Author: "Brunner, HG" - Searchworks@Jio Institute Digital Library Search Results

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569 results on '"Brunner, HG"'

1. Systemic Inflammation and Normocytic Anemia in DOCK11 Deficiency

Author: Block J, Rashkova C, Castanon I, Zoghi S, Platon J, Ardy RC, Fujiwara M, Chaves B, Schoppmeyer R, van der Made CI, Jimenez Heredia R, Harms FL, Alavi S, Alsina L, Sanchez Moreno P, Ávila Polo R, Cabrera-Pérez R, Kostel Bal S, Pfajfer L, Ransmayr B, Mautner AK, Kondo R, Tinnacher A, Caldera M, Schuster M, Domínguez Conde C, Platzer R, Salzer E, Boyer T, Brunner HG, Nooitgedagt-Frons JE, Iglesias E, Deyà-Martinez A, Camacho-Lovillo M, Menche J, Bock C, Huppa JB, Pickl WF, Distel M, Yoder JA, Traver D, Engelhardt KR, Linden T, Kager L, Hannich JT, Hoischen A, Hambleton S, Illsinger S, Da Costa L, Kutsche K, Chavoshzadeh Z, van Buul JD, Antón J, Calzada-Hernández J, Neth O, Viaud J, Nishikimi A, Dupré L, Boztug K
Published: 2023
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2. SLC7A8 coding for LAT2 is associated with early disease progression in osteosarcoma and transports doxorubicin.

Author: Hurkmans, EGE, Koenderink, JB, van den Heuvel, JJMW, Versleijen-Jonkers, YMH, Hillebrandt-Roeffen, MHS, Groothuismink, JM, Vos, HI, van der Graaf, WTA, Flucke, U, Muradjan, G, Schreuder, HWB, Hagleitner, MM, Brunner, HG, Gelderblom, H, Cleton-Jansen, A-M, Guchelaar, H-J, de Bont, ESJM, Touw, DJ, Nijhoff, GJ, Kremer, LCM, Caron, H, Windsor, R, Patiño-García, A, González-Neira, A, Saletta, F, McCowage, G, Nagabushan, S, Catchpoole, D, Te Loo, DMWM, Coenen, MJH, Hurkmans, EGE, Koenderink, JB, van den Heuvel, JJMW, Versleijen-Jonkers, YMH, Hillebrandt-Roeffen, MHS, Groothuismink, JM, Vos, HI, van der Graaf, WTA, Flucke, U, Muradjan, G, Schreuder, HWB, Hagleitner, MM, Brunner, HG, Gelderblom, H, Cleton-Jansen, A-M, Guchelaar, H-J, de Bont, ESJM, Touw, DJ, Nijhoff, GJ, Kremer, LCM, Caron, H, Windsor, R, Patiño-García, A, González-Neira, A, Saletta, F, McCowage, G, Nagabushan, S, Catchpoole, D, Te Loo, DMWM, and Coenen, MJH
Abstract: Background: Despite (neo) adjuvant chemotherapy with cisplatin, doxorubicin and methotrexate, some patients with primary osteosarcoma progress during first-line systemic treatment and have a poor prognosis. In this study, we investigated whether patients with early disease progression (EDP), are characterized by a distinctive pharmacogenetic profile. Methods and Findings: Germline DNA from 287 Dutch high-grade osteosarcoma patients was genotyped using the DMET Plus array (containing 1,936 genetic markers in 231 drug metabolism and transporter genes). Associations between genetic variants and EDP were assessed using logistic regression models and associated variants (p <0.05) were validated in independent cohorts of 146 (Spain and United Kingdom) and 28 patients (Australia). In the association analyses, EDP was significantly associated with an SLC7A8 locus and was independently validated (meta-analysis validation cohorts: OR 0.19 [0.06-0.55], p = 0.002). The functional relevance of the top hits was explored by immunohistochemistry staining and an in vitro transport models. SLC7A8 encodes for the L-type amino acid transporter 2 (LAT2). Transport assays in HEK293 cells overexpressing LAT2 showed that doxorubicin, but not cisplatin and methotrexate, is a substrate for LAT2 (p < 0.0001). Finally, SLC7A8 mRNA expression analysis and LAT2 immunohistochemistry of osteosarcoma tissue showed that the lack of LAT2 expression is a prognostic factor of poor prognosis and reduced overall survival in patients without metastases (p = 0.0099 and p = 0.14, resp.). Conclusion: This study identified a novel locus in SLC7A8 to be associated with EDP in osteosarcoma. Functional studies indicate LAT2-mediates uptake of doxorubicin, which could give new opportunities to personalize treatment of osteosarcoma patients.
Published: 2022

3. Genetic convergence of developmental and epileptic encephalopathies and intellectual disability

Author: Carvill, GL, Jansen, S, Lacroix, A, Zemel, M, Mehaffey, M, De Vries, P, Brunner, HG, Scheffer, IE, De Vries, BBA, Vissers, LELM, Mefford, HC, Carvill, GL, Jansen, S, Lacroix, A, Zemel, M, Mehaffey, M, De Vries, P, Brunner, HG, Scheffer, IE, De Vries, BBA, Vissers, LELM, and Mefford, HC
Abstract: AIM: To determine whether genes that cause developmental and epileptic encephalopathies (DEEs) are more commonly implicated in intellectual disability with epilepsy as a comorbid feature than in intellectual disability only. METHOD: We performed targeted resequencing of 18 genes commonly implicated in DEEs in a cohort of 830 patients with intellectual disability (59% male) and 393 patients with DEEs (52% male). RESULTS: We observed a significant enrichment of pathogenic/likely pathogenic variants in patients with epilepsy and intellectual disability (16 out of 159 in seven genes) compared with intellectual disability only (2 out of 671) (p<1.86×10-10 , odds ratio 37.22, 95% confidence interval 8.60-337.0). INTERPRETATION: We identified seven genes that are more likely to cause epilepsy and intellectual disability than intellectual disability only. Conversely, two genes, GRIN2B and SCN2A, can be implicated in intellectual disability without epilepsy; in these instances intellectual disability is not a secondary consequence of ongoing seizures but rather a primary cause. What this paper adds A subset of genes are more commonly implicated in epilepsy than other neurodevelopmental disorders. GRIN2B and SCN2A are implicated in intellectual disability and epilepsy independently.
Published: 2021

