Search

Your search keyword '"Moghadasi, S."' showing total 83 results
Start Over Author "Moghadasi, S."
83 results on '"Moghadasi, S."'

5. Neurofibromas in LZTR1 schwannomatosis

Author

Groen, J.L., Moghadasi, S., Spruijt, L., Korpershoek, E., Ierland, Y. van, Wezel, J.T. van, Duinen, S. van, Malessy, M.J., Oberstein, S.A., Groen, J.L., Moghadasi, S., Spruijt, L., Korpershoek, E., Ierland, Y. van, Wezel, J.T. van, Duinen, S. van, Malessy, M.J., and Oberstein, S.A.

Abstract

Item does not contain fulltext

Published
2022

7. DLG4-related synaptopathy: a new rare brain disorder

Author

Rodríguez-Palmero, A., Boerrigter, M.M., Gómez-Andrés, D., Aldinger, K.A., Marcos-Alcalde, Í., Popp, B., Everman, D.B., Lovgren, A.K., Arpin, S., Bahrambeigi, V., Beunders, G., Bisgaard, A.M., Bjerregaard, V.A., Bruel, A.L., Challman, T.D., Cogné, B., Coubes, C., Man, S.A. de, Denommé-Pichon, A.S., Dye, T.J., Elmslie, F., Feuk, L., García-Miñaúr, S., Gertler, T., Giorgio, E., Gruchy, N., Haack, T.B., Haldeman-Englert, C.R., Haukanes, B.I., Hoyer, J., Hurst, A.C.E., Isidor, B., Soller, M.J., Kushary, S., Kvarnung, M., Landau, Y.E., Leppig, K.A., Lindstrand, A., Kleinendorst, L., Mackenzie, A., Mandrile, G., Mendelsohn, B.A., Moghadasi, S., Morton, J.E., Moutton, S., Müller, A.J., O'Leary, M., Pacio-Míguez, M., Palomares-Bralo, M., Parikh, S., Pfundt, R., Pode-Shakked, B., Rauch, A., Repnikova, E., Revah-Politi, A., Ross, M.J., Ruivenkamp, C.A.L., Sarrazin, E., Savatt, J.M., Schlüter, A., Schönewolf-Greulich, B., Shad, Z., Shaw-Smith, C., Shieh, J.T., Shohat, M., Spranger, S., Thiese, H., Mau-Them, F.T., Bon, B. van, Burgt, I. van der, Laar, I. van de, Drie, E. van, Haelst, M.M. van, Ravenswaaij-Arts, C.M.A. van, Verdura, E., Vitobello, A., Waldmüller, S., Whiting, S., Zweier, C., Prada, C.E., Vries, B.B. de, Dobyns, W.B., Reiter, S.F., Gómez-Puertas, P., Pujol, A., Tümer, Z., Rodríguez-Palmero, A., Boerrigter, M.M., Gómez-Andrés, D., Aldinger, K.A., Marcos-Alcalde, Í., Popp, B., Everman, D.B., Lovgren, A.K., Arpin, S., Bahrambeigi, V., Beunders, G., Bisgaard, A.M., Bjerregaard, V.A., Bruel, A.L., Challman, T.D., Cogné, B., Coubes, C., Man, S.A. de, Denommé-Pichon, A.S., Dye, T.J., Elmslie, F., Feuk, L., García-Miñaúr, S., Gertler, T., Giorgio, E., Gruchy, N., Haack, T.B., Haldeman-Englert, C.R., Haukanes, B.I., Hoyer, J., Hurst, A.C.E., Isidor, B., Soller, M.J., Kushary, S., Kvarnung, M., Landau, Y.E., Leppig, K.A., Lindstrand, A., Kleinendorst, L., Mackenzie, A., Mandrile, G., Mendelsohn, B.A., Moghadasi, S., Morton, J.E., Moutton, S., Müller, A.J., O'Leary, M., Pacio-Míguez, M., Palomares-Bralo, M., Parikh, S., Pfundt, R., Pode-Shakked, B., Rauch, A., Repnikova, E., Revah-Politi, A., Ross, M.J., Ruivenkamp, C.A.L., Sarrazin, E., Savatt, J.M., Schlüter, A., Schönewolf-Greulich, B., Shad, Z., Shaw-Smith, C., Shieh, J.T., Shohat, M., Spranger, S., Thiese, H., Mau-Them, F.T., Bon, B. van, Burgt, I. van der, Laar, I. van de, Drie, E. van, Haelst, M.M. van, Ravenswaaij-Arts, C.M.A. van, Verdura, E., Vitobello, A., Waldmüller, S., Whiting, S., Zweier, C., Prada, C.E., Vries, B.B. de, Dobyns, W.B., Reiter, S.F., Gómez-Puertas, P., Pujol, A., and Tümer, Z.

Abstract

Contains fulltext : 245031.pdf (Publisher’s version ) (Closed access), PURPOSE: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants. METHODS: The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing. RESULTS: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies. CONCLUSION: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.

Published
2021

8. Putting genome-wide sequencing in neonates into perspective (vol 24, pg 1074, 2019)

Author

Sluijs, P.J. van der, Aten, E., Barge-Schaapveld, D.Q.C.M., Bijlsma, E.K., Bokenkamp-Gramann, R., Kaat, L.D., Doorn, R. van, Putte, D.F. van de, Haeringen, A. van, Harkel, A.D.J. ten, Hilhorst-Hofstee, Y., Hoffer, M.J.V., Hollander, N.S. den, Ierland, Y. van, Koopmans, M., Kriek, M., Moghadasi, S., Nibbeling, E.A.R., Peeters-Scholte, C.M.P.C.D., Potjer, T.P., Rij, M. van, Ruivenkamp, C.A.L., Rutten, J.W., Steggerda, S.J., Suerink, M., Tan, R.N.G.B., Tuin, K. van der, Visser, R., Werf-'t Lam, A.S. van der, Williams, M., Witlox, R., and Santen, G.W.E.

Published
2019
Full Text
View/download PDF

9. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification.

