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4. 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

5. 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

6. 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

8. Beyond CHEK2 in breast cancer: Search for additional moderately penetrant risk gene variants by analyzing the oligogenic disease course in CHEK2 mutation carriers

Author

Pohl, E., Borde, J., Hauke, J., Schmidt, S., Weber-Lassalle, K., Ernst, C., Niederacher, D., Arnold, N., Hellebrand, H., Meindl, A., Gehrig, A., Schmidt, G., Dutrannoy, V., Kast, K., Hahnen, E., Schmutzler, R., Pohl, E., Borde, J., Hauke, J., Schmidt, S., Weber-Lassalle, K., Ernst, C., Niederacher, D., Arnold, N., Hellebrand, H., Meindl, A., Gehrig, A., Schmidt, G., Dutrannoy, V., Kast, K., Hahnen, E., and Schmutzler, R.

Published
2018

9. Sicherung von Dämmen, Deichen und Stauanlagen : Handbuch für Theorie und Praxis ; Vol. V - 2015

Author

Sørensen, Carlo, Brandl, H., Szabo, M., Stamm, Jürgen, Heyer, Torsten, Koppe, Bärbel, Massolle, Christopher, Krebs, Armin, Daedler, Karsten, Neisser, Reinhold, Haufe, Holger, Krüger, Marc, Johann, Georg, Pohl, Christian, Heinrich, Martin, Hellebrand, H., Müller, C., Kneisel, C., Kreiter, T., Döring, Mathias, Düser, Olaf, Kisse, Aloys, Ellebracht, Martin, Mayor, Pierre A., Carstensen, D., Heß, M., Vollweiler, T., Brünkmann, R., Bielitz, E., Amani, E., Hering, F., Huber, Maximilian, Teixeira, Ana, Schweckendiek, Timo, Horst, Wouter ter, Wojciechowska, Karolina, Wöffler, Theide, Matelski, Birgit, Jensen, Frerk, Jensen, Jürgen, Schüttrumpf, Holger, Laursen, Charlotte, Kayser, Jan, Keßel, Marie-Therese van, Slomp, Robert, Knoeff, Han, Guo, Jinxing, Graeber, Peter-Wolfgang, Schmidt, J., Wieland, J., Findeisen, B., Schröder, Jan, Förster, Ulrich, Bezuijen, Adam, Arndt, Michael, Di Pietro, Paolo, Sänger, Franz, Seidl, M., Herrmann, Richard A., Löwen, Martin, Dräger, Elmar, Weiz, Thomas, Heide, Uwe, and Herrmann, Richard A. (Hrsg.)

Subjects
aktuelle Erfahrungsberichte, Flussdeiche, Talsperren, Bemessungsmodelle, Civil engineering, ddc:624
Abstract

Die Universität Siegen beschäftigt sich seit über 15 Jahren wissenschaftlich und im Bereich der anwendungsorientierten Forschung mit diesem Thema und hat dazu mittlerweile fünf Symposien durchgeführt. Mit der Veröffentlichung soll die langjährige Tradition als etablierte wissenschaftliche Plattform mit einem Wissensaustausch auf europäischer Ebene fortgesetzt werden. Die Bearbeitung dieser Thematik erfolgt auf der Basis der bewährten Kooperation zwischen Geotechnik und Wasserbau an der Universität Siegen. Aktuelle Ereignisse, wie z.B. die aus England oder Australien im Februar des Jahres 2014, machen uns aber auch deutlich, dass ein absoluter Schutz gegen Extremereignisse nicht möglich ist. Sie zeigen aber auch, dass dort wo technischer Hochwasserschutz konsequent umgesetzt wurde Schäden vermieden werden konnten. Wir sind nach den Ereignissen in den vergangenen Jahren aufgefordert wissenschaftlich noch leistungsfähigere und duktilere Systeme zu entwickeln. Weiter ist die Wissenschaft in der Pflicht, die Zivile Sicherheit im Hochwasser-schutz permanent zu bewerten, zu bearbeiten und ganzheitliche-interdisziplinäre und länderübergreifende Lösungen für die Zivilgesellschaft einzufordern.

Published
2016

10. Compelling evidence for FANCM as a breast cancer susceptibility gene

Author

Neidhardt, G., Hauke, J., Heilmann, S., Hellebrand, H., Surowy, H. M., Klaschik, K., Honisch, E., Gehrig, A., Sutter, C., Rump, A., Bogdanova-Markov, N., Bugert, P., Mangold, E., Steinemann, D., Ramirez, A., Ditsch, N., Arnold, N., Niederacher, D., Burwinkel, B., Thiele, H., Altmueller, I., Nuernberg, P., Engel, C., Wappenschmidt, B., Rhiem, K., Meindl, A., Schmutzler, R. K., Hahnen, E., Neidhardt, G., Hauke, J., Heilmann, S., Hellebrand, H., Surowy, H. M., Klaschik, K., Honisch, E., Gehrig, A., Sutter, C., Rump, A., Bogdanova-Markov, N., Bugert, P., Mangold, E., Steinemann, D., Ramirez, A., Ditsch, N., Arnold, N., Niederacher, D., Burwinkel, B., Thiele, H., Altmueller, I., Nuernberg, P., Engel, C., Wappenschmidt, B., Rhiem, K., Meindl, A., Schmutzler, R. K., and Hahnen, E.