4. Genetic variants for head size share genes and pathways with cancer

Author: Shihua Li, Melissa J. Green, Nagata M, Miyamoto S, Le Grand Q, Pourcain Bs, Grabe Hj, Catherine Helmer, William R. Reay, Nele Friedrich, Mazoyer B, Seshadri S, Per Hoffmann, Simon Haworth, Veronica Witte A, Yang Q, Max Lam, Teunissen Mw, Fang-Chi Hsu, Debette S, Murray J. Cairns, Amod Ar, Setoh K, Windham Bg, Shareefa Dalvie, Georg Homuth, Charlie S. DeCarli, Gennady V. Roshchupkin, Céline S. Reinbold, Mühleisen Tw, Nakahara S, Van der Auwera S, Xueqiu Jian, Cecil Ca, Jean-François Dartigues, Alexa S. Beiser, Stein Jl, Houlden H, Christiane Jockwitz, Moebus S, Claudia L. Satizabal, Tavia E. Evans, Matsuda F, Cora E. Lewis, Wittfeld K, Calhoun Vd, van der Lugt A, Teumer A, Pausova Z, W. T. Longstreth, Aniket Mishra, Tomáš Paus, Vernooij Mw, Medland Se, Palmer Nd, Ahmad R. Hariri, Adrian Preda, Clifford R. Jack, van Erp Tg, Amaia Carrion-Castillo, Werring Dj, Gwénaëlle Catheline, Asta Håberg, Robin Bülow, Sven Cichon, Yann Quidé, Muetzel R, Tabara Y, Sidney S, Cheung C, Brunner Hg, Annchen R. Knodt, Mosley Th, van Dam-Nolen Dh, Hostettler Ic, Jean Shin, Shapland Cy, Reut Avinun, Crivello F, Mäkitie O, Fornage M, Yoshida K, Villringer A, Lim K, Schreiner Pj, Bowden Dw, Thompson Pm, Daniel Bos, Uhlmann A, Enlund-Cerullo M, Schmidt R, Hieab H.H. Adams, Neda Jahanshad, Frauke Beyer, Gloria H.Y. Li, Fabio Macciardi, Lamballais S, Kämpe A, Judith M. Ford, Poot Ra, J. C. Bis, Yoichiro Kamatani, Ami Tsuchida, Markus Scholz, Ikram Ma, Andersson S, Lenore J. Launer, Stein Dj, Koudstaal Pj, Barry I. Freedman, Barbara Franke, Ikram Mk, Sim K, Marie-Gabrielle Duperron, Bryan Rn, Svenja Caspers, Pawlak Ma, Tonya White, Maria J. Knol, Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, and Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium
Subjects: Genetics, 0303 health sciences, education.field_of_study, biology, Population, Wnt signaling pathway, Macrocephaly, Cancer, medicine.disease, Biological pathway, 03 medical and health sciences, 0302 clinical medicine, medicine, biology.protein, PTEN, Human height, medicine.symptom, education, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: The size of the human head is determined by growth in the first years of life, while the rest of the body typically grows until early adulthood1. Such complex developmental processes are regulated by various genes and growth pathways2. Rare genetic syndromes have revealed genes that affect head size3, but the genetic drivers of variation in head size within the general population remain largely unknown. To elucidate biological pathways underlying the growth of the human head, we performed the largest genome-wide association study on human head size to date (N = 79,107). We identified 67 genetic loci, 50 of which are novel, and found that these loci are preferentially associated with head size and mostly independent from height. In subsequent neuroimaging analyses, the majority of genetic variants demonstrated widespread effects on the brain, whereas the effects of 17 variants could be localized to one or two specific brain regions. Through hypothesis-free approaches, we find a strong overlap of head size variants with both cancer pathways and cancer genes. Gene set analyses showed enrichment for different types of cancer and the p53, Wnt and ErbB signalling pathway. Genes overlapping or close to lead variants – such as TP53, PTEN and APC – were enriched for genes involved in macrocephaly syndromes (up to 37-fold) and high-fidelity cancer genes (up to 9-fold), whereas this enrichment was not seen for human height variants. This indicates that genes regulating early brain and cranial growth are associated with a propensity to neoplasia later in life, irrespective of height. Our results warrant further investigations of the link between head size and cancer, as well as its clinical implications in the general population.
Published: 2020

