke, Küry, Sébastien, Bezieau, Stephane, Arlt, Annabelle, Marbach, Felix, Li, Dong, Dupuis, Lucie, Mendoza-Londono, Roberto, Houge, Sofia Douzgou, Weis, Denisa, Mak, Christopher, Elcioglu, Nursel, Aykut, Ayca, Şimşek-Kiper, Peli, Bögershausen, Nina, Wollnik, Bernd, Bentzen, Heidi Beate, Kurth, Ingo, Netzer, Christian, Jezela-Stanek, Aleksandra, Devriendt, Koen, Gripp, Karen, Mücke, Martin, Verloes, Alain, Schaaf, Christian, Nellåker, Christoffer, Solomon, Benjamin, Nöthen, Markus, Abdalla, Ebtesam, Lyon, Gholson, Krawitz, Peter, Kayserili, Hulya, Toutouna, Louiza, Schmidt, Axel, Roth, Regina, Wieczorek, Dagmar, and Olinger, Eric

Abstract

The most important factor that complicates the work of dysmorphologists is the significant phenotypic variability of the human face. Next-Generation Phenotyping (NGP) tools that assist clinicians with recognizing characteristic syndromic patterns are particularly challenged when confronted with patients from populations different from their training data. To that end, we systematically analyzed the impact of genetic ancestry on facial dysmorphism. For that purpose, we established the GestaltMatcher Database (GMDB) as a reference dataset for medical images of patients with rare genetic disorders from around the world. We collected 10,980 frontal facial images - more than a quarter previously unpublished - from 8,346 patients, representing 581 rare disorders. Although the predominant ancestry is still European (67%), data from underrepresented populations have been increased considerably via global collaborations (19% Asian and 7% African). This includes previously unpublished reports for more than 40% of the African patients. The NGP analysis on this diverse dataset revealed characteristic performance differences depending on the composition of training and test sets corresponding to genetic relatedness. For clinical use of NGP, incorporating non-European patients resulted in a profound enhancement of GestaltMatcher performance. The top-5 accuracy rate increased by +11.29%. Importantly, this improvement in delineating the correct disorder from a facial portrait was achieved without decreasing the performance on European patients. By design, GMDB complies with the FAIR principles by rendering the curated medical data findable, accessible, interoperable, and reusable. This means GMDB can also serve as data for training and benchmarking. In summary, our study on facial dysmorphism on a global sample revealed a considerable cross ancestral phenotypic variability confounding NGP that should be counteracted by international efforts for increasing data diversity. GMDB wi

Published
2024

6. Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a pleiotropic disease spectrum from adult neurodegeneration to severe developmental disorders

Author

Calame, Daniel G, primary, Wong, Jovi Huixin, additional, Panda, Puravi, additional, Nguyen, Dat Tuan, additional, Leong, Nancy C.P., additional, Sangermano, Riccardo, additional, Patankar, Sohil G, additional, AlAbdi, Lama, additional, Safwat, Sylvia, additional, Flannery, Kyle, additional, Dardas, Zain, additional, Fatih, Jawid M, additional, Murali, Chaya, additional, Kannan, Varun, additional, Lotze, Timothy E, additional, Herman, Isabella, additional, Ammouri, Farrah, additional, Rezich, Brianna, additional, Efthymiou, Stephanie, additional, Alavi, Shahryar, additional, Murphy, David, additional, Firoozfar, Zahra, additional, Nasab, Mahya Ebrahimi, additional, Bahreini, Amir, additional, Ghasemi, Majid, additional, Haridy, Nourelhoda A, additional, Goldouzi, Hamid Reza, additional, Eghbal, Fatemeh, additional, Karimiani, Ehsan Ghayoor, additional, Srinivasan, Varunvenkat M, additional, Gowda, Vykuntaraju K, additional, Du, Haowei, additional, Jhangiani, Shalini N, additional, Coban-Akdemir, Zeynep, additional, Marafi, Dana, additional, Rodan, Lance, additional, Isikay, Sedat, additional, Rosenfeld, Jill A, additional, Ramanathan, Subhadra, additional, Staton, Michael, additional, Oberg, Kerby C, additional, Clark, Robin D, additional, Wenman, Catharina, additional, Loughlin, Sam, additional, Saad, Ramy, additional, Ashraf, Tazeen, additional, Male, Alison, additional, Tadros, Shereen, additional, Boostani, Reza, additional, Abdel-Salam, Ghada H.M., additional, Zaki, Maha, additional, Abdalla, Ebtesam, additional, Manzini, M Chiara, additional, Pehlivan, Davut, additional, Posey, Jennifer E, additional, Gibbs, Richard A, additional, Houlden, Henry, additional, Alkuraya, Fowzan S, additional, Bujakowska, Kinga, additional, Maroofian, Reza, additional, Lupski, James R, additional, and Nguyen, Long Nam, additional