Author

Feroce I., Schoenwiese U., Seggewiss J., Solanes A., Steinemann D., Stiller M., Stoppa-Lyonnet D., Sullivan K.J., Susman R., Sutter C., Tavtigian S.V., Teo S.H., Teule A., Thomassen M., Tibiletti M.G., Tischkowitz M., Tognazzo S., Toland A.E., Tornero E., Torngren T., Torres-Esquius S., Toss A., Trainer A.H., Tucker K.M., van Asperen C.J., van Mackelenbergh M.T., Varesco L., Vargas-Parra G., Varon R., Vega A., Velasco A., Vesper A.-S., Viel A., Vreeswijk M.P.G., Wagner S.A., Waha A., Walker L.C., Walters R.J., Wang-Gohrke S., Weber B.H.F., Weichert W., Wieland K., Wiesmuller L., Witzel I., Wockel A., Woodward E.R., Zachariae S., Zampiga V., Zeder-Goss C., Investigators K., Lazaro C., De Nicolo A., Radice P., Engel C., Schmutzler R.K., Goldgar D.E., Spurdle A.B., Harris M., Parsons M.T., Tudini E., Li H., Hahnen E., Wappenschmidt B., Feliubadalo L., Aalfs C.M., Agata S., Aittomaki K., Alducci E., Alonso-Cerezo M.C., Arnold N., Auber B., Austin R., Azzollini J., Balmana J., Barbieri E., Bartram C.R., Blanco A., Blumcke B., Bonache S., Bonanni B., Borg A., Bortesi B., Brunet J., Bruzzone C., Bucksch K., Cagnoli G., Caldes T., Caliebe A., Caligo M.A., Calvello M., Capone G.L., Caputo S.M., Carnevali I., Carrasco E., Caux-Moncoutier V., Cavalli P., Cini G., Clarke E.M., Concolino P., Cops E.J., Cortesi L., Couch F.J., Darder E., de la Hoya M., Dean M., Debatin I., Del Valle J., Delnatte C., Derive N., Diez O., Ditsch N., Domchek S.M., Dutrannoy V., Eccles D.M., Ehrencrona H., Enders U., Evans D.G., Farra C., Faust U., Felbor U., Fine M., Foulkes W.D., Galvao H.C.R., Gambino G., Gehrig A., Gensini F., Gerdes A.-M., Germani A., Giesecke J., Gismondi V., Gomez C., Gomez Garcia E.B., Gonzalez S., Grau E., Grill S., Gross E., Guerrieri-Gonzaga A., Guillaud-Bataille M., Gutierrez-Enriquez S., Haaf T., Hackmann K., Hansen T.V.O., Hauke J., Heinrich T., Hellebrand H., Herold K.N., Honisch E., Horvath J., Houdayer C., Hubbel V., Iglesias S., Izquierdo A., James P.A., Janssen L.A.M., Jeschke U., Kaulfuss S., Keupp K., Kiechle M., Kolbl A., Krieger S., Kruse T.A., Kvist A., Lalloo F., Larsen M., Lattimore V.L., Lautrup C., Ledig S., Leinert E., Lewis A.L., Lim J., Loeffler M., Lopez-Fernandez A., Lucci-Cordisco E., Maass N., Manoukian S., Marabelli M., Matricardi L., Meindl A., Michelli R.D., Moghadasi S., Moles-Fernandez A., Montagna M., Montalban G., Monteiro A.N., Montes E., Mori L., Moserle L., Muller C.R., Mundhenke C., Naldi N., Nathanson K.L., Navarro M., Nevanlinna H., Nichols C.B., Niederacher D., Nielsen H.R., Ong K.-R., Pachter N., Palmero E.I., Papi L., Pedersen I.S., Peissel B., Perez-Segura P., Pfeifer K., Pineda M., Pohl-Rescigno E., Poplawski N.K., Porfirio B., Quante A.S., Ramser J., Reis R.M., Revillion F., Rhiem K., Riboli B., Ritter J., Rivera D., Rofes P., Rump A., Salinas M., Sanchez de Abajo A.M., Schmidt G., Feroce I., Schoenwiese U., Seggewiss J., Solanes A., Steinemann D., Stiller M., Stoppa-Lyonnet D., Sullivan K.J., Susman R., Sutter C., Tavtigian S.V., Teo S.H., Teule A., Thomassen M., Tibiletti M.G., Tischkowitz M., Tognazzo S., Toland A.E., Tornero E., Torngren T., Torres-Esquius S., Toss A., Trainer A.H., Tucker K.M., van Asperen C.J., van Mackelenbergh M.T., Varesco L., Vargas-Parra G., Varon R., Vega A., Velasco A., Vesper A.-S., Viel A., Vreeswijk M.P.G., Wagner S.A., Waha A., Walker L.C., Walters R.J., Wang-Gohrke S., Weber B.H.F., Weichert W., Wieland K., Wiesmuller L., Witzel I., Wockel A., Woodward E.R., Zachariae S., Zampiga V., Zeder-Goss C., Investigators K., Lazaro C., De Nicolo A., Radice P., Engel C., Schmutzler R.K., Goldgar D.E., Spurdle A.B., Harris M., Parsons M.T., Tudini E., Li H., Hahnen E., Wappenschmidt B., Feliubadalo L., Aalfs C.M., Agata S., Aittomaki K., Alducci E., Alonso-Cerezo M.C., Arnold N., Auber B., Austin R., Azzollini J., Balmana J., Barbieri E., Bartram C.R., Blanco A., Blumcke B., Bonache S., Bonanni B., Borg A., Bortesi B., Brunet J., Bruzzone C., Bucksch K., Cagnoli G., Caldes T., Caliebe A., Caligo M.A., Calvello M., Capone G.L., Caputo S.M., Carnevali I., Carrasco E., Caux-Moncoutier V., Cavalli P., Cini G., Clarke E.M., Concolino P., Cops E.J., Cortesi L., Couch F.J., Darder E., de la Hoya M., Dean M., Debatin I., Del Valle J., Delnatte C., Derive N., Diez O., Ditsch N., Domchek S.M., Dutrannoy V., Eccles D.M., Ehrencrona H., Enders U., Evans D.G., Farra C., Faust U., Felbor U., Fine M., Foulkes W.D., Galvao H.C.R., Gambino G., Gehrig A., Gensini F., Gerdes A.-M., Germani A., Giesecke J., Gismondi V., Gomez C., Gomez Garcia E.B., Gonzalez S., Grau E., Grill S., Gross E., Guerrieri-Gonzaga A., Guillaud-Bataille M., Gutierrez-Enriquez S., Haaf T., Hackmann K., Hansen T.V.O., Hauke J., Heinrich T., Hellebrand H., Herold K.N., Honisch E., Horvath J., Houdayer C., Hubbel V., Iglesias S., Izquierdo A., James P.A., Janssen L.A.M., Jeschke U., Kaulfuss S., Keupp K., Kiechle M., Kolbl A., Krieger S., Kruse T.A., Kvist A., Lalloo F., Larsen M., Lattimore V.L., Lautrup C., Ledig S., Leinert E., Lewis A.L., Lim J., Loeffler M., Lopez-Fernandez A., Lucci-Cordisco E., Maass N., Manoukian S., Marabelli M., Matricardi L., Meindl A., Michelli R.D., Moghadasi S., Moles-Fernandez A., Montagna M., Montalban G., Monteiro A.N., Montes E., Mori L., Moserle L., Muller C.R., Mundhenke C., Naldi N., Nathanson K.L., Navarro M., Nevanlinna H., Nichols C.B., Niederacher D., Nielsen H.R., Ong K.-R., Pachter N., Palmero E.I., Papi L., Pedersen I.S., Peissel B., Perez-Segura P., Pfeifer K., Pineda M., Pohl-Rescigno E., Poplawski N.K., Porfirio B., Quante A.S., Ramser J., Reis R.M., Revillion F., Rhiem K., Riboli B., Ritter J., Rivera D., Rofes P., Rump A., Salinas M., Sanchez de Abajo A.M., and Schmidt G.

Abstract

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.Copyright © 2019 Wiley Periodicals, Inc.

Published
2019

10. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

Author

Parsons, MT, Tudini, E, Li, H, Hahnen, E, Wappenschmidt, B, Feliubadalo, L, Aalfs, CM, Agata, S, Aittomaki, K, Alducci, E, Concepcion Alonso-Cerezo, M, Arnold, N, Auber, B, Austin, R, Azzollini, J, Balmana, J, Barbieri, E, Bartram, CR, Blanco, A, Bluemcke, B, Bonache, S, Bonanni, B, Borg, A, Bortesi, B, Brunet, J, Bruzzone, C, Bucksch, K, Cagnoli, G, Caldes, T, Caliebe, A, Caligo, MA, Calvello, M, Capone, GL, Caputo, SM, Carnevali, I, Carrasco, E, Caux-Moncoutier, V, Cavalli, P, Cini, G, Clarke, EM, Concolino, P, Cops, EJ, Cortesi, L, Couch, FJ, Darder, E, de la Hoya, M, Dean, M, Debatin, I, Del Valle, J, Delnatte, C, Derive, N, Diez, O, Ditsch, N, Domchek, SM, Dutrannoy, V, Eccles, DM, Ehrencrona, H, Enders, U, Evans, DG, Farra, C, Faust, U, Felbor, U, Feroce, I, Fine, M, Foulkes, WD, Galvao, HC, Gambino, G, Gehrig, A, Gensini, F, Gerdes, A-M, Germani, A, Giesecke, J, Gismondi, V, Gomez, C, Garcia, EBG, Gonzalez, S, Grau, E, Grill, S, Gross, E, Guerrieri-Gonzaga, A, Guillaud-Bataille, M, Gutierrez-Enriquez, S, Haaf, T, Hackmann, K, Hansen, TV, Harris, M, Hauke, J, Heinrich, T, Hellebrand, H, Herold, KN, Honisch, E, Horvath, J, Houdayer, C, Huebbel, V, Iglesias, S, Izquierdo, A, James, PA, Janssen, LA, Jeschke, U, Kaulfuss, S, Keupp, K, Kiechle, M, Koelbl, A, Krieger, S, Kruse, TA, Kvist, A, Lalloo, F, Larsen, M, Lattimore, VL, Lautrup, C, Ledig, S, Leinert, E, Lewis, AL, Lim, J, Loeffler, M, Lopez-Fernandez, A, Lucci-Cordisco, E, Maass, N, Manoukian, S, Marabelli, M, Matricardi, L, Meindl, A, Michelli, RD, Moghadasi, S, Moles-Fernandez, A, Montagna, M, Montalban, G, Monteiro, AN, Montes, E, Mori, L, Moserle, L, Mueller, CR, Mundhenke, C, Naldi, N, Nathanson, KL, Navarro, M, Nevanlinna, H, Nichols, CB, Niederacher, D, Nielsen, HR, Ong, K-R, Pachter, N, Palmero, E, Papi, L, Pedersen, IS, Peissel, B, Perez-Segura, P, Pfeifer, K, Pineda, M, Pohl-Rescigno, E, Poplawski, NK, Porfirio, B, Quante, AS, Ramser, J, Reis, RM, Revillion, F, Rhiem, K, Riboli, B, Ritter, J, Rivera, D, Rofes, P, Rump, A, Salinas, M, Sanchez de Abajo, AM, Schmidt, G, Schoenwiese, U, Seggewiss, J, Solanes, A, Steinemann, D, Stiller, M, Stoppa-Lyonnet, D, Sullivan, KJ, Susman, R, Sutter, C, Tavtigian, S, Teo, SH, Teule, A, Thomassen, M, Tibiletti, MG, Tischkowitz, M, Tognazzo, S, Toland, AE, Tornero, E, Torngren, T, Torres-Esquius, S, Toss, A, Trainer, AH, Tucker, KM, van Asperen, CJ, van Mackelenbergh, MT, Varesco, L, Vargas-Parra, G, Varon, R, Vega, A, Velasco, A, Vesper, A-S, Viel, A, Vreeswijk, MPG, Wagner, SA, Waha, A, Walker, LC, Walters, RJ, Wang-Gohrke, S, Weber, BHF, Weichert, W, Wieland, K, Wiesmueller, L, Witzel, I, Woeckel, A, Woodward, ER, Zachariae, S, Zampiga, V, Zeder-Goss, C, Lazaro, C, De Nicolo, A, Radice, P, Engel, C, Schmutzler, RK, Goldgar, DE, Spurdle, AB, Parsons, MT, Tudini, E, Li, H, Hahnen, E, Wappenschmidt, B, Feliubadalo, L, Aalfs, CM, Agata, S, Aittomaki, K, Alducci, E, Concepcion Alonso-Cerezo, M, Arnold, N, Auber, B, Austin, R, Azzollini, J, Balmana, J, Barbieri, E, Bartram, CR, Blanco, A, Bluemcke, B, Bonache, S, Bonanni, B, Borg, A, Bortesi, B, Brunet, J, Bruzzone, C, Bucksch, K, Cagnoli, G, Caldes, T, Caliebe, A, Caligo, MA, Calvello, M, Capone, GL, Caputo, SM, Carnevali, I, Carrasco, E, Caux-Moncoutier, V, Cavalli, P, Cini, G, Clarke, EM, Concolino, P, Cops, EJ, Cortesi, L, Couch, FJ, Darder, E, de la Hoya, M, Dean, M, Debatin, I, Del Valle, J, Delnatte, C, Derive, N, Diez, O, Ditsch, N, Domchek, SM, Dutrannoy, V, Eccles, DM, Ehrencrona, H, Enders, U, Evans, DG, Farra, C, Faust, U, Felbor, U, Feroce, I, Fine, M, Foulkes, WD, Galvao, HC, Gambino, G, Gehrig, A, Gensini, F, Gerdes, A-M, Germani, A, Giesecke, J, Gismondi, V, Gomez, C, Garcia, EBG, Gonzalez, S, Grau, E, Grill, S, Gross, E, Guerrieri-Gonzaga, A, Guillaud-Bataille, M, Gutierrez-Enriquez, S, Haaf, T, Hackmann, K, Hansen, TV, Harris, M, Hauke, J, Heinrich, T, Hellebrand, H, Herold, KN, Honisch, E, Horvath, J, Houdayer, C, Huebbel, V, Iglesias, S, Izquierdo, A, James, PA, Janssen, LA, Jeschke, U, Kaulfuss, S, Keupp, K, Kiechle, M, Koelbl, A, Krieger, S, Kruse, TA, Kvist, A, Lalloo, F, Larsen, M, Lattimore, VL, Lautrup, C, Ledig, S, Leinert, E, Lewis, AL, Lim, J, Loeffler, M, Lopez-Fernandez, A, Lucci-Cordisco, E, Maass, N, Manoukian, S, Marabelli, M, Matricardi, L, Meindl, A, Michelli, RD, Moghadasi, S, Moles-Fernandez, A, Montagna, M, Montalban, G, Monteiro, AN, Montes, E, Mori, L, Moserle, L, Mueller, CR, Mundhenke, C, Naldi, N, Nathanson, KL, Navarro, M, Nevanlinna, H, Nichols, CB, Niederacher, D, Nielsen, HR, Ong, K-R, Pachter, N, Palmero, E, Papi, L, Pedersen, IS, Peissel, B, Perez-Segura, P, Pfeifer, K, Pineda, M, Pohl-Rescigno, E, Poplawski, NK, Porfirio, B, Quante, AS, Ramser, J, Reis, RM, Revillion, F, Rhiem, K, Riboli, B, Ritter, J, Rivera, D, Rofes, P, Rump, A, Salinas, M, Sanchez de Abajo, AM, Schmidt, G, Schoenwiese, U, Seggewiss, J, Solanes, A, Steinemann, D, Stiller, M, Stoppa-Lyonnet, D, Sullivan, KJ, Susman, R, Sutter, C, Tavtigian, S, Teo, SH, Teule, A, Thomassen, M, Tibiletti, MG, Tischkowitz, M, Tognazzo, S, Toland, AE, Tornero, E, Torngren, T, Torres-Esquius, S, Toss, A, Trainer, AH, Tucker, KM, van Asperen, CJ, van Mackelenbergh, MT, Varesco, L, Vargas-Parra, G, Varon, R, Vega, A, Velasco, A, Vesper, A-S, Viel, A, Vreeswijk, MPG, Wagner, SA, Waha, A, Walker, LC, Walters, RJ, Wang-Gohrke, S, Weber, BHF, Weichert, W, Wieland, K, Wiesmueller, L, Witzel, I, Woeckel, A, Woodward, ER, Zachariae, S, Zampiga, V, Zeder-Goss, C, Lazaro, C, De Nicolo, A, Radice, P, Engel, C, Schmutzler, RK, Goldgar, DE, and Spurdle, AB