5. The genetic architecture of the human cerebral cortex

Author: Grasby, KL, Jahanshad, N, Painter, JN, Colodro-Conde, L, Bralten, J, Hibar, DP, Lind, PA, Pizzagalli, F, Ching, CRK, McMahon, MAB, Shatokhina, N, Zsembik, LCP, Thomopoulos, SI, Zhu, AH, Strike, LT, Agartz, I, Alhusaini, S, Almeida, MAA, Alnaes, D, Amlien, IK, Andersson, M, Ard, T, Armstrong, NJ, Ashley-Koch, A, Atkins, JR, Bernard, M, Brouwer, RM, Buimer, EEL, Bulow, R, Burger, C, Cannon, DM, Chakravarty, M, Chen, Q, Cheung, JW, Couvy-Duchesne, B, Dale, AM, Dalvie, S, de Araujo, TK, de Zubicaray, GI, de Zwarte, SMC, den Braber, A, Nhat, TD, Dohm, K, Ehrlich, S, Engelbrecht, H-R, Erk, S, Fan, CC, Fedko, IO, Foley, SF, Ford, JM, Fukunaga, M, Garrett, ME, Ge, T, Giddaluru, S, Goldman, AL, Green, MJ, Groenewold, NA, Grotegerd, D, Gurholt, TP, Gutman, BA, Hansell, NK, Harris, MA, Harrison, MB, Haswell, CC, Hauser, M, Herms, S, Heslenfeld, DJ, Ho, NF, Hoehn, D, Hoffmann, P, Holleran, L, Hoogman, M, Hottenga, J-J, Ikeda, M, Janowitz, D, Jansen, IE, Jia, T, Jockwitz, C, Kanai, R, Karama, S, Kasperaviciute, D, Kaufmann, T, Kelly, S, Kikuchi, M, Klein, M, Knapp, M, Knodt, AR, Kramer, B, Lam, M, Lancaster, TM, Lee, PH, Lett, TA, Lewis, LB, Lopes-Cendes, I, Luciano, M, Macciardi, F, Marquand, AF, Mathias, SR, Melzer, TR, Milaneschi, Y, Mirza-Schreiber, N, Moreira, JCV, Muhleisen, TW, Mueller-Myhsok, B, Najt, P, Nakahara, S, Nho, K, Loohuis, LMO, Orfanos, DP, Pearson, JF, Pitcher, TL, Putz, B, Quide, Y, Ragothaman, A, Rashid, FM, Reay, WR, Redlich, R, Reinbold, CS, Repple, J, Richard, G, Riedel, BC, Risacher, SL, Rocha, CS, Mota, NR, Salminen, L, Saremi, A, Saykin, AJ, Schlag, F, Schmaal, L, Schofield, PR, Secolin, R, Shapland, CY, Shen, L, Shin, J, Shumskaya, E, Sonderby, IE, Sprooten, E, Tansey, KE, Teumer, A, Thalamuthu, A, Tordesillas-Gutierrez, D, Turner, JA, Uhlmann, A, Vallerga, CL, van der Meer, D, van Donkelaar, MMJ, van Eijk, L, van Erp, TGM, van Haren, NEM, van Rooij, D, van Tol, M-J, Veldink, JH, Verhoef, E, Walton, E, Wang, M, Wang, Y, Wardlaw, JM, Wen, W, Westlye, LT, Whelan, CD, Witt, SH, Wittfeld, K, Wolf, C, Wolfers, T, Wu, JQ, Yasuda, CL, Zaremba, D, Zhang, Z, Zwiers, MP, Artiges, E, Assareh, AA, Ayesa-Arriola, R, Belger, A, Brandt, CL, Brown, GG, Cichon, S, Curran, JE, Davies, GE, Degenhardt, F, Dennis, MF, Dietsche, B, Djurovic, S, Doherty, CP, Espiritu, R, Garijo, D, Gil, Y, Gowland, PA, Green, RC, Hausler, AN, Heindel, W, Ho, B-C, Hoffmann, WU, Holsboer, F, Homuth, G, Hosten, N, Jack, CR, Jang, M, Jansen, A, Kimbrel, NA, Kolskar, K, Koops, S, Krug, A, Lim, KO, Luykx, JJ, Mathalon, DH, Mather, KA, Mattay, VS, Matthews, S, Van Son, JM, McEwen, SC, Melle, I, Morris, DW, Mueller, BA, Nauck, M, Nordvik, JE, Noethen, MM, O'Leary, DS, Opel, N, Martinot, M-LP, Pike, GB, Preda, A, Quinlan, EB, Rasser, PE, Ratnakar, V, Reppermund, S, Steen, VM, Tooney, PA, Torres, FR, Veltman, DJ, Voyvodic, JT, Whelan, R, White, T, Yamamori, H, Adams, HHH, Bis, JC, Debette, S, Decarli, C, Fornage, M, Gudnason, V, Hofer, E, Ikram, MA, Launer, L, Longstreth, WT, Lopez, OL, Mazoyer, B, Mosley, TH, Roshchupkin, GV, Satizabal, CL, Schmidt, R, Seshadri, S, Yang, Q, Alvim, MKM, Ames, D, Anderson, TJ, Andreassen, OA, Arias-Vasquez, A, Bastin, ME, Baune, BT, Beckham, JC, Blangero, J, Boomsma, DI, Brodaty, H, Brunner, HG, Buckner, RL, Buitelaar, JK, Bustillo, JR, Cahn, W, Cairns, MJ, Calhoun, V, Carr, VJ, Caseras, X, Caspers, S, Cavalleri, GL, Cendes, F, Corvin, A, Crespo-Facorro, B, Dalrymple-Alford, JC, Dannlowski, U, de Geus, EJC, Deary, IJ, Delanty, N, Depondt, C, Desrivieres, S, Donohoe, G, Espeseth, T, Fernandez, G, Fisher, SE, Flor, H, Forstner, AJ, Francks, C, Franke, B, Glahn, DC, Gollub, RL, Grabe, HJ, Gruber, O, Haberg, AK, Hariri, AR, Hartman, CA, Hashimoto, R, Heinz, A, Henskens, FA, Hillegers, MHJ, Hoekstra, PJ, Holmes, AJ, Hong, LE, Hopkins, WD, Pol, HEH, Jernigan, TL, Jonsson, EG, Kahn, RS, Kennedy, MA, Kircher, TTJ, Kochunov, P, Kwok, JBJ, Le Hellard, S, Loughland, CM, Martin, NG, Martinot, J-L, McDonald, C, McMahon, KL, Meyer-Lindenberg, A, Michie, PT, Morey, RA, Mowry, B, Nyberg, L, Oosterlaan, J, Ophoff, RA, Pantelis, C, Paus, T, Pausova, Z, Penninx, BWJH, Polderman, TJC, Posthuma, D, Rietschel, M, Roffman, JL, Rowland, LM, Sachdev, PS, Samann, PG, Schall, U, Schumann, G, Scott, RJ, Sim, K, Sisodiya, SM, Smoller, JW, Sommer, IE, St Pourcain, B, Stein, DJ, Toga, AW, Trollor, JN, Van der Wee, NJA, van't