Published
2016

11. Assessing winter storm flow generation by means of permeability of the lithology and hydrological soil processes

Author

Hellebrand, H., Hoffmann, L., Juilleret, J., Pfister, L., and EGU, Publication

Subjects
[SDU.OCEAN] Sciences of the Universe [physics]/Ocean, Atmosphere, [SDU.STU] Sciences of the Universe [physics]/Earth Sciences, [SDU.ENVI] Sciences of the Universe [physics]/Continental interfaces, environment
Abstract

In this study two approaches are used to predict winter storm flow coefficients in meso-scale basins (10 km2 to 1000 km2) with a view to regionalization. The winter storm flow coefficient corresponds to the ratio between rainfall and direct discharge caused by this rainfall. It is basin specific and supposed to give an integrated response to rainfall. The two approaches, which used the permeability of the substratum and soil hydrological processes as basin attributes are compared. The study area is the Rhineland Palatinate and the Grand Duchy of Luxembourg and the study focuses on the Nahe basin and its 16 sub-basins (Rhineland Palatinate). For the comparison, three statistical models were derived by means of regression analysis. The models used the winter storm flow coefficient as the dependent variable in the models; the independent variables were the permeability of the substratum, preliminary derived hydrological soil processes and a combination of both. It is assumed that the permeability and the preliminary derived hydrological soil processes carry different layers of information. Cross-validation and a statistical test were used to determine and evaluate model differences. The cross-validation resulted in a best model performance for the model that used both parameters, followed by the model that used the preliminary hydrological soil processes. From the statistical test it was concluded that the models come from different populations, carrying different information layers. Analysis of the residuals of the models indicated that the permeability and hydrological soil processes did provide complementary information. Simple linear models appeared to perform well in describing the winter storm flow coefficient at the meso-scale when a combination of the permeability of the substratum and soil hydrological processes served as independent parameters.

Published
2007
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13. Chronic recurrent multifocal osteomyelitis (CRMO) : Evidence for a susceptibility gene located on chromosome 18q21.3-18q22

Author

Golla, A., Jansson, A., Ramser, J., Hellebrand, H., Zahn, R., Meitinger, T., Belohradsky, B.H., and Meindl, A.

Subjects
CRMO chronic recurrent multifocal osteomyelitis family based association study D18S60 genetic basis
Abstract

Chronic recurrent multifocal osteomyelitis (CRMO) is characterised by recurrent inflammatory lesions in the metaphyses of long bones and usually affects children and adolescents. Similarity with an autosomal recessive mouse disorder (cmo, chronic multifocal osteomyelitis) prompted us to perform a family based association study with two markers on chromosome 18q in the region homologous to the cmo localisation of the mouse. We found a significant association of CRMO with a rare allele of marker D18S60, resulting in a haplotype relative risk (HRR) of 18. This suggests the existence of a gene in this region contributing in a significant manner to the aetiology of CRMO and concomitantly demonstrates evidence for a genetic basis of CRMO for the first time. This gene is different from RANK, which is mutated in familial expansile osteolysis (FEO), but not in CRMO. Mutation screening in RANK and the genes PIGN and KIAA1468 led to detection of two variants (one in RANK and one in PIGN), which are in linkage disequilibrium with the rare D18S60 allele, but not independently associated with CRMO.

Published
2002

14. Identification and regionalization of dominant runoff processes – a GIS-based and a statistical approach

Author

Müller, C. (author), Hellebrand, H. (author), Seeger, M. (author), Schobel, S. (author), Müller, C. (author), Hellebrand, H. (author), Seeger, M. (author), and Schobel, S. (author)

Abstract

In this study two approaches are presented to identify Dominant Runoff Processes (DRP) with respect to regionalization. The approaches are a simplification of an existing method to determine DRP by means of an extensive field campaign. The first approach combines the permeability of the substratum, land-use and slope of the basin in a GIS-based analysis. The second approach makes use of discriminant analysis of the physiographic characteristics of the basin and links it to the GIS analysis. The results of the developed approaches are maps, which identify dominant runoff processes and represent a spatial distribution of the hydrological behaviour of the soil during prolonged rainfall events. The approaches have been developed in a micro-scale basin (Germany). An additional meso-scale basin was introduced in which the two approaches were applied for quality control. The thus generated maps for the micro-scale basin were compared with an existing DRP map, which was derived with the existing method. The first approach showed a resemblance of 79% when compared to this map, whereas the second approach showed only a resemblance of 51%. The generated maps for the meso-scale basin were compared to DRP that were determined point wise according to the existing method. The first approach showed in this case a resemblance of 81%, whereas the second approach showed a resemblance of 68%. Therefore, the first approach is preferred to the second approach when accuracy, data input and calculation time are concerned., Watermanagement, Civil Engineering and Geosciences

Published
2009

15. Identification and regionalization of dominant runoff processes - a GIS-based and a statistical approach

Author

Müller, C., Hellebrand, H., Seeger, K.M., Schobel, S., Müller, C., Hellebrand, H., Seeger, K.M., and Schobel, S.

Abstract

In this study two approaches are presented to identify Dominant Runoff Processes (DRP) with respect to regionalization. The approaches are a simplification of an existing method to determine DRP by means of an extensive field campaign. The first approach combines the permeability of the substratum, land-use and slope of the basin in a GIS-based analysis. The second approach makes use of discriminant analysis of the physiographic characteristics of the basin and links it to the GIS analysis. The results of the developed approaches are maps, which identify dominant runoff processes and represent a spatial distribution of the hydrological behaviour of the soil during prolonged rainfall events. The approaches have been developed in a micro-scale basin (Germany). An additional meso-scale basin was introduced in which the two approaches were applied for quality control. The thus generated maps for the micro-scale basin were compared with an existing DRP map, which was derived with the existing method. The first approach showed a resemblance of 79% when compared to this map, whereas the second approach showed only a resemblance of 51%. The generated maps for the meso-scale basin were compared to DRP that were determined point wise according to the existing method. The first approach showed in this case a resemblance of 81%, whereas the second approach showed a resemblance of 68%. Therefore, the first approach is preferred to the second approach when accuracy, data input and calculation time are concerned

Published
2009

16. Spatio-temporal variability of behavioral patterns in hydrology in meso-scale basins of the Rhineland Palatinate (1972–2002)

Author

Hellebrand, H. (author), Van den Bos, R. (author), Hoffmann, L. (author), Juilleret, J. (author), Krein, A. (author), Pfister, L. (author), Hellebrand, H. (author), Van den Bos, R. (author), Hoffmann, L. (author), Juilleret, J. (author), Krein, A. (author), and Pfister, L. (author)