Abstract

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.

Published
2019

11. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

Author

Parsons, M. T., Tudini, E., Li, H., Hahnen, E., Wappenschmidt, B., Feliubadalo, L., Aalfs, C. M., Agata, S., Aittomaki, K., Alducci, E., Alonso-Cerezo, M. C., Arnold, N., Auber, B., Austin, R., Azzollini, J., Balmana, J., Barbieri, E., Bartram, C. R., Blanco, A., Blumcke, B., Bonache, S., Bonanni, B., Borg, A., Bortesi, B., Brunet, J., Bruzzone, C., Bucksch, K., Cagnoli, G., Caldes, T., Caliebe, A., Caligo, M. A., Calvello, M., Capone, G. L., Caputo, S. M., Carnevali, I., Carrasco, E., Caux-Moncoutier, V., Cavalli, P., Cini, G., Clarke, E. M., Concolino, Paola, Cops, E. J., Cortesi, L., Couch, F. J., Darder, E., de la Hoya, M., Dean, M., Debatin, I., Del Valle, J., Delnatte, C., Derive, N., Diez, O., Ditsch, N., Domchek, S. M., Dutrannoy, V., Eccles, D. M., Ehrencrona, H., Enders, U., Evans, D. G., Farra, C., Faust, U., Felbor, U., Feroce, I., Fine, M., Foulkes, W. D., Galvao, H. C. R., Gambino, G., Gehrig, A., Gensini, F., Gerdes, A. -M., Germani, A., Giesecke, J., Gismondi, V., Gomez, C., Gomez Garcia, E. B., Gonzalez, S., Grau, E., Grill, S., Gross, E., Guerrieri-Gonzaga, A., Guillaud-Bataille, M., Gutierrez-Enriquez, S., Haaf, T., Hackmann, K., Hansen, T. V. O., Harris, M., Hauke, J., Heinrich, T., Hellebrand, H., Herold, K. N., Honisch, E., Horvath, J., Houdayer, C., Hubbel, V., Iglesias, S., Izquierdo, A., James, P. A., Janssen, L. A. M., Jeschke, U., Kaulfuss, S., Keupp, K., Kiechle, M., Kolbl, A., Krieger, S., Kruse, T. A., Kvist, A., Lalloo, F., Larsen, M., Lattimore, V. L., Lautrup, C., Ledig, S., Leinert, E., Lewis, A. L., Lim, J., Loeffler, M., Lopez-Fernandez, A., Lucci Cordisco, Emanuela, Maass, N., Manoukian, S., Marabelli, M., Matricardi, L., Meindl, A., Michelli, R. D., Moghadasi, S., Moles-Fernandez, A., Montagna, M., Montalban, G., Monteiro, A. N., Montes, E., Mori, L., Moserle, L., Muller, C. R., Mundhenke, C., Naldi, N., Nathanson, K. L., Navarro, M., Nevanlinna, H., Nichols, C. B., Niederacher, D., Nielsen, H. R., Ong, K. -R., Pachter, N., Palmero, E. I., Papi, L., Pedersen, I. S., Peissel, B., Perez-Segura, P., Pfeifer, K., Pineda, M., Pohl-Rescigno, E., Poplawski, N. K., Porfirio, B., Quante, A. S., Ramser, J., Reis, R. M., Revillion, F., Rhiem, K., Riboli, B., Ritter, J., Rivera, D., Rofes, P., Rump, A., Salinas, M., Sanchez de Abajo, A. M., Schmidt, G., Schoenwiese, U., Seggewiss, J., Solanes, A., Steinemann, D., Stiller, M., Stoppa-Lyonnet, D., Sullivan, K. J., Susman, R., Sutter, C., Tavtigian, S. V., Teo, S. H., Teule, A., Thomassen, M., Tibiletti, M. G., Tischkowitz, M., Tognazzo, S., Toland, A. E., Tornero, E., Torngren, T., Torres-Esquius, S., Toss, A., Trainer, A. H., Tucker, K. M., van Asperen, C. J., van Mackelenbergh, M. T., Varesco, L., Vargas-Parra, G., Varon, R., Vega, A., Velasco, A., Vesper, A. -S., Viel, A., Vreeswijk, M. P. G., Wagner, S. A., Waha, A., Walker, L. C., Walters, R. J., Wang-Gohrke, S., Weber, B. H. F., Weichert, W., Wieland, K., Wiesmuller, L., Witzel, I., Wockel, A., Woodward, E. R., Zachariae, S., Zampiga, V., Zeder-Goss, C., Investigators, K., Lazaro, C., De Nicolo, A., Radice, P., Engel, C., Schmutzler, R. K., Goldgar, D. E., Spurdle, A. B., Concolino P., Lucci Cordisco E. (ORCID:0000-0002-6279-7604), Parsons, M. T., Tudini, E., Li, H., Hahnen, E., Wappenschmidt, B., Feliubadalo, L., Aalfs, C. M., Agata, S., Aittomaki, K., Alducci, E., Alonso-Cerezo, M. C., Arnold, N., Auber, B., Austin, R., Azzollini, J., Balmana, J., Barbieri, E., Bartram, C. R., Blanco, A., Blumcke, B., Bonache, S., Bonanni, B., Borg, A., Bortesi, B., Brunet, J., Bruzzone, C., Bucksch, K., Cagnoli, G., Caldes, T., Caliebe, A., Caligo, M. A., Calvello, M., Capone, G. L., Caputo, S. M., Carnevali, I., Carrasco, E., Caux-Moncoutier, V., Cavalli, P., Cini, G., Clarke, E. M., Concolino, Paola, Cops, E. J., Cortesi, L., Couch, F. J., Darder, E., de la Hoya, M., Dean, M., Debatin, I., Del Valle, J., Delnatte, C., Derive, N., Diez, O., Ditsch, N., Domchek, S. M., Dutrannoy, V., Eccles, D. M., Ehrencrona, H., Enders, U., Evans, D. G., Farra, C., Faust, U., Felbor, U., Feroce, I., Fine, M., Foulkes, W. D., Galvao, H. C. R., Gambino, G., Gehrig, A., Gensini, F., Gerdes, A. -M., Germani, A., Giesecke, J., Gismondi, V., Gomez, C., Gomez Garcia, E. B., Gonzalez, S., Grau, E., Grill, S., Gross, E., Guerrieri-Gonzaga, A., Guillaud-Bataille, M., Gutierrez-Enriquez, S., Haaf, T., Hackmann, K., Hansen, T. V. O., Harris, M., Hauke, J., Heinrich, T., Hellebrand, H., Herold, K. N., Honisch, E., Horvath, J., Houdayer, C., Hubbel, V., Iglesias, S., Izquierdo, A., James, P. A., Janssen, L. A. M., Jeschke, U., Kaulfuss, S., Keupp, K., Kiechle, M., Kolbl, A., Krieger, S., Kruse, T. A., Kvist, A., Lalloo, F., Larsen, M., Lattimore, V. L., Lautrup, C., Ledig, S., Leinert, E., Lewis, A. L., Lim, J., Loeffler, M., Lopez-Fernandez, A., Lucci Cordisco, Emanuela, Maass, N., Manoukian, S., Marabelli, M., Matricardi, L., Meindl, A., Michelli, R. D., Moghadasi, S., Moles-Fernandez, A., Montagna, M., Montalban, G., Monteiro, A. N., Montes, E., Mori, L., Moserle, L., Muller, C. R., Mundhenke, C., Naldi, N., Nathanson, K. L., Navarro, M., Nevanlinna, H., Nichols, C. B., Niederacher, D., Nielsen, H. R., Ong, K. -R., Pachter, N., Palmero, E. I., Papi, L., Pedersen, I. S., Peissel, B., Perez-Segura, P., Pfeifer, K., Pineda, M., Pohl-Rescigno, E., Poplawski, N. K., Porfirio, B., Quante, A. S., Ramser, J., Reis, R. M., Revillion, F., Rhiem, K., Riboli, B., Ritter, J., Rivera, D., Rofes, P., Rump, A., Salinas, M., Sanchez de Abajo, A. M., Schmidt, G., Schoenwiese, U., Seggewiss, J., Solanes, A., Steinemann, D., Stiller, M., Stoppa-Lyonnet, D., Sullivan, K. J., Susman, R., Sutter, C., Tavtigian, S. V., Teo, S. H., Teule, A., Thomassen, M., Tibiletti, M. G., Tischkowitz, M., Tognazzo, S., Toland, A. E., Tornero, E., Torngren, T., Torres-Esquius, S., Toss, A., Trainer, A. H., Tucker, K. M., van Asperen, C. J., van Mackelenbergh, M. T., Varesco, L., Vargas-Parra, G., Varon, R., Vega, A., Velasco, A., Vesper, A. -S., Viel, A., Vreeswijk, M. P. G., Wagner, S. A., Waha, A., Walker, L. C., Walters, R. J., Wang-Gohrke, S., Weber, B. H. F., Weichert, W., Wieland, K., Wiesmuller, L., Witzel, I., Wockel, A., Woodward, E. R., Zachariae, S., Zampiga, V., Zeder-Goss, C., Investigators, K., Lazaro, C., De Nicolo, A., Radice, P., Engel, C., Schmutzler, R. K., Goldgar, D. E., Spurdle, A. B., Concolino P., and Lucci Cordisco E. (ORCID:0000-0002-6279-7604)