Published
2024
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7. GestaltMatcher Database - A global reference for the facial phenotypic variability of rare human diseases

Author

Lesmann, Hellen, primary, Hustinx, Alexander, additional, Moosa, Shahida, additional, Marchi, Elaine, additional, Caro, Pilar, additional, Abdelrazek, Ibrahim M., additional, Pantel, Jean Tori, additional, Klinkhammer, Hannah, additional, ten Hagen, Merle, additional, Kamphans, Tom, additional, Meiswinkel, Wolfgang, additional, Li, Jing-Mei, additional, Javanmardi, Behnam, additional, Knaus, Alexej, additional, Uwineza, Annette, additional, Knopp, Cordula, additional, Tkemaladze, Tinatin, additional, Elbracht, Miriam, additional, Mattern, Larissa, additional, Jamra, Rami Abou, additional, Velmans, Clara, additional, Strehlow, Vincent, additional, Goel, Himanshu, additional, Nunes, Beatriz Carvalho, additional, Vilella, Thainá, additional, Pinheiro, Isabel Furquim, additional, Kim, Chong Ae, additional, Melaragno, Maria Isabel, additional, Barakat, Tahsin Stefan, additional, Nabil, Amira, additional, Suh, Julia, additional, Averdunk, Luisa, additional, Ekure, Ekanem, additional, Graziano, Claudio, additional, Phowthongkum, Prasit, additional, Güzel, Nergis, additional, Haack, Tobias B., additional, Brunet, Theresa, additional, Rudnik-Schöneborn, Sabine, additional, Platzer, Konrad, additional, Borovikov, Artem, additional, Schnabel, Franziska, additional, Heuft, Lara, additional, Herrmann, Vera, additional, Martinez-Monseny, Antonio F., additional, Höller, Matthias, additional, Alaaeldin, Khoshoua, additional, Jezela-Stanek, Aleksandra, additional, Mohamed, Amal, additional, Lasa-Aranzasti, Amaia, additional, Sayer, John A., additional, Hu, Ping, additional, Hanchard, Suzanna E. Ledgister, additional, Elmakkawy, Gehad, additional, Safwat, Sylvia, additional, Ebstein, Frédéric, additional, Krüger, Elke, additional, Küry, Sébastien, additional, Arlt, Annabelle, additional, Marbach, Felix, additional, Netzer, Christian, additional, Kaptain, Sophia, additional, Weiland, Hannah, additional, Li, Dong, additional, Dupuis, Lucie, additional, Mendoza-Londono, Roberto, additional, Houge, Sofia Douzgou, additional, Weis, Denisa, additional, Chung, Brian Hon-Yin, additional, Mak, Christopher C.Y., additional, Devriendt, Koen, additional, Gripp, Karen W., additional, Mücke, Martin, additional, Verloes, Alain, additional, Schaaf, Christian P., additional, Nellåker, Christoffer, additional, Solomon, Benjamin D., additional, Waikel, Rebekah L., additional, Nöthen, Markus M., additional, Abdalla, Ebtesam, additional, Lyon, Gholson J., additional, Krawitz, Peter M., additional, and Hsieh, Tzung-Chien, additional

Published
2023
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9. Lipoid proteinosis: Novel ECM1 pathogenic variants and intrafamilial variability in four unrelated Arab families.