Abstract

Changes in spatio-temporal rainfall patterns have an effect on the hydrological behavior of river basins, the magnitude of the effects depending among others on the physiographic basin characteristics. To assess climate and discharge fluctuations, a visualization tool was developed as a contribution to exploratory data analysis. The tool combined statistical tests of hydro-climatological variables with physiographic basin characteristics. Test results agree with previous studies and suggested a relationship between rainfall, discharge and mean date of the annual maximum discharge on the one the hand and lithology, altitude and west to east positioning of the basins on the other hand. The visualization tool capable of combining the statistical test results with the geologic and topographic configuration of the study area and allowed a reflection on the hydro-climatological as well as spatio-temporal behavior of meso-scale basins by means of exploratory data analysis., Watermanagement, Civil Engineering and Geosciences

Published
2008
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28. Regensburg 1998: Gravitation und Relativitätstheorie/Theoretische und Mathematische Grundlagen der Physik/Umweltphysik/Agrar- und Ökosystemphysik/Strahlenphysik und Strahlenwirkung/Fachsitzung “Abrüstung und Verifikation”/Didaktik der Physik/Lehrertag/Ber

Author

Kiefer, C., primary, Fredenhagen, K., additional, Roether, W., additional, Hellebrand, H. J., additional, Kiefer, J., additional, Neuneck, G., additional, Scheffran, J., additional, Schlichting, H. J., additional, Nestle, N., additional, Risch, L., additional, and Luther, J., additional

Published
1998
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30. A gene (RPGR) with homology to the RCC1 guanine nucleotide exchange factor is mutated in X–linked retinitis pigmentosa (RP3)

Author

Meindl, A., primary, Dry, K., additional, Herrmann, K., additional, Manson, E., additional, Ciccodicola, A., additional, Edgar, A., additional, Carvalho, M.R.S., additional, Achatz, H., additional, Hellebrand, H., additional, Lennon, A., additional, Migliaccio, C., additional, Porter, K., additional, Zrenner, E., additional, Bird, A., additional, Jay, M., additional, Lorenz, B., additional, Wittwer, B., additional, D'Urso, M., additional, Meitinger, T., additional, and Wright, A., additional

Published
1996
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33. Modelling dominant runoff production processes at the micro-scale — a GIS-based and a statistical approach.

Author

Müller, C., Hellebrand, H., Seeger, M., and Schobel, S.

Abstract

In this study two approaches are presented to model Dominant Runoff production Processes (DRP) with respect to regionalization. The approaches have been developed in the micro-scale experimental Zemmer basin (Germany). The first approach combines the permeability of the substratum, land-use and slope of the basin in a GIS-based analysis. The second approach makes use of discriminant analysis of the physiographic characteristics of the basin and links it to the GIS analysis. The net results were two maps indicating modelled DRP for the Zemmer basin, which were then compared to an existing DRP map of the Zemmer basin. Both approaches provided satisfactory results when compared to this existing DRP map. The first approach was strongly linked to the geological conditions of the basin while the second approach revealed a strong dependence on the topography. Therefore, impermeability of the substratum and the topography of the basin were used as suitable parameters for modelling dominant runoff processes. [ABSTRACT FROM AUTHOR]

Published
2008

34. Carbon Monoxide from Composting due to Thermal Oxidation of Biomass.

Author

Hellebrand, H. J. and Schade, G. W.

Subjects
CARBON monoxide, EMISSIONS (Air pollution), COMPOSTING, ORGANIC wastes, ANIMAL waste, PLANT litter, THERMOCHEMISTRY, AIR quality
Abstract

This paper discusses the emissions of carbon monoxide from compost. The authors measured air from a compost heap, leaf litter pile air samples and emissions from livestock waste compost at a farm. They included hay samples of fixed moisture content using a temperature and ventilation controlled substrate container to investigate the origin of the carbon monoxide emissions. According to the authors, the analysis resulted in activation energies for thermochemically produced carbon monoxide from the compost substrates. They concluded that carbon monoxide emissions could affect local air quality.

Published
2008
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36. Ergebnisse aus gefassversuchen mit graskomposten und messungen von gasemissionen aus einer graskompostanlage

Author

Leipnitz, W., Hellebrand, H. J., and Haus, R.

Abstract

In den Jahren von 1993 bis 1995 wurde die Wirkung verschiedener Graskomposte auf den Haferertrag (oberirdische Masse und Wurzeln) in Mitscherlich-Gefassen gepruft. Schwerpunkte waren: gemahlener gegenuber ungemahlenem Kompost, verschiedene Zusatze wie Muttererde, Stalldung, Laub, Aste und Nahrlosungen. Ab 1994 wurde zusatzlich eine Kompostprobe der Berliner Stadtreinigungsbetriebe zum Vergleich untersucht. Kompost von auszuhagernden Wiesen enthalt keine Schadstoffe und kann unbedenklich eigesetzt werden. Signifikant gesicherte Minderertrage hatten die gemahlenen Kompostvarianten. Graskompost ersetzt die Wirkung von P und K. Das Kompostgut mit einem Stickstoffdunger anzureichern, wird empfohlen. Im Jahre 1994 wurden Gasemissionen bei Ammoniak (NH3), Lachgas (N2O), Methan (CH4) und Kohlendioxid (CO2) in verschiedenen Schichten der Varianten Gras und Muttererde sowie Gras und Stalldung der Versuchskompostanlage gemessen.