Abstract

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.

Published
2019

12. Correction to: Putting genome-wide sequencing in neonates into perspective

Author

Sluijs, P.J. (Pleuntje) van der, Aten, J.A. (Jacob), Barge-Schaapveld, D.Q.C.M. (Daniela), Bijlsma, E.K. (Emilia), Bökenkamp-Gramann, R. (Regina), Donker Kaat, L. (Laura), Doorn, R. (Remco) van, Putte, D.F. (Dietje Fransen) van de, Haeringen, A. (Arie) van, Harkel, A.D.J. (Arend) ten, Hilhorst-Hofstee, Y. (Yvonne), Hoffer, M.J.V. (Mariëtte), Hollander, N.S. (Nicolette) den, Ierland, Y. (Yvette) van, Koopmans, M. (Marije), Kriek, N. (Nadia), Moghadasi, S. (Setareh), Nibbeling, E.A.R. (Esther), Peeters-Scholte, C.M.P.C.D. (Cacha), Potjer, T.P. (Thomas P.), Rij, M.C. (Maartje) van, Ruivenkamp, C.A. (Claudia), Rutten, J.W. (Julie), Steggerda, S.J. (Sylke), Suerink, M. (Manon), Tan, R.N.G.B. (Ratna), van der Tuin, K. (Karin), Visser, R. (Remco), Werf –’t Lam, A.-S. (Anne-Sophie) van der, Williams, M. (Monique), Witlox, R. (Ruben), Santen, G.W.E. (Gijs), Sluijs, P.J. (Pleuntje) van der, Aten, J.A. (Jacob), Barge-Schaapveld, D.Q.C.M. (Daniela), Bijlsma, E.K. (Emilia), Bökenkamp-Gramann, R. (Regina), Donker Kaat, L. (Laura), Doorn, R. (Remco) van, Putte, D.F. (Dietje Fransen) van de, Haeringen, A. (Arie) van, Harkel, A.D.J. (Arend) ten, Hilhorst-Hofstee, Y. (Yvonne), Hoffer, M.J.V. (Mariëtte), Hollander, N.S. (Nicolette) den, Ierland, Y. (Yvette) van, Koopmans, M. (Marije), Kriek, N. (Nadia), Moghadasi, S. (Setareh), Nibbeling, E.A.R. (Esther), Peeters-Scholte, C.M.P.C.D. (Cacha), Potjer, T.P. (Thomas P.), Rij, M.C. (Maartje) van, Ruivenkamp, C.A. (Claudia), Rutten, J.W. (Julie), Steggerda, S.J. (Sylke), Suerink, M. (Manon), Tan, R.N.G.B. (Ratna), van der Tuin, K. (Karin), Visser, R. (Remco), Werf –’t Lam, A.-S. (Anne-Sophie) van der, Williams, M. (Monique), Witlox, R. (Ruben), and Santen, G.W.E. (Gijs)

Abstract

The original version of this Article contained an error in the spelling of the author Pleuntje J. van der Sluijs, which was incorrectly given as Eline (P. J.) van der Sluijs. This has now been corrected in both the PDF and HTML versions of the Article.

Published
2018
Full Text
View/download PDF

13. Performance of BRCA1/2 mutation prediction models in male breast cancer patients

Author

Moghadasi, S, Grundeken, V, Janssen, LAM, Dijkstra, NH, Rodriguez-Girondo, M, van Zelst-Stams, W A G, Oosterwijk, JC, Ausems, M, Oldenburg, Rogier, Adank, MA (Muriel), Blom, EW, Ruijs, MWG, van Os, TAM, van Deurzen, Carolien, Martens, John, Schroder, CP, Wijnen, JT, Vreeswijk, MPG, van Asperen, CJ, Moghadasi, S, Grundeken, V, Janssen, LAM, Dijkstra, NH, Rodriguez-Girondo, M, van Zelst-Stams, W A G, Oosterwijk, JC, Ausems, M, Oldenburg, Rogier, Adank, MA (Muriel), Blom, EW, Ruijs, MWG, van Os, TAM, van Deurzen, Carolien, Martens, John, Schroder, CP, Wijnen, JT, Vreeswijk, MPG, and van Asperen, CJ

Published
2018

14. Hereditary breast cancer and the clinical significance of variants in the BRCA1 and BRCA2 genes

Author

Moghadasi, S., Asperen, C.J. van, Devilee, P., Vreeswijk, M.P.G., Baas, F., Smit, V.T.H.B.M., Eccles, D.M., Gomez Garcia, E., Rookus, M., and Leiden University

Subjects
Male_Breast_Cancer, Hereditary_breast_cancer, Multifactorial_Likelihood_Model, Variant_of_Uncertain_Significance, BRCA1, Breast_Cancer, BRCA2, VUS
Abstract

This thesis is aimed at improving the classification of the variants of uncertain clinical significance in the BRCA1/2 genes. Furthermore, it describes the optimization and standardisation of guidelines for communication of the VUS with the counselees in clinical practice.