Ent, D, Volzke, H, Walter, H, Weber, B, Weinberger, DR, Wright, MJ, Zhou, J, Stein, JL, Thompson, PM, Medland, SE, Grasby, KL, Jahanshad, N, Painter, JN, Colodro-Conde, L, Bralten, J, Hibar, DP, Lind, PA, Pizzagalli, F, Ching, CRK, McMahon, MAB, Shatokhina, N, Zsembik, LCP, Thomopoulos, SI, Zhu, AH, Strike, LT, Agartz, I, Alhusaini, S, Almeida, MAA, Alnaes, D, Amlien, IK, Andersson, M, Ard, T, Armstrong, NJ, Ashley-Koch, A, Atkins, JR, Bernard, M, Brouwer, RM, Buimer, EEL, Bulow, R, Burger, C, Cannon, DM, Chakravarty, M, Chen, Q, Cheung, JW, Couvy-Duchesne, B, Dale, AM, Dalvie, S, de Araujo, TK, de Zubicaray, GI, de Zwarte, SMC, den Braber, A, Nhat, TD, Dohm, K, Ehrlich, S, Engelbrecht, H-R, Erk, S, Fan, CC, Fedko, IO, Foley, SF, Ford, JM, Fukunaga, M, Garrett, ME, Ge, T, Giddaluru, S, Goldman, AL, Green, MJ, Groenewold, NA, Grotegerd, D, Gurholt, TP, Gutman, BA, Hansell, NK, Harris, MA, Harrison, MB, Haswell, CC, Hauser, M, Herms, S, Heslenfeld, DJ, Ho, NF, Hoehn, D, Hoffmann, P, Holleran, L, Hoogman, M, Hottenga, J-J, Ikeda, M, Janowitz, D, Jansen, IE, Jia, T, Jockwitz, C, Kanai, R, Karama, S, Kasperaviciute, D, Kaufmann, T, Kelly, S, Kikuchi, M, Klein, M, Knapp, M, Knodt, AR, Kramer, B, Lam, M, Lancaster, TM, Lee, PH, Lett, TA, Lewis, LB, Lopes-Cendes, I, Luciano, M, Macciardi, F, Marquand, AF, Mathias, SR, Melzer, TR, Milaneschi, Y, Mirza-Schreiber, N, Moreira, JCV, Muhleisen, TW, Mueller-Myhsok, B, Najt, P, Nakahara, S, Nho, K, Loohuis, LMO, Orfanos, DP, Pearson, JF, Pitcher, TL, Putz, B, Quide, Y, Ragothaman, A, Rashid, FM, Reay, WR, Redlich, R, Reinbold, CS, Repple, J, Richard, G, Riedel, BC, Risacher, SL, Rocha, CS, Mota, NR, Salminen, L, Saremi, A, Saykin, AJ, Schlag, F, Schmaal, L, Schofield, PR, Secolin, R, Shapland, CY, Shen, L, Shin, J, Shumskaya, E, Sonderby, IE, Sprooten, E, Tansey, KE, Teumer, A, Thalamuthu, A, Tordesillas-Gutierrez, D, Turner, JA, Uhlmann, A, Vallerga, CL, van der Meer, D, van Donkelaar, MMJ, van Eijk, L, van Erp, TGM, van Haren, NEM, van Rooij, D, van Tol, M-J, Veldink, JH, Verhoef, E, Walton, E, Wang, M, Wang, Y, Wardlaw, JM, Wen, W, Westlye, LT, Whelan, CD, Witt, SH, Wittfeld, K, Wolf, C, Wolfers, T, Wu, JQ, Yasuda, CL, Zaremba, D, Zhang, Z, Zwiers, MP, Artiges, E, Assareh, AA, Ayesa-Arriola, R, Belger, A, Brandt, CL, Brown, GG, Cichon, S, Curran, JE, Davies, GE, Degenhardt, F, Dennis, MF, Dietsche, B, Djurovic, S, Doherty, CP, Espiritu, R, Garijo, D, Gil, Y, Gowland, PA, Green, RC, Hausler, AN, Heindel, W, Ho, B-C, Hoffmann, WU, Holsboer, F, Homuth, G, Hosten, N, Jack, CR, Jang, M, Jansen, A, Kimbrel, NA, Kolskar, K, Koops, S, Krug, A, Lim, KO, Luykx, JJ, Mathalon, DH, Mather, KA, Mattay, VS, Matthews, S, Van Son, JM, McEwen, SC, Melle, I, Morris, DW, Mueller, BA, Nauck, M, Nordvik, JE, Noethen, MM, O'Leary, DS, Opel, N, Martinot, M-LP, Pike, GB, Preda, A, Quinlan, EB, Rasser, PE, Ratnakar, V, Reppermund, S, Steen, VM, Tooney, PA, Torres, FR, Veltman, DJ, Voyvodic, JT, Whelan, R, White, T, Yamamori, H, Adams, HHH, Bis, JC, Debette, S, Decarli, C, Fornage, M, Gudnason, V, Hofer, E, Ikram, MA, Launer, L, Longstreth, WT, Lopez, OL, Mazoyer, B, Mosley, TH, Roshchupkin, GV, Satizabal, CL, Schmidt, R, Seshadri, S, Yang, Q, Alvim, MKM, Ames, D, Anderson, TJ, Andreassen, OA, Arias-Vasquez, A, Bastin, ME, Baune, BT, Beckham, JC, Blangero, J, Boomsma, DI, Brodaty, H, Brunner, HG, Buckner, RL, Buitelaar, JK, Bustillo, JR, Cahn, W, Cairns, MJ, Calhoun, V, Carr, VJ, Caseras, X, Caspers, S, Cavalleri, GL, Cendes, F, Corvin, A, Crespo-Facorro, B, Dalrymple-Alford, JC, Dannlowski, U, de Geus, EJC, Deary, IJ, Delanty, N, Depondt, C, Desrivieres, S, Donohoe, G, Espeseth, T, Fernandez, G, Fisher, SE, Flor, H, Forstner, AJ, Francks, C, Franke, B, Glahn, DC, Gollub, RL, Grabe, HJ, Gruber, O, Haberg, AK, Hariri, AR, Hartman, CA, Hashimoto, R, Heinz, A, Henskens, FA, Hillegers, MHJ, Hoekstra, PJ, Holmes, AJ, Hong, LE, Hopkins, WD, Pol, HEH, Jernigan, TL, Jonsson, EG, Kahn, RS, Kennedy, MA, Kircher, TTJ, Kochunov, P, Kwok, JBJ, Le Hellard, S, Loughland, CM, Martin, NG, Martinot, J-L, McDonald, C, McMahon, KL, Meyer-Lindenberg, A, Michie, PT, Morey, RA, Mowry, B, Nyberg, L, Oosterlaan, J, Ophoff, RA, Pantelis, C, Paus, T, Pausova, Z, Penninx, BWJH, Polderman, TJC, Posthuma, D, Rietschel, M, Roffman, JL, Rowland, LM, Sachdev, PS, Samann, PG, Schall, U, Schumann, G, Scott, RJ, Sim, K, Sisodiya, SM, Smoller, JW, Sommer, IE, St Pourcain, B, Stein, DJ, Toga, AW, Trollor, JN, Van der Wee, NJA, van't Ent, D, Volzke, H, Walter, H, Weber, B, Weinberger, DR, Wright, MJ, Zhou, J, Stein, JL, Thompson, PM, and Medland, SE
Abstract: The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.
Published: 2020