Published
1996
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38. Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance

Author

Ingo Meuthen, Janet Kerwin, Teresa de Berardinis, Alfons Meindl, Costantino Schiavi, Robyn V. Jamieson, Christina Pieh, Hagit N. Baris, Bettina Wabbels, Feray Koc, Wei He, Scott L. Pomeroy, Maree Flaherty, Joseph L. Demer, David A. Mackey, Emin Cumhur Sener, Jonathan B Ruddle, Lionel Van Maldergem, Louise J. Sabol, Susan Lindsay, Nicolas Uzcategui, Irene Gottlob, David F. Callen, Max A. Tischfield, Richard L. Robertson, Clara E. de Uzcategui, Thomas D. Bird, Janet S. Soul, Alex V. Levin, Marco Pastore-Trossello, Thomas Meitinger, Hans Ulrik Møller, Elizabeth C. Engle, Mary Louise Z. Collins, David G. Hunter, Maria Descartes, Edward J. Doherty, Mohan L. Gupta, Adriano Magli, Agnes M. F. Wong, Caroline Andrews, Chen Wu, Elias I. Traboulsi, Wai-Man Chan, Michael T. Geraghty, David Pellman, Anna Newlin, G. Rudolph, Heide Hellebrand, USA, M. A. TISCHFIELD, H. N. BARIS, C. WU, G. RUDOLPH, L. VAN MALDERGEM, W. HE, WAI-MAN CHAN, C. ANDREWS, J. L. DEMER, R. L. ROBERTSON, D. A. MACKEY, J. B. RUDDLE, T. D. BIRD, I. GOTTLOB, C. PIEH, E. TRABOULSI, S. POMEROY, D. HUNTER, J. S. SOUL, A. NEWLIN, L. J. SABOL, E. J. DOHERTY, C. E. DE UZCATEGUI, N. DE UZCATEGUI, M. L. Z. COLLINS, E. C. SENER, B. WABBELS, H. HELLEBRAND, T. MEITINGER, T. DE BERARDINIS, A. MAGLI, C. SCHIAVI, M. PASTORE-TROSSELLO, F. KOC, A. M. WONG, A. L. LEVIN, M. T. GERAGHTY, M. DESCARTES, M. FLAHERTY, R. V. JAMIESON, H. U. MOELLER, I. MEUTHEN, D. F. CALLEN, J. KERWIN, S. LINDSAY, A. MEINDLI, M.L. GUPTA Jr, D. PELLMAN, E. C. ENGLE, Acibadem University Dspace, Tischfield, Ma, Baris, Hn, Wu, C, Rudolph, G, Van Maldergem, L, He, W, Chan, Wm, Andrews, C, Demer, Jl, Robertson, Rl, Mackey, Da, Ruddle, Jb, Bird, Td, Gottlob, I, Pieh, C, Traboulsi, Ei, Pomeroy, Sl, Hunter, Dg, Soul, J, Newlin, A, Sabol, Lj, Doherty, Ej, de Uzcátegui, Ce, de Uzcátegui, N, Collins, Ml, Sener, Ec, Wabbels, B, Hellebrand, H, Meitinger, T, DE BERARDINIS, Teresa, Magli, Adriano, Schiavi, C, Pastore Trossello, M, Koc, F, Wong, Am, Levin, Av, Geraghty, Mt, Descartes, M, Flaherty, M, Jamieson, Rv, Møller, Hu, Meuthen, I, Callen, Df, Kerwin, J, Lindsay, S, Meindl, A, Gupta ML, Jr, Pellman, D, and Engle, E. C.

Subjects
Male, Models, Molecular, Nervous system, Cell Survival, Developmental Disabilities, Molecular Sequence Data, Mutation, Missense, HUMDISEASE, Kinesins, Anterior commissure, Biology, medicine.disease_cause, Microtubules, MOLNEURO, General Biochemistry, Genetics and Molecular Biology, Mice, Tubulin, Microtubule, medicine, Animals, Humans, Missense mutation, Amino Acid Sequence, Child, Genetics, Mutation, Biochemistry, Genetics and Molecular Biology(all), Brain, Axons, extraocular muscles, Mice, Inbred C57BL, Protein Transport, medicine.anatomical_structure, biology.protein, TUBB3 syndrome, Kinesin, Female, CELLBIO, Axon guidance, CFEOM3, Neuroscience
Abstract

none 49 We report that eight heterozygous missense mutations in TUBB3, encoding the neuron-specific beta-tubulin isotype III, result in a spectrum of human nervous system disorders that we now call the TUBB3 syndromes. Each mutation causes the ocular motility disorder CFEOM3, whereas some also result in intellectual and behavioral impairments, facial paralysis, and/or later-onset axonal sensorimotor polyneuropathy. Neuroimaging reveals a spectrum of abnormalities including hypoplasia of oculomotor nerves and dysgenesis of the corpus callosum, anterior commissure, and corticospinal tracts. A knock-in disease mouse model reveals axon guidance defects without evidence of cortical cell migration abnormalities. We show that the disease-associated mutations can impair tubulin heterodimer formation in vitro, although folded mutant heterodimers can still polymerize into microtubules. Modeling each mutation in yeast tubulin demonstrates that all alter dynamic instability whereas a subset disrupts the interaction of microtubules with kinesin motors. These findings demonstrate that normal TUBB3 is required for axon guidance and maintenance in mammals. none M. A. TISCHFIELD; H. N. BARIS; C. WU; G. RUDOLPH; L. VAN MALDERGEM; W. HE; WAI-MAN CHAN; C. ANDREWS; J. L. DEMER; R. L. ROBERTSON; D. A. MACKEY; J. B. RUDDLE; T. D. BIRD; I. GOTTLOB; C. PIEH; E. TRABOULSI; S. POMEROY; D. HUNTER; J. S. SOUL; A. NEWLIN; L. J. SABOL; E. J. DOHERTY; C. E. DE UZCATEGUI; N. DE UZCATEGUI; M. L. Z. COLLINS; E. C. SENER; B. WABBELS; H. HELLEBRAND; T. MEITINGER; T. DE BERARDINIS; A. MAGLI; C. SCHIAVI; M. PASTORE-TROSSELLO; F. KOC; A. M. WONG; A. L. LEVIN; M. T. GERAGHTY; M. DESCARTES; M. FLAHERTY; R. V. JAMIESON; H. U. MOELLER; I. MEUTHEN; D. F. CALLEN; J. KERWIN; S. LINDSAY; A. MEINDLI; M.L. GUPTA Jr; D. PELLMAN; E. C. ENGLE M. A. TISCHFIELD; H. N. BARIS; C. WU; G. RUDOLPH; L. VAN MALDERGEM; W. HE; WAI-MAN CHAN; C. ANDREWS; J. L. DEMER; R. L. ROBERTSON; D. A. MACKEY; J. B. RUDDLE; T. D. BIRD; I. GOTTLOB; C. PIEH; E. TRABOULSI; S. POMEROY; D. HUNTER; J. S. SOUL; A. NEWLIN; L. J. SABOL; E. J. DOHERTY; C. E. DE UZCATEGUI; N. DE UZCATEGUI; M. L. Z. COLLINS; E. C. SENER; B. WABBELS; H. HELLEBRAND; T. MEITINGER; T. DE BERARDINIS; A. MAGLI; C. SCHIAVI; M. PASTORE-TROSSELLO; F. KOC; A. M. WONG; A. L. LEVIN; M. T. GERAGHTY; M. DESCARTES; M. FLAHERTY; R. V. JAMIESON; H. U. MOELLER; I. MEUTHEN; D. F. CALLEN; J. KERWIN; S. LINDSAY; A. MEINDLI; M.L. GUPTA Jr; D. PELLMAN; E. C. ENGLE