Published
2017

15. Performance of BRCA1/2 mutation prediction models in male breast cancer patients

Author

Moghadasi, S. (Setareh), Grundeken, V. (V.), Janssen, L.A.M. (L. A.M.), Dijkstra, N.H. (N. H.), Rodríguez-Girondo, M. (M.), Zelst-Stams, W.A. van, Oosterwijk, J.C. (Jan), Ausems, M.G.E.M. (Margreet), Oldenburg, R.A. (Rogier), Adank, M.A. (Muriel), Blom, E.W. (E. W.), Ruijs, M.W.G. (Marielle), Os, T.A.M. (Theo) van, Deurzen, C.H.M. (Carolien) van, Martens, J.W.M. (John), Schroder, C.P. (C. P.), Wijnen, J.T. (Juul), Vreeswijk, M.P. (Maaike), van Asperen, C.J. (C. J.), Moghadasi, S. (Setareh), Grundeken, V. (V.), Janssen, L.A.M. (L. A.M.), Dijkstra, N.H. (N. H.), Rodríguez-Girondo, M. (M.), Zelst-Stams, W.A. van, Oosterwijk, J.C. (Jan), Ausems, M.G.E.M. (Margreet), Oldenburg, R.A. (Rogier), Adank, M.A. (Muriel), Blom, E.W. (E. W.), Ruijs, M.W.G. (Marielle), Os, T.A.M. (Theo) van, Deurzen, C.H.M. (Carolien) van, Martens, J.W.M. (John), Schroder, C.P. (C. P.), Wijnen, J.T. (Juul), Vreeswijk, M.P. (Maaike), and van Asperen, C.J. (C. J.)

Abstract

To establish whether existing mutation prediction models can identify which male breast cancer (MBC) patients should be offered BRCA1 and BRCA2 diagnostic DNA screening, we compared the performance of BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm), BRCAPRO (BRCA probability) and the Myriad prevalence table ("Myriad"). These models were evaluated using the family data of 307 Dutch MBC probands tested for BRCA1/2, 58 (19%) of whom were carriers. We compared the numbers of observed vs predicted carriers and assessed the Area Under the Receiver Operating Characteristic (ROC) Curve (AUC) for each model. BOADICEA predicted the total number of BRCA1/2 mutation carriers quite accurately (observed/predicted ratio: 0.94). When a cut-off of 10% and 20% prior probability was used, BRCAPRO showed a non-significant better performance (observed/predicted ratio BOADICEA: 0.81, 95% confidence interval [CI]: [0.60-1.09] and 0.79, 95% CI: [0.57-1.09], vs. BRCAPRO: 1.02, 95% CI: [0.75-1.38] and 0.94, 95% CI: [0.68-1.31], respectively). Myriad underestimated the number of carriers in up to 69% of the cases. BRCAPRO showed a non-significant, higher AUC than BOADICEA (0.798 vs 0.776). Myriad showed a significantly lower AUC (0.671). BRCAPRO and BOADICEA can efficiently identify MBC patients as BRCA1/2 mutation carriers. Besides their general applicability, these tools will be of particular value in countries with limited healthcare resources.

Published
2017
Full Text
View/download PDF

16. Performance of BRCA1/ 2 mutation prediction models in male breast cancer patients

Author

Moghadasi, S., primary, Grundeken, V., additional, Janssen, L.A.M., additional, Dijkstra, N.H., additional, Rodríguez-Girondo, M., additional, van Zelst-Stams, W.A.G., additional, Oosterwijk, J.C., additional, Ausems, M.G.E.M., additional, Oldenburg, R.A., additional, Adank, M.A., additional, Blom, E.W., additional, Ruijs, M.W.G., additional, van Os, T.A.M., additional, van Deurzen, C.H.M., additional, Martens, J.W.M., additional, Schroder, C.P., additional, Wijnen, J.T., additional, Vreeswijk, M.P.G., additional, and van Asperen, C.J., additional

Published
2017
Full Text
View/download PDF

20. Effects of Viral Peptide Presentation on CD4+ T Cell Responses to MHC Class II-Restricted Tumor Peptides.

Author

Shabgah, Arezoo Gowhari, Navashenaq, Jamshid Gholizadeh, Seyedzadeh, Mir Hadi, Moghadasi, S. A. Hamid, Shokri, Fazel, Razavi, Seyed Alireza, and Kardar, Gholam Ali

Subjects
ENZYME-linked immunosorbent assay, IMMUNOTHERAPY, INTERFERONS, PEPTIDES, T cells, CANCER vaccines, INDIVIDUALIZED medicine
Abstract

Background: Designing a vaccine against a defined tumor is a promising but complicated process that can be used as tumor immunotherapy. The presence of human telomerase reverse transcriptase (hTERT) has been proved in about 85% of tumors; therefore, this enzyme is a promising vaccine target. Most studies in tumor immunotherapy have focused on induction and reinforcement of CD8+ T cell responses against tumor antigens, but some evidence indicates that CD4+ T cell responses are important for induction of CD8+ Tcell response and memory. Therefore, in this in vitro study, we combined an hTERT peptide with HIV peptides restricted to HLA-DRB1*11:03/04, the most common MHC class II molecule in Iran, to induce CD4+ T cell responses in healthy individuals and lung cancer patients. Methods: Peripheral blood mononuclear cells (PBMCs) were isolated by Ficoll gradient centrifugation from nine healthy individuals and six lung cancer patients who were HLA-DRB1*11:03/04 positive. PBMCs were incubated with the tumoral and viral peptides for five days and then exposed to A549 cells to evaluate specific proliferative responses. The proliferation of PBMCs was examined by the MTT assay. Then, levels of secreted interferon-γ in culture media were analyzed by enzyme-linked immunosorbent assay (ELISA). Results: Proliferation of PBMCs was significantly greater in the presence of the tumoral peptide than in controls (P = 0.001). In addition, PBMC proliferation was greater when the viral peptides were added than with the tumoral peptide alone (P= 0.000). The IFN-γ secretion assay results supported the MTT assay (P = 0.000). Conclusions: In this study, we demonstrated that the hTERT-derived peptide induced CD4+T cell proliferation in healthy individuals and patients with lung cancer. Both PBMC proliferation and IFN-γ secretion were further induced by the addition of tumor and viral peptides in combination. [ABSTRACT FROM AUTHOR]

Published
2017
Full Text
View/download PDF

22. Downregulation of vertebrate Tel (ETV6) and Drosophila Yan is facilitated by an evolutionary conserved mechanism of F-box-mediated ubiquitination

Author

Roukens, M.G. (Guy), Alloul-Ramdhani, M. (Mariam), Moghadasi, S. (Setareh), Op den Brouw, M. (Marjolein), Baker, D.A. (David), Roukens, M.G. (Guy), Alloul-Ramdhani, M. (Mariam), Moghadasi, S. (Setareh), Op den Brouw, M. (Marjolein), and Baker, D.A. (David)

Abstract

The vertebrate Ets transcriptional repressor Tel (ETV6) and its invertebrate orthologue, Yan, are both indispensable for development, and they orchestrate cell growth and differentiation by binding to DNA, thus inhibiting gene expression. To trigger cell differentiation, these barriers to transcriptional activation must be relieved, and it is established that posttranslational modifications, such as phosphorylation and sumoylation, can specifically impair the repressive functions of Tel and Yan and are crucial for modulating their transcriptional activity. To date, however, relatively little is known about the control of Tel and Yan protein degradation. In recent years, there has been a concentrated effort to assign functions to the large number of F-box proteins encoded by both vertebrate and invertebrate genomes. Here, we report the identification and characterization of a previously unreported, evolutionarily conserved F-box protein named Fbl6. We isolated both human and Drosophila melanogaster fbl6 cDNA and show that the encoded Fbl6 protein binds to both Tel and Yan via their SAM domains. We demonstrate that both Tel and Yan are ubiquitinated, a process which is stimulated by Fbl6 and leads to proteasomal degradation. We recently established that the sumoylation of Tel on lysine 11 negatively regulates its repressive function and that the sumoylation of Tel monomers, but not that of Tel oligomers, may sensitize Tel for proteasomal degradation. Here, we found that Fbl6 regulates Tel/Yan protein stability and allows appropriate spatiotemporal control of gene expression by these repressors. Copyright

Published
2008
Full Text
View/download PDF

36. Loading bioactive peptides within different nanocarriers to enhance their functionality and bioavailability; in vitro and in vivo studies.

Author

Mazloomi N, Safari B, Can Karaca A, Karimzadeh L, Moghadasi S, Ghanbari M, Assadpour E, Sarabandi K, and Jafari SM

Subjects
Humans, Animals, Biological Availability, Peptides chemistry, Peptides pharmacology, Drug Carriers chemistry, Nanoparticles chemistry
Abstract

A hydrolyzed protein is a blend of peptides and amino acids which is the result of hydrolysis by enzymes, acids or alkalis. The Bioactive Peptides (BPs) show important biological roles including antioxidant, antimicrobial, anti-diabetic, anti-cancer, and anti-hypertensive effects, as well as positive effects on the immune, nervous, and digestive systems. Despite the benefits of BPs, challenges such as undesired organoleptic properties, solubility profile, chemical instability, and low bioavailability limit their use in functional food formulations and dietary supplements. Nanocarriers have emerged as a promising solution for overcoming these challenges by improving the stability, solubility, resistance to gastric digestion, and bioavailability, allowing for the targeted and controlled delivery, and reduction or masking of the undesirable flavor of BPs. This study reviews the recent scientific accomplishments concerning the loading of BPs into various nanocarriers including lipid, carbohydrate and protein based-nanocarriers. A special emphasis is given to their application in food formulations in accordance to the challenges associated with their use., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Published
2024
Full Text
View/download PDF

37. Environmental exposure to titanium dioxide nanoparticles disrupts DAZL gene expression and male reproductive function in mice: Protective role of lutein.