6. A Genetics-First Approach Revealed Monogenic Disorders in Patients With ARM and VACTERL Anomalies

Author: van de Putte, R, Dworschak, GC, Brosens, Erwin, Reutter, HM, Marcelis, CL, Acuna-Hidalgo, R, Kurtas, NE, Steehouwer, M, Dunwoodie, SL, Schmiedeke, E, Marzheuser, S, Schwarzer, N, Brooks, Alice, de Klein, Annelies, Sloots, C.E.J., Tibboel, Dick, Brisighelli, G, Morandi, A, Bedeschi, MF, Bates, MD, Levitt, MA, de la Pena, A, de Blaauw, I, Roeleveld, N, Brunner, HG, de Rooij, I, Hoischen, A, van de Putte, R, Dworschak, GC, Brosens, Erwin, Reutter, HM, Marcelis, CL, Acuna-Hidalgo, R, Kurtas, NE, Steehouwer, M, Dunwoodie, SL, Schmiedeke, E, Marzheuser, S, Schwarzer, N, Brooks, Alice, de Klein, Annelies, Sloots, C.E.J., Tibboel, Dick, Brisighelli, G, Morandi, A, Bedeschi, MF, Bates, MD, Levitt, MA, de la Pena, A, de Blaauw, I, Roeleveld, N, Brunner, HG, de Rooij, I, and Hoischen, A
Published: 2020

7. Disruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders

Author: Guo, H, Bettella, E, Marcogliese, PC, Zhao, R, Andrews, JC, Nowakowski, TJ, Gillentine, MA, Hoekzema, K, Wang, T, Wu, H, Jangam, S, Liu, C, Ni, H, Willemsen, MH, van Bon, BW, Rinne, T, Stevens, SJC, Kleefstra, T, Brunner, HG, Yntema, HG, Long, M, Zhao, W, Hu, Z, Colson, C, Richard, N, Schwartz, CE, Romano, C, Castiglia, L, Bottitta, M, Dhar, SU, Erwin, DJ, Emrick, L, Keren, B, Afenjar, A, Zhu, B, Bai, B, Stankiewicz, P, Herman, K, Mercimek-Andrews, S, Juusola, J, Wilfert, AB, Abou Jamra, R, Buettner, B, Mefford, HC, Muir, AM, Scheffer, IE, Regan, BM, Malone, S, Gecz, J, Cobben, J, Weiss, MM, Waisfisz, Q, Bijlsma, EK, Hoffer, MJ, Ruivenkamp, CAL, Sartori, S, Xia, F, Rosenfeld, JA, Bernier, RA, Wangler, MF, Yamamoto, S, Xia, K, Stegmann, APA, Bellen, HJ, Murgia, A, Eichler, EE, Nickerson, DA, Bamshad, MJ, Guo, H, Bettella, E, Marcogliese, PC, Zhao, R, Andrews, JC, Nowakowski, TJ, Gillentine, MA, Hoekzema, K, Wang, T, Wu, H, Jangam, S, Liu, C, Ni, H, Willemsen, MH, van Bon, BW, Rinne, T, Stevens, SJC, Kleefstra, T, Brunner, HG, Yntema, HG, Long, M, Zhao, W, Hu, Z, Colson, C, Richard, N, Schwartz, CE, Romano, C, Castiglia, L, Bottitta, M, Dhar, SU, Erwin, DJ, Emrick, L, Keren, B, Afenjar, A, Zhu, B, Bai, B, Stankiewicz, P, Herman, K, Mercimek-Andrews, S, Juusola, J, Wilfert, AB, Abou Jamra, R, Buettner, B, Mefford, HC, Muir, AM, Scheffer, IE, Regan, BM, Malone, S, Gecz, J, Cobben, J, Weiss, MM, Waisfisz, Q, Bijlsma, EK, Hoffer, MJ, Ruivenkamp, CAL, Sartori, S, Xia, F, Rosenfeld, JA, Bernier, RA, Wangler, MF, Yamamoto, S, Xia, K, Stegmann, APA, Bellen, HJ, Murgia, A, Eichler, EE, Nickerson, DA, and Bamshad, MJ
Abstract: Postsynaptic density (PSD) proteins have been implicated in the pathophysiology of neurodevelopmental and psychiatric disorders. Here, we present detailed clinical and genetic data for 20 patients with likely gene-disrupting mutations in TANC2-whose protein product interacts with multiple PSD proteins. Pediatric patients with disruptive mutations present with autism, intellectual disability, and delayed language and motor development. In addition to a variable degree of epilepsy and facial dysmorphism, we observe a pattern of more complex psychiatric dysfunction or behavioral problems in adult probands or carrier parents. Although this observation requires replication to establish statistical significance, it also suggests that mutations in this gene are associated with a variety of neuropsychiatric disorders consistent with its postsynaptic function. We find that TANC2 is expressed broadly in the human developing brain, especially in excitatory neurons and glial cells, but shows a more restricted pattern in Drosophila glial cells where its disruption affects behavioral outcomes.
Published: 2019

8. Exome chip association study excluded the involvement of rare coding variants with large effect sizes in the etiology of anorectal malformations

Author: van de Putte, R, Wijers, CHW, Reutter, H, Vermeulen, SH, Marcelis, CLM, Brosens, Erwin, Broens, PMA, Homberg, M, Ludwig, M, Jenetzky, E, Zwink, N, Sloots, C.E.J., de Klein, Annelies, Brooks, Alice, Hofstra, Robert, Holsink, SAC, van der Zanden, LFM, Galesloot, TE, Tam, PKH, Steehouwer, M, Acuna-Hidalgo, R, van de Vorst, M, Kiemeney, LA, Garcia-Barcelo, MM, de Blaauw, I, Brunner, HG, Roeleveld, N, de Rooij, I, van de Putte, R, Wijers, CHW, Reutter, H, Vermeulen, SH, Marcelis, CLM, Brosens, Erwin, Broens, PMA, Homberg, M, Ludwig, M, Jenetzky, E, Zwink, N, Sloots, C.E.J., de Klein, Annelies, Brooks, Alice, Hofstra, Robert, Holsink, SAC, van der Zanden, LFM, Galesloot, TE, Tam, PKH, Steehouwer, M, Acuna-Hidalgo, R, van de Vorst, M, Kiemeney, LA, Garcia-Barcelo, MM, de Blaauw, I, Brunner, HG, Roeleveld, N, and de Rooij, I
Published: 2019

9. A Tyr368His RPE65 founder mutation is associated with variable expression and progression of early onset retinal dystrophy in 10 families of a genetically isolated population