Published
2010

39. TP53 germline mutations in the context of families with hereditary breast and ovarian cancer: a clinical challenge.

Author

Grill S, Ramser J, Hellebrand H, Pfarr N, Boxberg M, Brambs C, Ditsch N, Meindl A, Groß E, Meitinger T, Kiechle M, and Quante AS

Subjects
Female, Genetic Predisposition to Disease, Germ-Line Mutation, Humans, Middle Aged, Breast Neoplasms genetics, Li-Fraumeni Syndrome genetics, Ovarian Neoplasms genetics, Tumor Suppressor Protein p53 genetics
Abstract

Purpose: TP53germline (g) mutations, associated with the Li-Fraumeni syndrome (LFS), have rarely been reported in the context of hereditary breast and ovarian cancer (HBOC). The prevalence and cancer risks in this target group are unknown and counseling remains challenging. Notably an extensive high-risk surveillance program is implemented, which evokes substantial psychological discomfort. Emphasizing the lack of consensus about clinical implications, we aim to further characterize TP53g mutations in HBOC families., Methods: Next-generation sequencing was conducted on 1876 breast cancer (BC) patients who fulfilled the inclusion criteria for HBOC., Results: (Likely) pathogenic variants in TP53 gene were present in 0.6% of the BC cohort with higher occurrence in early onset BC < 36 years. (1.1%) and bilateral vs. unilateral BC (1.1% vs. 0.3%). Two out of eleven patients with a (likely) pathogenic TP53g variant (c.542G > A; c.375G > A) did not comply with classic LFS/Chompret criteria. Albeit located in the DNA-binding domain of the p53-protein and therefore revealing no difference to LFS-related variants, they only displayed a medium transactivity reduction constituting a retainment of wildtype-like anti-proliferative functionality., Conclusion: Among our cohort of HBOC families, we were able to describe a clinical subgroup, which is distinct from the classic LFS-families. Strikingly, two families did not adhere to the LFS criteria, and functional analysis revealed a reduced impact on TP53 activity, which may suit to the attenuated phenotype. This is an approach that could be useful in developing individualized screening efforts for TP53g mutation carrier in HBOC families. Due to the low incidence, national/international cooperation is necessary to further explore clinical implications. This might allow providing directions for clinical recommendations in the future.

Published
2021
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40. 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
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41. The RAD51C exonic splice-site mutations c.404G>C and c.404G>T are associated with familial breast and ovarian cancer.

Author

Neidhardt G, Becker A, Hauke J, Horváth J, Bogdanova Markov N, Heilmann-Heimbach S, Hellebrand H, Thiele H, Altmüller J, Nürnberg P, Meindl A, Rhiem K, Blümcke B, Wappenschmidt B, Schmutzler RK, and Hahnen E

Subjects
Breast Neoplasms diagnosis, DNA-Binding Proteins, Exons, Female, Humans, Ovarian Neoplasms diagnosis, Pedigree, Breast Neoplasms genetics, Genetic Predisposition to Disease, Mutation, Ovarian Neoplasms genetics
Abstract

Whereas RAD51C mutations increase the relative risk for ovarian cancer (OC) to 5.88 (95% confidence interval=2.91-11.88, P=7.65×10), the associated risks for breast cancer (BC) remain largely unknown, as deleterious RAD51C alterations are extremely rare in BC-only families. Here, we report the results of a RAD51C mutational screening in a large series of German familial index patients negative for pathogenic BRCA1/2 mutations and the in-vitro characterization of two novel exonic RAD51C splice-site mutations. A total of 610 index cases derived from BC/OC (n=587) or OC-only families (n=23) were screened for potentially deleterious germline mutations in RAD51C. The frequencies of two splice-site mutations were assessed by single-nucleotide polymorphism genotyping in 1410 additional cases not enriched for OC family history. In three independent families, we identified novel splice-site mutations affecting the last nucleotide of exon 2 (c.404G>C, c.404G>T). Both mutations disrupt proper RAD51C pre-mRNA processing and cause a missense substitution immediately followed by a stop codon (p.Cys135Serfs*2; p.Cys135Leufs*2). Even though both mutations have similar effects on the protein level, they are associated with either BC/OC, OC-only, or BC-only family histories. The rare finding of a clearly truncating RAD51C mutation in an early-onset BC patient with a BC-only family history supports the notion that compromised RAD51C function may result in both BC and OC. Large international collaborative studies are needed to quantify the relative risk of RAD51C alterations for BC and to unravel the genetic modifying factors that determine phenotypic variability with respect to cancer site.

Published
2017
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42. RAD51C deletion screening identifies a recurrent gross deletion in breast cancer and ovarian cancer families.