Author

Khodadadi R, Jalali A, Moghadasi S, and Farahani M

Subjects
Animals, Male, Mice, Oxidative Stress drug effects, Testosterone blood, Environmental Exposure adverse effects, Reproduction drug effects, Nanoparticles toxicity, Metal Nanoparticles toxicity, Antioxidants pharmacology, Spermatozoa drug effects, Titanium toxicity, Lutein pharmacology, Testis drug effects, Testis metabolism, RNA-Binding Proteins metabolism, RNA-Binding Proteins genetics
Abstract

Titanium dioxide nanoparticles (TiO 2 NPs) are widely used nanomaterials with potential environmental health concerns, including impacts on male fertility. This study investigated the effects of TiO 2 NPs on male reproductive function in mice and the potential protective role of lutein, a dietary antioxidant. Male NMRI mice were exposed to TiO 2 NPs (50, 150, and 300 mg/kg) with or without co-administration of lutein (5 or 10 mg/kg) for 35 days. Compared to controls, TiO 2 NP exposure significantly decreased DAZL gene expression, testosterone levels, antioxidant capacity, sperm quality (motility, density, morphology, DNA integrity), and testicular tissue parameters (seminiferous tubules volume, germinal epithelium height, spermatogenic cell counts). These effects were associated with increased oxidative stress markers (malondialdehyde levels) and altered testicular architecture (interstitial tissue volume). Notably, co-administration of lutein significantly ameliorated these TiO 2 NP-induced adverse effects, suggesting its potential protective role against testicular oxidative stress and dysfunction. Our findings highlight the potential detrimental effects of environmental TiO 2 NP exposure on male fertility and the potential benefit of dietary lutein as a protective strategy. Further research is needed to explore the underlying mechanisms and translate these findings to human health., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Published
2025
Full Text
View/download PDF

38. Comparative study of radioprotective effects of endurance training in irradiation-induced nephropathy of rat model.

Author

Parastesh M, Molavi S, and Moghadasi S

Subjects
Animals, Rats, Oxidative Stress, Antioxidants pharmacology, Endurance Training
Abstract

Objectives: Considering the antioxidant properties of endurance training, this study aimed to investigate the effects of endurance training on serum levels of oxidative stress and structural changes in the kidney tissue of rats exposed to X-ray irradiation., Methods: In this experimental study, 24 rats weighing 220±20 g were randomly divided into four groups (healthy control, healthy with moderate-intensity continuous training, X-ray control, and X-ray with moderate-intensity continuous training). The two groups of rats were irradiated with 4 Gy X-rays. The two training groups also performed moderate-intensity continuous training for 10 weeks. Twenty-four hour after the last training session, the blood serum of rats was collected and kidney tissue was isolated for stereological studies., Results: In this study, X-ray irradiation of the whole body of rats caused a significant increase in kidney volume, cortex volume, interstitial tissue volume, glomerular volume, and serum level of MDA (p≤0.05), but the medulla volume, volume of proximal tubules (total volume, volume of epithelium, and lumen), volume of distal tubules (total volume, volume of epithelium, and lumen), and the length of the proximal and distal tubules had no effect. In addition, TAC and SOD levels were significantly decreased in the radiation control group. Furthermore, performing endurance training in X-ray-irradiated rats significantly reduced kidney volume, cortex volume, glomerular volume, and serum MDA level (p≤0.05)., Conclusions: Moderate-intensity continuous training can improve the rate of destruction of kidney tissue in rats exposed to X-rays by reducing oxidative stress and subsequently increasing antioxidant capacity., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Published
2024
Full Text
View/download PDF

39. The Effects of Pifithrin-µ on Spermatogonial Stem Cell Viability and Pluripotency.

Author

Moghadasi S, Razeghian E, Shamsara M, and Heidari F

Abstract

Introduction: Spermatogonial stem cells (SSCs) offer remarkable competencies for animal reproduction and overcoming human disease as a result of their differentiation capability. We evaluated the effect of small molecule pifithrin-mu (PFT-µ), a well-known inhibitor of P53 on SSC biological processes such as viability, apoptosis, and gene expression pattern., Methods: The SSCs were isolated from the testes of adult NMRI mice and then cultured in DMEM/F12 medium containing 10% FBS. Then, they were characterized by the immunocytochemistry technique by high PLZF and low c-Kit expressions. SSC colony formation assay was carried out and their viability was estimated by methylthiazolyldiphenyl-tetrazolium bromide (MTT, or 3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2H-tetrazolium bromide) assay upon exposure to PFT-µ (0, 0.6, 1.2, 2.5, and 5 µm). The apoptosis percentages were also measured using FACS analysis, and finally, Oct4 and Stra8 expression at mRNA levels was assessed using real-time quantitative PCR., Results: The 0.6 and 1.2 µm PFT-µ improved the viability of SSC based on MTT assay results; however, 2.5 and 5 µm PFT-µ reduced SSC viability compared with the control group. Moreover, PFT-µ at lower concentrations enhanced the colony size of SSCs and diminished their apoptosis. As well, exposure to PFT-µ upregulated Oct4 expression while downregulating the meiotic entry marker, Stra8., Conclusion: Based on findings, optimized concentrations of PFT-µ can decrease SSC apoptosis, and conversely potentiate their pluripotency and self-renewal capacities in vitro., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Published
2023
Full Text
View/download PDF

41. Neurofibromas in LZTR1 schwannomatosis.

Author

Groen JL, Moghadasi S, Spruijt L, Korpershoek E, van Ierland Y, van Wezel JT, van Duinen S, Malessy MJA, and Lesnik Oberstein SAJ

Subjects
Humans, Transcription Factors, Neurilemmoma diagnosis, Neurilemmoma genetics, Neurofibromatoses diagnosis, Neurofibromatoses genetics, Skin Neoplasms diagnosis, Skin Neoplasms genetics
Published
2022
Full Text
View/download PDF

42. Case series, chemotherapy-induced cardiomyopathy: mind the family history!

Author

Moghadasi S, Fijn R, Beeres SLMA, Bikker H, Jongbloed JDH, Josephus Jitta D, Kroep JR, Lekanne Deprez RH, Vos YJ, de Vreede MJM, Antoni ML, and Barge-Schaapveld DQCM

Abstract

Background: Cardiotoxicity presenting as cardiomyopathy is a common side effect in cancer treatment especially with anthracyclines. The role of genetic predisposition is still being investigated., Case Summary: Four unrelated patients with a familial burden for cardiac disease, who developed cardiomyopathy after anthracycline treatment are presented. Case 1 received chemotherapy for breast cancer and developed a dilated left ventricle just after treatment. Her father had died unexpectedly while being screened for heart transplant. Case 2 was known with a family history of sudden cardiac death prior to her breast cancer diagnosis. She received anthracycline-containing chemotherapy treatment twice in 5 years due to recurrence of breast cancer. During that period, two brothers developed a cardiomyopathy. Eighteen years later, a genetic predisposition for cardiomyopathy was ascertained and at screening an asymptomatic non-ischaemic cardiomyopathy was established. Case 3 was diagnosed with a dilated cardiomyopathy 1 year after chemotherapy treatment for breast cancer. Her mother had developed a dilated cardiomyopathy several years before. Case 4 received chemotherapy treatment for Non-Hodgkin's lymphoma and developed dilated cardiomyopathy 1 year later. His brother died from congestive heart failure which he developed after chemotherapy for Non-Hodgkin's lymphoma and a grandmother had died suddenly during child delivery. In all four cases, genetic screening showed (likely) pathogenic variants in cardiomyopathy-associated genes., Discussion: Current guidelines recommend cardiac evaluation in cancer patients receiving chemotherapy based on the presence of cardiovascular risk factors at the start of treatment. This series emphasizes the importance of including a thorough family history in this process., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Published
2021
Full Text
View/download PDF

43. A paradigm shift in cell-free approach: the emerging role of MSCs-derived exosomes in regenerative medicine.

Author

Moghadasi S, Elveny M, Rahman HS, Suksatan W, Jalil AT, Abdelbasset WK, Yumashev AV, Shariatzadeh S, Motavalli R, Behzad F, Marofi F, Hassanzadeh A, Pathak Y, and Jarahian M

Subjects
Cell Differentiation, Humans, Regenerative Medicine, Exosomes, Mesenchymal Stem Cells, MicroRNAs
Abstract

Recently, mesenchymal stem/stromal cells (MSCs) due to their pro-angiogenic, anti-apoptotic, and immunoregulatory competencies along with fewer ethical issues are presented as a rational strategy for regenerative medicine. Current reports have signified that the pleiotropic effects of MSCs are not related to their differentiation potentials, but rather are exerted through the release of soluble paracrine molecules. Being nano-sized, non-toxic, biocompatible, barely immunogenic, and owning targeting capability and organotropism, exosomes are considered nanocarriers for their possible use in diagnosis and therapy. Exosomes convey functional molecules such as long non-coding RNAs (lncRNAs) and micro-RNAs (miRNAs), proteins (e.g., chemokine and cytokine), and lipids from MSCs to the target cells. They participate in intercellular interaction procedures and enable the repair of damaged or diseased tissues and organs. Findings have evidenced that exosomes alone are liable for the beneficial influences of MSCs in a myriad of experimental models, suggesting that MSC- exosomes can be utilized to establish a novel cell-free therapeutic strategy for the treatment of varied human disorders, encompassing myocardial infarction (MI), CNS-related disorders, musculoskeletal disorders (e.g. arthritis), kidney diseases, liver diseases, lung diseases, as well as cutaneous wounds. Importantly, compared with MSCs, MSC- exosomes serve more steady entities and reduced safety risks concerning the injection of live cells, such as microvasculature occlusion risk. In the current review, we will discuss the therapeutic potential of MSC- exosomes as an innovative approach in the context of regenerative medicine and highlight the recent knowledge on MSC- exosomes in translational medicine, focusing on in vivo researches., (© 2021. The Author(s).)