Author: Yzer, S, van den Born, LI, Schuil, J, Kroes, HY, van Genderen, MM, Boonstra, FN, van den Helm, B, Brunner, HG, Koenekoop, RK, and Cremers, FPM
Subjects: Gene mutations -- Analysis -- Research -- Genetic aspects, Retinal degeneration -- Genetic aspects -- Research, Medical genetics -- Research -- Analysis, Health, Analysis, Research, Genetic aspects
Abstract: Autosomal recessive retinal dystrophies cause visual impairment in approximately 1 in 4000 individuals worldwide. (1) The non-syndromic forms are highly heterogeneous and can be classified into clinical subgroups, the most [...]
Published: 2003

10. De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder

Author: Reijnders, MRF, Miller, KA, Alvi, M, Goos, JAC, Lees, MM, de Burca, A, Henderson, A, Kraus, A, Mikat, B, de Vries, BBA, Isidor, B, Kerr, B, Marcelis, C, Schluth-Bolard, C, Deshpande, C, Ruivenkamp, CAL, Wieczorek, D, Deciphering Developmental Disorders Study, Baralle, D, Blair, EM, Engels, H, Lüdecke, H-J, Eason, J, Santen, GWE, Clayton-Smith, J, Chandler, K, Tatton-Brown, K, Payne, K, Helbig, K, Radtke, K, Nugent, KM, Cremer, K, Strom, TM, Bird, LM, Sinnema, M, Bitner-Glindzicz, M, van Dooren, MF, Alders, M, Koopmans, M, Brick, L, Kozenko, M, Harline, ML, Klaassens, M, Steinraths, M, Cooper, NS, Edery, P, Yap, P, Terhal, PA, van der Spek, PJ, Lakeman, P, Taylor, RL, Littlejohn, RO, Pfundt, R, Mercimek-Andrews, S, Stegmann, APA, Kant, SG, McLean, S, Joss, S, Swagemakers, SMA, Douzgou, S, Wall, SA, Küry, S, Calpena, E, Koelling, N, McGowan, SJ, Twigg, SRF, Mathijssen, IMJ, Nellaker, C, Brunner, HG, and Wilkie, AOM
Subjects: Adult, Male, Adolescent, kinase, Messenger, Inheritance Patterns, Translocation, Medical and Health Sciences, Cell Line, Young Adult, Genetic, Clinical Research, Loss of Function Mutation, Genetics, 2.1 Biological and endogenous factors, Humans, Aetiology, Child, Preschool, Genetic Association Studies, Genetics & Heredity, Tousled-like, Base Sequence, Human Genome, Neurosciences, Facies, Infant, Deciphering Developmental Disorders Study, Biological Sciences, Brain Disorders, haploinsufficiency, Neurodevelopmental Disorders, intellectual disability, RNA, Female, Protein Kinases, facial averaging, Biotechnology
Abstract: Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2.
Published: 2018

11. PURA syndrome: clinical delineation and genotype-phenotype study in 32 individuals with review of published literature

Author: Reijnders, MRF, Janowski, R, Alvi, M, Self, JE, van Essen, TJ, Vreeburg, M, Rouhl, RPW, Stevens, SJC, Stegmann, APA, Schieving, J, Pfundt, R, van Dijk, K, Smeets, E, Stumpel, CTRM, Bok, LA, Cobben, JM, Engelen, M, Mansour, S, Whiteford, M, Chandler, KE, Douzgou, S, Cooper, NS, Tan, E-C, Foo, R, Lai, AHM, Rankin, J, Green, A, Loennqvist, T, Isohanni, P, Williams, S, Ruhoy, I, Carvalho, KS, Dowling, JJ, Lev, DL, Sterbova, K, Lassuthova, P, Neupauerova, J, Waugh, JL, Keros, S, Clayton-Smith, J, Smithson, SF, Brunner, HG, van Hoeckel, C, Anderson, M, Clowes, VE, Siu, VM, Selber, P, Leventer, RJ, Nellaker, C, Niessing, D, Hunt, D, Baralle, D, Reijnders, MRF, Janowski, R, Alvi, M, Self, JE, van Essen, TJ, Vreeburg, M, Rouhl, RPW, Stevens, SJC, Stegmann, APA, Schieving, J, Pfundt, R, van Dijk, K, Smeets, E, Stumpel, CTRM, Bok, LA, Cobben, JM, Engelen, M, Mansour, S, Whiteford, M, Chandler, KE, Douzgou, S, Cooper, NS, Tan, E-C, Foo, R, Lai, AHM, Rankin, J, Green, A, Loennqvist, T, Isohanni, P, Williams, S, Ruhoy, I, Carvalho, KS, Dowling, JJ, Lev, DL, Sterbova, K, Lassuthova, P, Neupauerova, J, Waugh, JL, Keros, S, Clayton-Smith, J, Smithson, SF, Brunner, HG, van Hoeckel, C, Anderson, M, Clowes, VE, Siu, VM, Selber, P, Leventer, RJ, Nellaker, C, Niessing, D, Hunt, D, and Baralle, D
Abstract: BACKGROUND: De novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia. OBJECTIVES: To delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations. METHODS: Diagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of Drosophila-derived Pur-alpha homologues. Finally, we explored genotype-phenotype correlations by analysis of both recurrent mutations as well as mutation classes. RESULTS: We report mutations in PURA (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes. CONCLUSION: We delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and
Published: 2018