Author

Li, Mingfeng, Fischer, Judith, Safwat, Sylvia, Shoman, Walaa, Chazli, Yasmine El, Alter, Svenja, Has, Cristina, and Abdalla, Ebtesam

Subjects
PHENOTYPIC plasticity, VOICE disorders, HOARSENESS, EXTRACELLULAR matrix proteins, FAMILIES, EXTRACELLULAR matrix, SYMPTOMS
Abstract

Background/objectives: Lipoid proteinosis (LP) is a rare autosomal recessive multisystem disorder that is caused by loss‐of‐function pathogenic variants in the extracellular matrix protein‐1 (ECM1) gene. The typical clinical manifestations of LP include hoarseness of voice, beaded papules on the eyelids, infiltration and scarring of the skin and mucosa, as well as neuropsychological abnormalities. Currently, more than 70 pathogenic variants have been reported, including nonsense, missense, splice site, deletion and insertion pathogenic variants, and more than half of them occurred in exons 6 and 7. Methods: Clinical evaluation and Sanger sequencing were performed on eight patients from four unrelated Arab families. Results: We identified two novel ECM1 variants, one nonsense pathogenic variant in exon 6 (c.579G>A, p.Trp193*) and a deletion of three nucleotides (c.1390_1392del, p.Glu464del) in exon 9, and two previously reported frameshift variants; c.692_693delAG, in exon 6 and c.11dupC in exon 1. Conclusions: Although all patients had characteristic manifestations of lipoid proteinosis, we observed intrafamilial phenotypic variability. Our data expand the pathogenic variant spectrum of ECM1 and also supports the fact that exon 6 is one of the most common hot spots of pathological variants in ECM1. [ABSTRACT FROM AUTHOR]

Published
2023
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11. Biallelic variation in the choline and ethanolamine transporter FLVCR1underlies a severe developmental disorder spectrum

Author

Calame, Daniel G., Wong, Jovi Huixin, Panda, Puravi, Nguyen, Dat Tuan, Leong, Nancy C.P., Sangermano, Riccardo, Patankar, Sohil G., Abdel-Hamid, Mohamed S., AlAbdi, Lama, Safwat, Sylvia, Flannery, Kyle P., Dardas, Zain, Fatih, Jawid M., Murali, Chaya, Kannan, Varun, Lotze, Timothy E., Herman, Isabella, Ammouri, Farah, Rezich, Brianna, Efthymiou, Stephanie, Alavi, Shahryar, Murphy, David, Firoozfar, Zahra, Nasab, Mahya Ebrahimi, Bahreini, Amir, Ghasemi, Majid, Haridy, Nourelhoda A., Goldouzi, Hamid Reza, Eghbal, Fatemeh, Karimiani, Ehsan Ghayoor, Begtrup, Amber, Elloumi, Houda, Srinivasan, Varunvenkat M., Gowda, Vykuntaraju K., Du, Haowei, Jhangiani, Shalini N., Coban-Akdemir, Zeynep, Marafi, Dana, Rodan, Lance, Isikay, Sedat, Rosenfeld, Jill A., Ramanathan, Subhadra, Staton, Michael, Oberg, Kerby C., Clark, Robin D., Wenman, Catharina, Loughlin, Sam, Saad, Ramy, Ashraf, Tazeen, Male, Alison, Tadros, Shereen, Boostani, Reza, Abdel-Salam, Ghada M.H., Zaki, Maha, Mardi, Ali, Hashemi-Gorji, Farzad, Abdalla, Ebtesam, Manzini, M. Chiara, Pehlivan, Davut, Posey, Jennifer E., Gibbs, Richard A., Houlden, Henry, Alkuraya, Fowzan S., Bujakowska, Kinga, Maroofian, Reza, Lupski, James R., and Nguyen, Long Nam

Abstract

FLVCR1encodes a solute carrier protein implicated in heme, choline, and ethanolamine transport. Although Flvcr1−/−mice exhibit skeletal malformations and defective erythropoiesis reminiscent of Diamond-Blackfan anemia (DBA), biallelic FLVCR1variants in humans have previously only been linked to childhood or adult-onset ataxia, sensory neuropathy, and retinitis pigmentosa.

Published
2024
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12. GestaltMatcher Database - A global reference for facial phenotypic variability in rare human diseases.