Author

Schnurbein G, Hauke J, Wappenschmidt B, Weber-Lassalle N, Engert S, Hellebrand H, Garbes L, Becker A, Neidhardt G, Rhiem K, Meindl A, Schmutzler RK, and Hahnen E

Subjects
Adult, Female, Gene Deletion, Humans, Pedigree, Breast Neoplasms genetics, Ovarian Neoplasms genetics, Rad51 Recombinase genetics
Abstract

RAD51C is an integral part of the DNA double-strand repair through homologous recombination, and monoallelic mutations were found in ~1.3% of BRCA1/2-negative breast cancer (BC) and/or ovarian cancer (OC) families. Several studies confirmed the occurrence of RAD51C mutations predominantly in BC and/or OC families, although with varying frequencies, clearly establishing RAD51C as a cancer-predisposing gene. There is ongoing debate whether pathogenic RAD51C alterations increase the relative risk for BC in addition to that for OC, which was estimated to be 5.88 (95% confidence interval = 2.91 to 11.88; P = 7.65 × 10(-7)).

Published
2013
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43. Germline mutations in the PALB2 gene are population specific and occur with low frequencies in familial breast cancer.

Author

Hellebrand H, Sutter C, Honisch E, Gross E, Wappenschmidt B, Schem C, Deissler H, Ditsch N, Gress V, Kiechle M, Bartram CR, Schmutzler RK, Niederacher D, Arnold N, and Meindl A

Subjects
Adult, BRCA2 Protein genetics, Codon, Nonsense, DNA Mutational Analysis, Fanconi Anemia Complementation Group N Protein, Female, Genetic Predisposition to Disease, Germany, Humans, Middle Aged, Mutation, Missense, Breast Neoplasms genetics, Germ-Line Mutation, Nuclear Proteins genetics, Tumor Suppressor Proteins genetics
Abstract

The Partner and Localizer of BRCA2 (PALB2) protein has been linked to Fanconi anemia and breast cancer predisposition. Here we present data of a comprehensive mutation screening of the PALB2 gene in 818 familial cases of breast cancer from Germany. By analyzing the entire coding region of PALB2, we found seven truncating mutations (six of them novel) in families tested negative for BRCA1/2-mutations. In addition, two novel potentially disease causing missense mutations were found. Remarkably, only one mutation reported previously in other populations, was also identified in the German population. No PALB2 mutation carriers were identified in 450 unaffected controls. Thus, our observations indicate a low prevalence of deleterious PALB2 mutations and a specific mutation profile within the German population. As PALB2-deficient tumors were shown to be sensitive to Poly(ADP-ribose) Polymerase (PARP) inhibitors, our study has implications for newly developed, favorable treatment options in familial breast cancer., (© 2011 Wiley-Liss, Inc.)

Published
2011
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44. Low-risk variants FGFR2, TNRC9 and LSP1 in German familial breast cancer patients.

Author

Hemminki K, Müller-Myhsok B, Lichtner P, Engel C, Chen B, Burwinkel B, Försti A, Sutter C, Wappenschmidt B, Hellebrand H, Illig T, Arnold N, Niederacher D, Dworniczak B, Deissler H, Kast K, Gadzicki D, Meitinger T, Wichmann HE, Kiechle M, Bartram CR, Schmutzler RK, and Meindl A

Subjects
Adult, Aged, Apoptosis Regulatory Proteins, Breast Neoplasms pathology, Case-Control Studies, Chromosomes, Human, Pair 6 genetics, Female, Genotype, Germany, Heterozygote, High Mobility Group Proteins, Humans, Middle Aged, Phenotype, Prognosis, Receptors, Estrogen metabolism, Trans-Activators, Breast Neoplasms genetics, Genetic Predisposition to Disease, Microfilament Proteins genetics, Polymorphism, Single Nucleotide genetics, Receptor, Fibroblast Growth Factor, Type 2 genetics, Receptors, Progesterone genetics
Abstract

To validate common low-risk variants predisposing for breast cancer (BC) in a large set of BRCA1/2 negative familial or genetically enriched cases from Germany, we genotyped 1,415 cases and 1,830 healthy women by MALDI-TOF in 105 candidate SNPs. Significantly higher ORs than previously reported for heterozygous unselected cases were found for the minor allele in FGFR2 (OR = 1.43, 95% CI 1.30-1.59, p-value = 1.24 x 10(-12)) and for TNRC9 (OR = 1.33, 95% CI 1.19-1.46, p-value = 1.54 x 10(-7)). Most intriguing, however, were the ORs for homozygous carriers from high-risk families for FGFR2 (OR = 2.05, 95% CI 1.68-2.51, LSP1 (OR = 0.49, 95% CI 0.28-0.86) and TNRC9 (OR = 1.62, 95% CI 1.27-2.07). Moreover, the additional validation of 99 CGEMS-SNPs identified putative novel susceptibility alleles within the LSP1 gene (OR = 0.73, 95% CI 0.61-0.87, p-value = 5.23 x 10(-4)). Finally, we provide evidence for the first time that a low-risk variant located at 6q22.33 (rs6569479) is associated with estrogen receptor negative BC in familial cases (OR = 1.33, 95% CI 1.06-1.66; p-value = 0.012). Our data confirm the impact of the previously identified susceptibility loci and provide preliminary evidence for novel susceptibility loci in familial BC cases and correlate them to specific histopathological subtypes defined by estrogen receptor status.

Published
2010
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45. Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene.

Author

Meindl A, Hellebrand H, Wiek C, Erven V, Wappenschmidt B, Niederacher D, Freund M, Lichtner P, Hartmann L, Schaal H, Ramser J, Honisch E, Kubisch C, Wichmann HE, Kast K, Deissler H, Engel C, Müller-Myhsok B, Neveling K, Kiechle M, Mathew CG, Schindler D, Schmutzler RK, and Hanenberg H

Subjects
Alleles, Case-Control Studies, DNA-Binding Proteins genetics, Fanconi Anemia genetics, Female, Germany, Humans, Models, Genetic, Mutation, Pedigree, Phenotype, Breast Neoplasms genetics, Genetic Predisposition to Disease, Germ-Line Mutation, Ovarian Neoplasms genetics
Abstract

Germline mutations in a number of genes involved in the recombinational repair of DNA double-strand breaks are associated with predisposition to breast and ovarian cancer. RAD51C is essential for homologous recombination repair, and a biallelic missense mutation can cause a Fanconi anemia-like phenotype. In index cases from 1,100 German families with gynecological malignancies, we identified six monoallelic pathogenic mutations in RAD51C that confer an increased risk for breast and ovarian cancer. These include two frameshift-causing insertions, two splice-site mutations and two nonfunctional missense mutations. The mutations were found exclusively within 480 pedigrees with the occurrence of both breast and ovarian tumors (BC/OC; 1.3%) and not in 620 pedigrees with breast cancer only or in 2,912 healthy German controls. These results provide the first unambiguous evidence of highly penetrant mutations associated with human cancer in a RAD51 paralog and support the 'common disease, rare allele' hypothesis.