Published
2021
Full Text
View/download PDF

44. DLG4-related synaptopathy: a new rare brain disorder.

Author

Rodríguez-Palmero A, Boerrigter MM, Gómez-Andrés D, Aldinger KA, Marcos-Alcalde Í, Popp B, Everman DB, Lovgren AK, Arpin S, Bahrambeigi V, Beunders G, Bisgaard AM, Bjerregaard VA, Bruel AL, Challman TD, Cogné B, Coubes C, de Man SA, Denommé-Pichon AS, Dye TJ, Elmslie F, Feuk L, García-Miñaúr S, Gertler T, Giorgio E, Gruchy N, Haack TB, Haldeman-Englert CR, Haukanes BI, Hoyer J, Hurst ACE, Isidor B, Soller MJ, Kushary S, Kvarnung M, Landau YE, Leppig KA, Lindstrand A, Kleinendorst L, MacKenzie A, Mandrile G, Mendelsohn BA, Moghadasi S, Morton JE, Moutton S, Müller AJ, O'Leary M, Pacio-Míguez M, Palomares-Bralo M, Parikh S, Pfundt R, Pode-Shakked B, Rauch A, Repnikova E, Revah-Politi A, Ross MJ, Ruivenkamp CAL, Sarrazin E, Savatt JM, Schlüter A, Schönewolf-Greulich B, Shad Z, Shaw-Smith C, Shieh JT, Shohat M, Spranger S, Thiese H, Mau-Them FT, van Bon B, van de Burgt I, van de Laar IMBH, van Drie E, van Haelst MM, van Ravenswaaij-Arts CM, Verdura E, Vitobello A, Waldmüller S, Whiting S, Zweier C, Prada CE, de Vries BBA, Dobyns WB, Reiter SF, Gómez-Puertas P, Pujol A, and Tümer Z

Subjects
Brain, Disks Large Homolog 4 Protein genetics, Humans, Phenotype, Autism Spectrum Disorder diagnosis, Autism Spectrum Disorder genetics, Brain Diseases, Intellectual Disability, Neurodevelopmental Disorders diagnosis, Neurodevelopmental Disorders genetics
Abstract

Purpose: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants., Methods: The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing., Results: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies., Conclusion: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.

Published
2021
Full Text
View/download PDF

45. Functional Categorization of BRCA1 Variants of Uncertain Clinical Significance in Homologous Recombination Repair Complementation Assays.

Author

Bouwman P, van der Heijden I, van der Gulden H, de Bruijn R, Braspenning ME, Moghadasi S, Wessels LFA, Vreeswijk MPG, and Jonkers J

Subjects
Animals, BRCA1 Protein deficiency, Breast Neoplasms diagnosis, Breast Neoplasms epidemiology, Datasets as Topic, Female, Gene Knock-In Techniques, Genetic Counseling methods, Genetic Predisposition to Disease, Humans, Mice, Mouse Embryonic Stem Cells, Mutagenesis, Site-Directed, Mutation, Missense, Ovarian Neoplasms diagnosis, Ovarian Neoplasms epidemiology, Sensitivity and Specificity, Sequence Deletion, BRCA1 Protein genetics, Breast Neoplasms genetics, Genetic Testing methods, Ovarian Neoplasms genetics, Recombinational DNA Repair
Abstract

Purpose: Because BRCA1 is a high-risk breast/ovarian cancer susceptibility gene, BRCA1 sequence variants of uncertain clinical significance (VUS) complicate genetic counseling. As most VUS are rare, reliable classification based on clinical and genetic data is often impossible. However, all pathogenic BRCA1 variants analyzed result in defective homologous recombination DNA repair (HRR). Thus, BRCA1 VUS may be categorized based on their functional impact on this pathway., Experimental Design: Two hundred thirty-eight BRCA1 VUS-comprising most BRCA1 VUS known in the Netherlands and Belgium-were tested for their ability to complement Brca1- deficient mouse embryonic stem cells in HRR, using cisplatin and olaparib sensitivity assays and a direct repeat GFP (DR-GFP) HRR assay. Assays were validated using 25 known benign and 25 known pathogenic BRCA1 variants. For assessment of pathogenicity by a multifactorial likelihood analysis method, we collected clinical and genetic data for functionally deleterious VUS and VUS occurring in three or more families., Results: All three assays showed 100% sensitivity and specificity (95% confidence interval, 83%-100%). Out of 238 VUS, 45 showed functional defects, 26 of which were deleterious in all three assays. For 13 of these 26 variants, we could calculate the probability of pathogenicity using clinical and genetic data, resulting in the identification of 7 (likely) pathogenic variants., Conclusions: We have functionally categorized 238 BRCA1 VUS using three different HRR-related assays. Classification based on clinical and genetic data alone for a subset of these variants confirmed the high sensitivity and specificity of our functional assays., (©2020 American Association for Cancer Research.)

Published
2020
Full Text
View/download PDF

46. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification.

Author

Parsons MT, Tudini E, Li H, Hahnen E, Wappenschmidt B, Feliubadaló L, Aalfs CM, Agata S, Aittomäki K, Alducci E, Alonso-Cerezo MC, Arnold N, Auber B, Austin R, Azzollini J, Balmaña J, Barbieri E, Bartram CR, Blanco A, Blümcke B, Bonache S, Bonanni B, Borg Å, Bortesi B, Brunet J, Bruzzone C, Bucksch K, Cagnoli G, Caldés T, Caliebe A, Caligo MA, Calvello M, Capone GL, Caputo SM, Carnevali I, Carrasco E, Caux-Moncoutier V, Cavalli P, Cini G, Clarke EM, Concolino P, Cops EJ, Cortesi L, Couch FJ, Darder E, de la Hoya M, Dean M, Debatin I, Del Valle J, Delnatte C, Derive N, Diez O, Ditsch N, Domchek SM, Dutrannoy V, Eccles DM, Ehrencrona H, Enders U, Evans DG, Farra C, Faust U, Felbor U, Feroce I, Fine M, Foulkes WD, Galvao HCR, Gambino G, Gehrig A, Gensini F, Gerdes AM, Germani A, Giesecke J, Gismondi V, Gómez C, Gómez Garcia EB, González S, Grau E, Grill S, Gross E, Guerrieri-Gonzaga A, Guillaud-Bataille M, Gutiérrez-Enríquez S, Haaf T, Hackmann K, Hansen TVO, Harris M, Hauke J, Heinrich T, Hellebrand H, Herold KN, Honisch E, Horvath J, Houdayer C, Hübbel V, Iglesias S, Izquierdo A, James PA, Janssen LAM, Jeschke U, Kaulfuß S, Keupp K, Kiechle M, Kölbl A, Krieger S, Kruse TA, Kvist A, Lalloo F, Larsen M, Lattimore VL, Lautrup C, Ledig S, Leinert E, Lewis AL, Lim J, Loeffler M, López-Fernández A, Lucci-Cordisco E, Maass N, Manoukian S, Marabelli M, Matricardi L, Meindl A, Michelli RD, Moghadasi S, Moles-Fernández A, Montagna M, Montalban G, Monteiro AN, Montes E, Mori L, Moserle L, Müller CR, Mundhenke C, Naldi N, Nathanson KL, Navarro M, Nevanlinna H, Nichols CB, Niederacher D, Nielsen HR, Ong KR, Pachter N, Palmero EI, Papi L, Pedersen IS, Peissel B, Perez-Segura P, Pfeifer K, Pineda M, Pohl-Rescigno E, Poplawski NK, Porfirio B, Quante AS, Ramser J, Reis RM, Revillion F, Rhiem K, Riboli B, Ritter J, Rivera D, Rofes P, Rump A, Salinas M, Sánchez de Abajo AM, Schmidt G, Schoenwiese U, Seggewiß J, Solanes A, Steinemann D, Stiller M, Stoppa-Lyonnet D, Sullivan KJ, Susman R, Sutter C, Tavtigian SV, Teo SH, Teulé A, Thomassen M, Tibiletti MG, Tischkowitz M, Tognazzo S, Toland AE, Tornero E, Törngren T, Torres-Esquius S, Toss A, Trainer AH, Tucker KM, van Asperen CJ, van Mackelenbergh MT, Varesco L, Vargas-Parra G, Varon R, Vega A, Velasco Á, Vesper AS, Viel A, Vreeswijk MPG, Wagner SA, Waha A, Walker LC, Walters RJ, Wang-Gohrke S, Weber BHF, Weichert W, Wieland K, Wiesmüller L, Witzel I, Wöckel A, Woodward ER, Zachariae S, Zampiga V, Zeder-Göß C, Lázaro C, De Nicolo A, Radice P, Engel C, Schmutzler RK, Goldgar DE, and Spurdle AB

Subjects
Alternative Splicing, Early Detection of Cancer, Female, Genetic Predisposition to Disease, Humans, Likelihood Functions, Male, Multifactorial Inheritance, Neoplasms genetics, BRCA1 Protein genetics, BRCA2 Protein genetics, Computational Biology methods, Mutation, Missense, Neoplasms diagnosis
Abstract

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification., (© 2019 Wiley Periodicals, Inc.)