Author

Lesmann H, Hustinx A, Moosa S, Klinkhammer H, Marchi E, Caro P, Abdelrazek IM, Pantel JT, Hagen MT, Thong MK, Mazlan RAB, Tae SK, Kamphans T, Meiswinkel W, Li JM, Javanmardi B, Knaus A, Uwineza A, Knopp C, Tkemaladze T, Elbracht M, Mattern L, Jamra RA, Velmans C, Strehlow V, Jacob M, Peron A, Dias C, Nunes BC, Vilella T, Pinheiro IF, Kim CA, Melaragno MI, Weiland H, Kaptain S, Chwiałkowska K, Kwasniewski M, Saad R, Wiethoff S, Goel H, Tang C, Hau A, Barakat TS, Panek P, Nabil A, Suh J, Braun F, Gomy I, Averdunk L, Ekure E, Bergant G, Peterlin B, Graziano C, Gaboon N, Fiesco-Roa M, Spinelli AM, Wilpert NM, Phowthongkum P, Güzel N, Haack TB, Bitar R, Tzschach A, Rodriguez-Palmero A, Brunet T, Rudnik-Schöneborn S, Contreras-Capetillo SN, Oberlack A, Samango-Sprouse C, Sadeghin T, Olaya M, Platzer K, Borovikov A, Schnabel F, Heuft L, Herrmann V, Oegema R, Elkhateeb N, Kumar S, Komlosi K, Mohamed K, Kalantari S, Sirchia F, Martinez-Monseny AF, Höller M, Toutouna L, Mohamed A, Lasa-Aranzasti A, Sayer JA, Ehmke N, Danyel M, Sczakiel H, Schwartzmann S, Boschann F, Zhao M, Adam R, Einicke L, Horn D, Chew KS, Kam CC, Karakoyun M, Pode-Shakked B, Eliyahu A, Rock R, Carrion T, Chorin O, Zarate YA, Conti MM, Karakaya M, Tung ML, Chandra B, Bouman A, Lumaka A, Wasif N, Shinawi M, Blackburn PR, Wang T, Niehues T, Schmidt A, Roth RR, Wieczorek D, Hu P, Waikel RL, Ledgister Hanchard SE, Elmakkawy G, Safwat S, Ebstein F, Krüger E, Küry S, Bézieau S, Arlt A, Olinger E, Marbach F, Li D, Dupuis L, Mendoza-Londono R, Houge SD, Weis D, Chung BH, Mak CCY, Kayserili H, Elcioglu N, Aykut A, Şimşek-Kiper PÖ, Bögershausen N, Wollnik B, Bentzen HB, Kurth I, Netzer C, Jezela-Stanek A, Devriendt K, Gripp KW, Mücke M, Verloes A, Schaaf CP, Nellåker C, Solomon BD, Nöthen MM, Abdalla E, Lyon GJ, Krawitz PM, and Hsieh TC

Abstract

The most important factor that complicates the work of dysmorphologists is the significant phenotypic variability of the human face. Next-Generation Phenotyping (NGP) tools that assist clinicians with recognizing characteristic syndromic patterns are particularly challenged when confronted with patients from populations different from their training data. To that end, we systematically analyzed the impact of genetic ancestry on facial dysmorphism. For that purpose, we established the GestaltMatcher Database (GMDB) as a reference dataset for medical images of patients with rare genetic disorders from around the world. We collected 10,980 frontal facial images - more than a quarter previously unpublished - from 8,346 patients, representing 581 rare disorders. Although the predominant ancestry is still European (67%), data from underrepresented populations have been increased considerably via global collaborations (19% Asian and 7% African). This includes previously unpublished reports for more than 40% of the African patients. The NGP analysis on this diverse dataset revealed characteristic performance differences depending on the composition of training and test sets corresponding to genetic relatedness. For clinical use of NGP, incorporating non-European patients resulted in a profound enhancement of GestaltMatcher performance. The top-5 accuracy rate increased by +11.29%. Importantly, this improvement in delineating the correct disorder from a facial portrait was achieved without decreasing the performance on European patients. By design, GMDB complies with the FAIR principles by rendering the curated medical data findable, accessible, interoperable, and reusable. This means GMDB can also serve as data for training and benchmarking. In summary, our study on facial dysmorphism on a global sample revealed a considerable cross ancestral phenotypic variability confounding NGP that should be counteracted by international efforts for increasing data diversity. GMDB will serve as a vital reference database for clinicians and a transparent training set for advancing NGP technology.

Published
2024
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13. A novel missense variant in the ATPase domain of ATP8A2 and review of phenotypic variability of ATP8A2 -related disorders caused by missense changes.