12. De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder

Author: Reijnders, M R F, Miller, KA, Alvi, M, Goos, Jacqueline, Lees, MM, de Burca, A, Henderson, A, Kraus, A, Mikat, B, de Vries, BBA, Isidor, B, Kerr, B, Marcelis, C, Schluth-Bolard, C, Deshpande, C, Ruivenkamp, CAL, Wieczorek, D, Baralle, D, Blair, EM, Engels, H, Ludecke, HJ, Eason, J, Santen, GWE, Clayton-Smith, J, Chandler, K, Tatton-Brown, K, Payne, K, Helbig, K, Radtke, K, Nugent, KM, Cremer, K, Strom, TM, Bird, LM, Sinnema, M, Bitner-Glindzicz, M, van Dooren, Marieke, Alders, M, Koopmans, M, Brick, L, Kozenko, M, Harline, ML, Klaassens, M, Steinraths, M, Cooper, NS, Edery, P, Yap, P, Terhal, PA, van der Spek, Peter, Lakeman, P, Taylor, RL, Littlejohn, RO, Pfundt, R, Mercimek-Andrews, S, Stegmann, APA, Kant, SG, McLean, S, Joss, S, Swagemakers, Sigrid, Douzgou, S, Wall, SA, Kury, S, Calpena, E, Koelling, N, McGowan, SJ, Twigg, SRF, Mathijssen, Irene, Nellaker, C, Brunner, HG, Wilkie, AOM, Reijnders, M R F, Miller, KA, Alvi, M, Goos, Jacqueline, Lees, MM, de Burca, A, Henderson, A, Kraus, A, Mikat, B, de Vries, BBA, Isidor, B, Kerr, B, Marcelis, C, Schluth-Bolard, C, Deshpande, C, Ruivenkamp, CAL, Wieczorek, D, Baralle, D, Blair, EM, Engels, H, Ludecke, HJ, Eason, J, Santen, GWE, Clayton-Smith, J, Chandler, K, Tatton-Brown, K, Payne, K, Helbig, K, Radtke, K, Nugent, KM, Cremer, K, Strom, TM, Bird, LM, Sinnema, M, Bitner-Glindzicz, M, van Dooren, Marieke, Alders, M, Koopmans, M, Brick, L, Kozenko, M, Harline, ML, Klaassens, M, Steinraths, M, Cooper, NS, Edery, P, Yap, P, Terhal, PA, van der Spek, Peter, Lakeman, P, Taylor, RL, Littlejohn, RO, Pfundt, R, Mercimek-Andrews, S, Stegmann, APA, Kant, SG, McLean, S, Joss, S, Swagemakers, Sigrid, Douzgou, S, Wall, SA, Kury, S, Calpena, E, Koelling, N, McGowan, SJ, Twigg, SRF, Mathijssen, Irene, Nellaker, C, Brunner, HG, and Wilkie, AOM
Published: 2018

13. Toward clinical and molecular understanding of pathogenic variants in the ZBTB18 gene

Author: van der Schoot, V, de Munnik, S, Venselaar, H, Elting, M, Verheijen - Mancini, Grazia, van Ravenswaaij-Arts, CMA, Anderlid, BM, Brunner, HG, Stevens, SJC, van der Schoot, V, de Munnik, S, Venselaar, H, Elting, M, Verheijen - Mancini, Grazia, van Ravenswaaij-Arts, CMA, Anderlid, BM, Brunner, HG, and Stevens, SJC
Published: 2018

14. Cellular interference in craniofrontonasal syndrome: males mosaic for mutations in the X-linked EFNB1 gene are more severely affected than true hemizygotes

Author: Twigg, SR, Babbs, C, van den Elzen, ME, Goriely, A, Taylor, S, McGowan, SJ, Giannoulatou, E, Lonie, L, Ragoussis, J, Sadighi Akha, E, Knight, SJ, Zechi-Ceide, RM, Hoogeboom, JA, Pober, BR, Toriello, HV, Wall, SA, Rita Passos-Bueno, M, Brunner, HG, Mathijssen, IM, Wilkie, AO, and Plastic and Reconstructive Surgery and Hand Surgery
Subjects: Hemizygote, Male, Heterozygote, Sex Characteristics, Mosaicism, Infant, Newborn, Infant, Articles, Ephrin-B1, Pedigree, Craniofacial Abnormalities, Phenotype, X Chromosome Inactivation, Child, Preschool, Humans, Point Mutation, Female, Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6], Child, Gene Deletion
Abstract: Contains fulltext : 118112.pdf (Publisher’s version ) (Open Access) Craniofrontonasal syndrome (CFNS), an X-linked disorder caused by loss-of-function mutations of EFNB1, exhibits a paradoxical sex reversal in phenotypic severity: females characteristically have frontonasal dysplasia, craniosynostosis and additional minor malformations, but males are usually more mildly affected with hypertelorism as the only feature. X-inactivation is proposed to explain the more severe outcome in heterozygous females, as this leads to functional mosaicism for cells with differing expression of EPHRIN-B1, generating abnormal tissue boundaries-a process that cannot occur in hemizygous males. Apparently challenging this model, males occasionally present with a more severe female-like CFNS phenotype. We hypothesized that such individuals might be mosaic for EFNB1 mutations and investigated this possibility in multiple tissue samples from six sporadically presenting males. Using denaturing high performance liquid chromatography, massively parallel sequencing and multiplex-ligation-dependent probe amplification (MLPA) to increase sensitivity above standard dideoxy sequencing, we identified mosaic mutations of EFNB1 in all cases, comprising three missense changes, two gene deletions and a novel point mutation within the 5' untranslated region (UTR). Quantification by Pyrosequencing and MLPA demonstrated levels of mutant cells between 15 and 69%. The 5' UTR variant mutates the stop codon of a small upstream open reading frame that, using a dual-luciferase reporter construct, was demonstrated to exacerbate interference with translation of the wild-type protein. These results demonstrate a more severe outcome in mosaic than in constitutionally deficient males in an X-linked dominant disorder and provide further support for the cellular interference mechanism, normally related to X-inactivation in females.
Published: 2013