Published
2019
Full Text
View/download PDF

47. Correction: Putting genome-wide sequencing in neonates into perspective.

Author

van der Sluijs PJ, Aten E, Barge-Schaapveld DQCM, Bijlsma EK, Bökenkamp-Gramann R, Kaat LD, van Doorn R, van de Putte DF, van Haeringen A, Ten Harkel ADJ, Hilhorst-Hofstee Y, Hoffer MJV, den Hollander NS, van Ierland Y, Koopmans M, Kriek M, Moghadasi S, Nibbeling EAR, Peeters-Scholte CMPCD, Potjer TP, van Rij M, Ruivenkamp CAL, Rutten JW, Steggerda SJ, Suerink M, Tan RNGB, van der Tuin K, Visser R, van der Werf-'t Lam AS, Williams M, Witlox R, and Santen GWE

Abstract

The original version of this Article contained an error in the spelling of the author Pleuntje J. van der Sluijs, which was incorrectly given as Eline (P. J.) van der Sluijs. This has now been corrected in both the PDF and HTML versions of the Article.

Published
2019
Full Text
View/download PDF

48. Putting genome-wide sequencing in neonates into perspective.

Author

van der Sluijs PJ, Aten E, Barge-Schaapveld DQCM, Bijlsma EK, Bökenkamp-Gramann R, Donker Kaat L, van Doorn R, van de Putte DF, van Haeringen A, Ten Harkel ADJ, Hilhorst-Hofstee Y, Hoffer MJV, den Hollander NS, van Ierland Y, Koopmans M, Kriek M, Moghadasi S, Nibbeling EAR, Peeters-Scholte CMPCD, Potjer TP, van Rij M, Ruivenkamp CAL, Rutten JW, Steggerda SJ, Suerink M, Tan RNGB, van der Tuin K, Visser R, van der Werf-'t Lam AS, Williams M, Witlox R, and Santen GWE

Subjects
Chromosome Mapping methods, Exome genetics, Female, Genetic Testing economics, Genome-Wide Association Study methods, Humans, Infant, Newborn, Intensive Care, Neonatal, Male, Retrospective Studies, Exome Sequencing economics, Exome Sequencing methods, Infant, Newborn, Diseases diagnosis, Infant, Newborn, Diseases genetics
Abstract

Purpose: Several studies have reported diagnostic yields up to 57% for rapid exome or genome sequencing (rES/GS) as a single test in neonatal intensive care unit (NICU) patients, but the additional yield of rES/GS compared with other available diagnostic options still remains unquantified in this population., Methods: We retrospectively evaluated all genetic NICU consultations in a 2-year period., Results: In 132 retrospectively evaluated NICU consultations 27 of 32 diagnoses (84.4%) were made using standard genetic workup. Most diagnoses (65.6%) were made within 16 days. Diagnostic ES yield was 5/29 (17.2%). Genetic diagnoses had a direct effect on clinical management in 90.6% (29/32) of patients., Conclusions: Our study shows that exome sequencing has a place in NICU diagnostics, but given the associated costs and the high yield of alternative diagnostic strategies, we recommend to first perform clinical genetic consultation.

Published
2019
Full Text
View/download PDF

49. Substantial evidence for the clinical significance of missense variant BRCA1 c.5309G>T p.(Gly1770Val).

Author

Tudini E, Moghadasi S, Parsons MT, van der Kolk L, van den Ouweland AMW, Niederacher D, Feliubadaló L, Wappenschmidt B, Spurdle AB, and Lazaro C

Subjects
Animals, Bayes Theorem, Breast Neoplasms pathology, Conserved Sequence, DNA Repair genetics, Female, Humans, Mice, Mutation, Missense genetics, Sequence Alignment, BRCA1 Protein genetics, Breast Neoplasms genetics, Evolution, Molecular, Genetic Predisposition to Disease
Abstract

Purpose: Classification of rare BRCA1 missense variants presents a major challenge for the counseling and treatment of patients. Variant classification can be complicated by conflicting lines of evidence. BRCA1 c.5309G>T p.(Gly1770Val) has been shown to abrogate BRCA1 protein homologous DNA repair; however, multiple sequence alignment demonstrates a lack of sequence conservation at this position, suggesting that glycine at position 1770 may not be essential for cellular maintenance in humans. We analyzed clinical information to resolve the classification of BRCA1 c.5309G>T p.(Gly1770Val)., Methods: We performed multifactorial likelihood analysis combining segregation data for 14 informative families, and breast tumor histopathological data for 17 variant carriers, ascertained through the ENIGMA consortium., Results: Bayes segregation analysis gave a likelihood ratio of 101:1 in favor of pathogenicity. The vast majority of breast tumors showed features indicative of pathogenic variant carrier status, resulting in a likelihood ratio of 15800794:1 towards pathogenicity. Despite a low prior probability of pathogenicity (0.03) based on bioinformatic prediction, multifactorial likelihood analysis including segregation and histopathology analysis gave a posterior probability of > 0.99 and final classification of Pathogenic., Conclusions: We provide evidence that BRCA1 c.5309G>T p.(Gly1770Val), previously described as a Moroccan founder variant, should be treated as a disease-causing variant despite a lack of evolutionary conservation at this amino acid position. Additionally, we stress that bioinformatic information should be used in combination with other data, either direct clinical evidence or some form of clinical calibration, to arrive at a final clinical classification.

Published
2018
Full Text
View/download PDF

50. The BRCA1 c. 5096G>A p.Arg1699Gln (R1699Q) intermediate risk variant: breast and ovarian cancer risk estimation and recommendations for clinical management from the ENIGMA consortium.

Author

Moghadasi S, Meeks HD, Vreeswijk MP, Janssen LA, Borg Å, Ehrencrona H, Paulsson-Karlsson Y, Wappenschmidt B, Engel C, Gehrig A, Arnold N, Hansen TVO, Thomassen M, Jensen UB, Kruse TA, Ejlertsen B, Gerdes AM, Pedersen IS, Caputo SM, Couch F, Hallberg EJ, van den Ouweland AM, Collée MJ, Teugels E, Adank MA, van der Luijt RB, Mensenkamp AR, Oosterwijk JC, Blok MJ, Janin N, Claes KB, Tucker K, Viassolo V, Toland AE, Eccles DE, Devilee P, Van Asperen CJ, Spurdle AB, Goldgar DE, and García EG

Subjects
Chromosome Segregation, Female, Humans, Risk Factors, BRCA1 Protein genetics, Breast Neoplasms genetics, Genetic Predisposition to Disease, Mutation genetics, Ovarian Neoplasms genetics
Abstract

Background: We previously showed that the BRCA1 variant c.5096G>A p.Arg1699Gln (R1699Q) was associated with an intermediate risk of breast cancer (BC) and ovarian cancer (OC). This study aimed to assess these cancer risks for R1699Q carriers in a larger cohort, including follow-up of previously studied families, to further define cancer risks and to propose adjusted clinical management of female BRCA1 *R1699Q carriers., Methods: Data were collected from 129 BRCA1 *R1699Q families ascertained internationally by ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) consortium members. A modified segregation analysis was used to calculate BC and OC risks. Relative risks were calculated under both monogenic model and major gene plus polygenic model assumptions., Results: In this cohort the cumulative risk of BC and OC by age 70 years was 20% and 6%, respectively. The relative risk for developing cancer was higher when using a model that included the effects of both the R1699Q variant and a residual polygenic component compared with monogenic model (for BC 3.67 vs 2.83, and for OC 6.41 vs 5.83)., Conclusion: Our results confirm that BRCA1 *R1699Q confers an intermediate risk for BC and OC. Breast surveillance for female carriers based on mammogram annually from age 40 is advised. Bilateral salpingo-oophorectomy should be considered based on family history., Competing Interests: Competing interests: EGG has received an honorarium in the past 3 years from AstraZeneca for giving a course and a lecture. HE (or rather, his department with him as primary contact) has received funding from Novartis Oncology (unrestricted grant) and AstraZeneca (invited speaker). KT has received an honorarium for chairing a mainstreaming genetic testing subcommittee and day seminar for AstraZeneca. AET declares to have received an honorarium from American Cancer Society for grant review, NIH NCI PDQ as editorial board, Italian Ministry of Health for grant review. DEE receives an honorarium from AstraZeneca via a contract with the university to provide consultancy advice from time to time (one or two advisory boards each year on average at the moment). DEG has received royalties from patents on the BRCA1 and BRCA2 genes from the University of Utah that are licensed to Myriad Genetics. All the other authors declare to have no conflicts of interest., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Published
2018
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results