Author

Flannery KP, Safwat S, Matsell E, Battula N, Hamed AAA, Mohamed IN, Elseed MA, Koko M, Abubaker R, Abozar F, Elsayed LEO, Bhise V, Molday RS, Salih MA, Yahia A, and Manzini MC

Abstract

ATPase, class 1, type 8A, member 2 (ATP8A2) is a P4-ATPase with a critical role in phospholipid translocation across the plasma membrane. Pathogenic variants in ATP8A2 are known to cause cerebellar ataxia, mental retardation, and disequilibrium syndrome 4 (CAMRQ4) which is often associated with encephalopathy, global developmental delay, and severe motor deficits. Here, we present a family with two siblings presenting with global developmental delay, intellectual disability, spasticity, ataxia, nystagmus, and thin corpus callosum. Whole exome sequencing revealed a homozygous missense variant in the nucleotide binding domain of ATP8A2 (p.Leu538Pro) that results in near complete loss of protein expression. This is in line with other missense variants in the same domain leading to protein misfolding and loss of ATPase function. In addition, by performing diffusion-weighted imaging, we identified bilateral hyperintensities in the posterior limbs of the internal capsule suggesting possible microstructural changes in axon tracts that had not been appreciated before and could contribute to the sensorimotor deficits in these individuals., Competing Interests: Conflict of Interest The authors declare no conflicts of interest.

Published
2024
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14. Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a pleiotropic disease spectrum from adult neurodegeneration to severe developmental disorders.

Author

Calame DG, Wong JH, Panda P, Nguyen DT, Leong NCP, Sangermano R, Patankar SG, Abdel-Hamid M, AlAbdi L, Safwat S, Flannery KP, Dardas Z, Fatih JM, Murali C, Kannan V, Lotze TE, Herman I, Ammouri F, Rezich B, Efthymiou S, Alavi S, Murphy D, Firoozfar Z, Nasab ME, Bahreini A, Ghasemi M, Haridy NA, Goldouzi HR, Eghbal F, Karimiani EG, Srinivasan VM, Gowda VK, Du H, Jhangiani SN, Coban-Akdemir Z, Marafi D, Rodan L, Isikay S, Rosenfeld JA, Ramanathan S, Staton M, Kerby C Oberg, Clark RD, Wenman C, Loughlin S, Saad R, Ashraf T, Male A, Tadros S, Boostani R, Abdel-Salam GMH, Zaki M, Abdalla E, Manzini MC, Pehlivan D, Posey JE, Gibbs RA, Houlden H, Alkuraya FS, Bujakowska K, Maroofian R, Lupski JR, and Nguyen LN

Abstract

FLVCR1 encodes Feline leukemia virus subgroup C receptor 1 (FLVCR1), a solute carrier (SLC) transporter within the Major Facilitator Superfamily. FLVCR1 is a widely expressed transmembrane protein with plasma membrane and mitochondrial isoforms implicated in heme, choline, and ethanolamine transport. While Flvcr1 knockout mice die in utero with skeletal malformations and defective erythropoiesis reminiscent of Diamond-Blackfan anemia, rare biallelic pathogenic FLVCR1 variants are linked to childhood or adult-onset neurodegeneration of the retina, spinal cord, and peripheral nervous system. We ascertained from research and clinical exome sequencing 27 individuals from 20 unrelated families with biallelic ultra-rare missense and predicted loss-of-function (pLoF) FLVCR1 variant alleles. We characterize an expansive FLVCR1 phenotypic spectrum ranging from adult-onset retinitis pigmentosa to severe developmental disorders with microcephaly, reduced brain volume, epilepsy, spasticity, and premature death. The most severely affected individuals, including three individuals with homozygous pLoF variants, share traits with Flvcr1 knockout mice and Diamond-Blackfan anemia including macrocytic anemia and congenital skeletal malformations. Pathogenic FLVCR1 missense variants primarily lie within transmembrane domains and reduce choline and ethanolamine transport activity compared with wild-type FLVCR1 with minimal impact on FLVCR1 stability or subcellular localization. Several variants disrupt splicing in a mini-gene assay which may contribute to genotype-phenotype correlations. Taken together, these data support an allele-specific gene dosage model in which phenotypic severity reflects residual FLVCR1 activity. This study expands our understanding of Mendelian disorders of choline and ethanolamine transport and demonstrates the importance of choline and ethanolamine in neurodevelopment and neuronal homeostasis., Competing Interests: Potential Conflict of Interest J.R.L. has stock ownership in 23andMe, is a paid consultant for Genome International, and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, genomic disorders, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing conducted at Baylor Genetics (BG) Laboratories. Other authors have no potential conflicts to disclose.

Published
2024
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