Published
2010
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46. Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance.

Author

Tischfield MA, Baris HN, Wu C, Rudolph G, Van Maldergem L, He W, Chan WM, Andrews C, Demer JL, Robertson RL, Mackey DA, Ruddle JB, Bird TD, Gottlob I, Pieh C, Traboulsi EI, Pomeroy SL, Hunter DG, Soul JS, Newlin A, Sabol LJ, Doherty EJ, de Uzcátegui CE, de Uzcátegui N, Collins ML, Sener EC, Wabbels B, Hellebrand H, Meitinger T, de Berardinis T, Magli A, Schiavi C, Pastore-Trossello M, Koc F, Wong AM, Levin AV, Geraghty MT, Descartes M, Flaherty M, Jamieson RV, Møller HU, Meuthen I, Callen DF, Kerwin J, Lindsay S, Meindl A, Gupta ML Jr, Pellman D, and Engle EC

Subjects
Amino Acid Sequence, Animals, Axons metabolism, Brain embryology, Brain metabolism, Cell Survival, Child, Developmental Disabilities, Female, Humans, Kinesins metabolism, Male, Mice, Mice, Inbred C57BL, Microtubules metabolism, Models, Molecular, Molecular Sequence Data, Mutation, Missense, Protein Transport, Tubulin chemistry, Tubulin genetics, Tubulin metabolism
Abstract

We report that eight heterozygous missense mutations in TUBB3, encoding the neuron-specific beta-tubulin isotype III, result in a spectrum of human nervous system disorders that we now call the TUBB3 syndromes. Each mutation causes the ocular motility disorder CFEOM3, whereas some also result in intellectual and behavioral impairments, facial paralysis, and/or later-onset axonal sensorimotor polyneuropathy. Neuroimaging reveals a spectrum of abnormalities including hypoplasia of oculomotor nerves and dysgenesis of the corpus callosum, anterior commissure, and corticospinal tracts. A knock-in disease mouse model reveals axon guidance defects without evidence of cortical cell migration abnormalities. We show that the disease-associated mutations can impair tubulin heterodimer formation in vitro, although folded mutant heterodimers can still polymerize into microtubules. Modeling each mutation in yeast tubulin demonstrates that all alter dynamic instability whereas a subset disrupts the interaction of microtubules with kinesin motors. These findings demonstrate that normal TUBB3 is required for axon guidance and maintenance in mammals.

Published
2010
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47. KIF21A variant R954W in familial or sporadic cases of CFEOM1.

Author

Rudolph G, Nentwich M, Hellebrand H, Pollack K, Gordes R, Bau V, Kampik A, and Meindl A

Subjects
Adult, Child, Preschool, Chromosomes, Human, Pair 16 genetics, DNA Mutational Analysis, Female, Fibrosis congenital, Genetic Linkage, Haplotypes, Humans, Male, Ophthalmoplegia, Chronic Progressive External pathology, Pedigree, Blepharoptosis genetics, Kinesins genetics, Mutation, Oculomotor Muscles pathology, Ophthalmoplegia, Chronic Progressive External genetics
Abstract

Purpose: To demonstrate the clinical characteristics and determine mutations in the KIF21A gene, encoding a kinesin motor protein in patients with congenital fibrosis of the extraocular muscles (CFEOM) type 1., Methods: Patients of five families with congenital fibrosis syndrome and two simplex patients with CFEOM underwent ophthalmologic examination and mutation analysis in the KIF21A gene., Results: Clinical examination and passive motility testing prior to surgery met criteria for CFEOM. All patients had congenital restrictive ophthalmoplegia primarily affecting muscles innervated by the oculomotor nerve. Complete mutation screening in the KIF21A gene revealed the presence of the known and most common recurrent variant R954W in three families and in two simplex cases. Two families demonstrated linkage to chromosome 16., Conclusions: The patients included in the study had marked restriction of movement bilaterally with nearly complete loss of vertical ocular motility, graded reduction of horizontal motility, ptosis, and compensatory chin elevation. The phenotype was variable in patients carrying the same mutation. In one family, all patients were diagnosed with mental retardation, indicating that this syndrome might not only affect the development of cranial nerves, but can also be responsible for general neurologic dysfunction. The screening data suggest frequent and exclusive appearance of the R454W variant in sporadic and familial cases of CFEOM1 in Germany.

Published
2009
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48. Decreased expression of angiogenesis antagonist EFEMP1 in sporadic breast cancer is caused by aberrant promoter methylation and points to an impact of EFEMP1 as molecular biomarker.

Author

Sadr-Nabavi A, Ramser J, Volkmann J, Naehrig J, Wiesmann F, Betz B, Hellebrand H, Engert S, Seitz S, Kreutzfeld R, Sasaki T, Arnold N, Schmutzler R, Kiechle M, Niederacher D, Harbeck N, Dahl E, and Meindl A

Subjects
Adult, Aged, Aged, 80 and over, Angiogenesis Inhibitors therapeutic use, Antineoplastic Agents, Hormonal therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, DNA Mutational Analysis, Epigenesis, Genetic, Female, Gene Expression, Humans, Immunohistochemistry, Loss of Heterozygosity, Middle Aged, Oligonucleotide Array Sequence Analysis, Reverse Transcriptase Polymerase Chain Reaction, Tissue Array Analysis, Biomarkers, Tumor genetics, Breast Neoplasms genetics, DNA Methylation genetics, Extracellular Matrix Proteins biosynthesis, Neovascularization, Pathologic genetics, Promoter Regions, Genetic genetics
Abstract

EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1) was recently described as an antagonist of angiogenesis. Motivated by a strong dependence of tumor growth and metastasis on angiogenesis, we investigated the role of EFEMP1 in human breast cancer. We applied RNA microarray expression analysis and quantitative real-time PCR (QRT) in a total of 45 sporadic breast cancer tissues and found EFEMP1 down-regulation in 59% and 61% of the analyzed tissues, respectively. This down-regulation was confirmed on protein level. Immunohistochemistry in 211 breast cancer tissues resulted in reduced or even abolished EFEMP1 expression in 57-62.5% of the tumors. Bisulphite genomic sequencing in breast cancer cell lines and primary breast cancer tissues revealed promoter methylation as the major cause of this down-regulation. Furthermore, analysis of 203 clinically well characterized primary breast cancers displayed a significant correlation of reduced EFEMP1 protein expression with poor disease-free (p = 0.037) and overall survival (p = 0.032), particularly in those node-positive patients who received adjuvant anthracycline-based chemotherapy, but not in those treated by either cyclophosphamide-methotrexate-5-fluorouracil (CMF) or Tamoxifen. In summary, the presented data demonstrate for the first time the reduced EFEMP1 expression on RNA and protein level in a substantial number of sporadic breast carcinomas and its correlation with epigenetic alterations. Furthermore, these data point towards a possible predictive impact of EFEMP1 expression in primary breast cancer.

Published
2009
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49. MLPA screening in the BRCA1 gene from 1,506 German hereditary breast cancer cases: novel deletions, frequent involvement of exon 17, and occurrence in single early-onset cases.

Author

Engert S, Wappenschmidt B, Betz B, Kast K, Kutsche M, Hellebrand H, Goecke TO, Kiechle M, Niederacher D, Schmutzler RK, and Meindl A

Subjects
Age of Onset, Exons, Family, Female, Gene Rearrangement, Genes, BRCA2, Genetic Testing, Germany, Humans, Male, Ovarian Neoplasms genetics, Polymerase Chain Reaction, Breast Neoplasms genetics, Genes, BRCA1, Sequence Deletion
Abstract

We present a comprehensive analysis of 1,506 German families for large genomic rearrangements (LGRs) in the BRCA1 gene and of 450 families in the BRCA2 gene by the multiplex ligation-dependent probe amplification (MLPA) technique. A total of 32 pathogenic rearrangements in the BRCA1 gene were found, accounting for 1.6% of all mutations, but for 9.6% of all BRCA1 mutations identified in a total of 1,996 families, including 490 with small pathogenic BRCA1/2 mutations. Considering only high risk groups for hereditary breast/ovarian cancer, the prevalence of rearrangements is 2.1%. Interestingly, deletions involving exon 17 of the BRCA1 gene seem to be most frequent in Germany. Apart from recurrent aberrations like del ex17, dupl ex13, and del ex22, accounting for more than 50% of all BRCA1 LGRs, we could fully characterize 11 novel deletions. Moreover, one novel deletion involving exons 1-7 and one deletion affecting the entire BRCA1 gene were identified. All rearrangements were detected in families with: 1) at least two breast cancer cases prior to the age of 51 years; 2) breast and ovarian cancer cases; 3) ovarian cancer only families with at least two ovarian cancer cases; or 4) a single breast cancer case prior to the age of 36 years, while no mutations were detected in breast cancer only families with no or only one breast cancer case prior to the age of 51 years. Analysis for gross rearrangements in 412 high-risk individuals, revealed no event in the BRCA2 gene and only two known CHEK2 mutations. However, in an additional 38 high-risk families with cooccurrence of female breast/ovarian and male breast cancer, one rearrangement in the BRCA2 gene was found. In summary, we advise restricting BRCA1 MLPA screening to those subgroups that revealed LGRs and recommend BRCA2 MLPA screening only for families presenting with cooccurrence of female and male breast cancer.

Published
2008
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50. Rare missense and synonymous variants in UBE1 are associated with X-linked infantile spinal muscular atrophy.

Author

Ramser J, Ahearn ME, Lenski C, Yariz KO, Hellebrand H, von Rhein M, Clark RD, Schmutzler RK, Lichtner P, Hoffman EP, Meindl A, and Baumbach-Reardon L

Subjects
DNA Mutational Analysis, Female, Humans, Infant, Infant, Newborn, Male, Pedigree, Genes, X-Linked, Mutation, Missense, Point Mutation, Spinal Muscular Atrophies of Childhood genetics, Ubiquitin-Activating Enzymes genetics
Abstract

X-linked infantile spinal muscular atrophy (XL-SMA) is an X-linked disorder presenting with the clinical features hypotonia, areflexia, and multiple congenital contractures (arthrogryposis) associated with loss of anterior horn cells and infantile death. To identify the XL-SMA disease gene, we performed large-scale mutation analysis in genes located between markers DXS8080 and DXS7132 (Xp11.3-Xq11.1). This resulted in detection of three rare novel variants in exon 15 of UBE1 that segregate with disease: two missense mutations (c.1617 G-->T, p.Met539Ile; c.1639 A-->G, p.Ser547Gly) present each in one XL-SMA family, and one synonymous C-->T substitution (c.1731 C-->T, p.Asn577Asn) identified in another three unrelated families. Absence of the missense mutations was demonstrated for 3550 and absence of the synonymous mutation was shown in 7914 control X chromosomes; therefore, these results yielded statistical significant evidence for the association of the synonymous substitution and the two missense mutations with XL-SMA (p = 2.416 x 10(-10), p = 0.001815). We also demonstrated that the synonymous C-->T substitution leads to significant reduction of UBE1 expression and alters the methylation pattern of exon 15, implying a plausible role of this DNA element in developmental UBE1 expression in humans. Our observations indicate first that XL-SMA is part of a growing list of neurodegenerative disorders associated with defects in the ubiquitin-proteasome pathway and second that synonymous C-->T transitions might have the potential to affect gene expression.

Published
2008
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