15. Novel genetic loci associated with hippocampal volume

Author: Hibar, DP, Adams, HHH, Jahanshad, N, Chauhan, G, Stein, JL, Hofer, E, Renteria, ME, Bis, JC, Arias-Vasquez, A, Ikram, MK, Desrivieres, S, Vernooij, MW, Abramovic, L, Alhusaini, S, Amin, N, Andersson, M, Arfanakis, K, Aribisala, BS, Armstrong, NJ, Athanasiu, L, Axelsson, T, Beecham, AH, Beiser, A, Bernard, M, Blanton, SH, Bohlken, MM, Boks, MP, Bralten, J, Brickman, AM, Carmichael, O, Chakravarty, MM, Chen, Q, Ching, CRK, Chouraki, V, Cuellar-Partida, G, Crivello, F, Den Braber, A, Nhat, TD, Ehrlich, S, Giddaluru, S, Goldman, AL, Gottesman, RF, Grimm, O, Griswold, ME, Guadalupe, T, Gutman, BA, Hass, J, Haukvik, UK, Hoehn, D, Holmes, AJ, Hoogman, M, Janowitz, D, Jia, T, Jorgensen, KN, Karbalai, N, Kasperaviciute, D, Kim, S, Klein, M, Kraemer, B, Lee, PH, Liewald, DCM, Lopez, LM, Luciano, M, Macare, C, Marquand, AF, Matarin, M, Mather, KA, Mattheisen, M, McKay, DR, Milaneschi, Y, Maniega, SM, Nho, K, Nugent, AC, Nyquist, P, Loohuis, LMO, Oosterlaan, J, Papmeyer, M, Pirpamer, L, Puetz, B, Ramasamy, A, Richards, JS, Risacher, SL, Roiz-Santianez, R, Rommelse, N, Ropele, S, Rose, EJ, Royle, NA, Rundek, T, Saemann, PG, Saremi, A, Satizabal, CL, Schmaal, L, Schork, AJ, Shen, L, Shin, J, Shumskaya, E, Smith, AV, Sprooten, E, Strike, LT, Teumer, A, Tordesillas-Gutierrez, D, Toro, R, Trabzuni, D, Trompet, S, Vaidya, D, Van der Grond, J, Van der Lee, SJ, Van der Meer, D, Van Donkelaar, MMJ, Van Eijk, KR, Van Erp, TGM, Van Rooij, D, Walton, E, Westlye, LT, Whelan, CD, Windham, BG, Winkler, AM, Wittfeld, K, Woldehawariat, G, Wolf, C, Wolfers, T, Yanek, LR, Yang, J, Zijdenbos, A, Zwiers, MP, Agartz, I, Almasy, L, Ames, D, Amouyel, P, Andreassen, OA, Arepalli, S, Assareh, AA, Barral, S, Bastin, ME, Becker, DM, Becker, JT, Bennett, DA, Blangero, J, van Bokhoven, H, Boomsma, DI, Brodaty, H, Brouwer, RM, Brunner, HG, Buckner, RL, Buitelaar, JK, Bulayeva, KB, Cahn, W, Calhoun, VD, Cannon, DM, Cavalleri, GL, Cheng, C-Y, Cichon, S, Cookson, MR, Corvin, A, Crespo-Facorro, B, Curran, JE, Czisch, M, Dale, AM, Davies, GE, De Craen, AJM, De Geus, EJC, De Jager, PL, De Zubicaray, GI, Deary, IJ, Debette, S, DeCarli, C, Delanty, N, Depondt, C, DeStefano, A, Dillman, A, Djurovic, S, Donohoe, G, Drevets, WC, Duggirala, R, Dyer, TD, Enzinger, C, Erk, S, Espeseth, T, Fedko, IO, Fernandez, G, Ferrucci, L, Fisher, SE, Fleischman, DA, Ford, I, Fornage, M, Foroud, TM, Fox, PT, Francks, C, Fukunaga, M, Gibbs, JR, Glahn, DC, Gollub, RL, Goring, HHH, Green, RC, Gruber, O, Gudnason, V, Guelfi, S, Haberg, AK, Hansell, NK, Hardy, J, Hartman, CA, Hashimoto, R, Hegenscheid, K, Heinz, A, Le Hellard, S, Hernandez, DG, Heslenfeld, DJ, Ho, B-C, Hoekstra, PJ, Hoffmann, W, Hofman, A, Holsboer, F, Homuth, G, Hosten, N, Hottenga, J-J, Huentelman, M, Pol, HEH, Ikeda, M, Jack, CR, Jenkinson, M, Johnson, R, Joensson, EG, Jukema, JW, Kahn, RS, Kanai, R, Kloszewska, I, Knopman, DS, Kochunov, P, Kwok, JB, Lawrie, SM, Lemaitre, H, Liu, X, Longo, DL, Lopez, OL, Lovestone, S, Martinez, O, Martinot, J-L, Mattay, VS, McDonald, C, McIntosh, AM, McMahon, FJ, McMahon, KL, Mecocci, P, Melle, I, Meyer-Lindenberg, A, Mohnke, S, Montgomery, GW, Morris, DW, Mosley, TH, Muhleisen, TW, Mueller-Myhsok, B, Nalls, MA, Nauck, M, Nichols, TE, Niessen, WJ, Nothen, MM, Nyberg, L, Ohi, K, Olvera, RL, Ophoff, RA, Pandolfo, M, Paus, T, Pausova, Z, Penninx, BWJH, Pike, GB, Potkin, SG, Psaty, BM, Reppermund, S, Rietschel, M, Roffman, JL, Romanczuk-Seiferth, N, Rotter, JI, Ryten, M, Sacco, RL, Sachdev, PS, Saykin, AJ, Schmidt, R, Schmidt, H, Schofield, PR, Sigursson, S, Simmons, A, Singleton, A, Sisodiya, SM, Smith, C, Smoller, JW, Soininen, H, Steen, VM, Stott, DJ, Sussmann, JE, Thalamuthu, A, Toga, AW, Traynor, BJ, Troncoso, J, Tsolaki, M, Tzourio, C, Uitterlinden, AG, Hernandez, MCV, Van der Brug, M, van der Lugt, A, van der Wee, NJA, Van Haren, NEM, van't Ent, D, Van Tol, M-J, Vardarajan, BN, Vellas, B, Veltman, DJ, Voelzke, H, Walter, H, Wardlaw, JM, Wassink, TH, Weale, ME, Weinberger, DR, Weiner, MW, Wen, W, Westman, E, White, T, Wong, TY, Wright, CB, Zielke, RH, Zonderman, AB, Martin, NG, Van Duijn, CM, Wright, MJ, Longstreth, WT, Schumann, G, Grabe, HJ, Franke, B, Launer, LJ, Medland, SE, Seshadri, S, Thompson, PM, Ikram, MA, Hibar, DP, Adams, HHH, Jahanshad, N, Chauhan, G, Stein, JL, Hofer, E, Renteria, ME, Bis, JC, Arias-Vasquez, A, Ikram, MK, Desrivieres, S, Vernooij, MW, Abramovic, L, Alhusaini, S, Amin, N, Andersson, M, Arfanakis, K, Aribisala, BS, Armstrong, NJ, Athanasiu, L, Axelsson, T, Beecham, AH, Beiser, A, Bernard, M, Blanton, SH, Bohlken, MM, Boks, MP, Bralten, J, Brickman, AM, Carmichael, O, Chakravarty, MM, Chen, Q, Ching, CRK, Chouraki, V, Cuellar-Partida, G, Crivello, F, Den Braber, A, Nhat, TD, Ehrlich, S, Giddaluru, S, Goldman, AL, Gottesman, RF, Grimm, O, Griswold, ME, Guadalupe, T, Gutman, BA, Hass, J, Haukvik, UK, Hoehn, D, Holmes, AJ, Hoogman, M, Janowitz, D, Jia, T, Jorgensen, KN, Karbalai, N, Kasperaviciute, D, Kim, S, Klein, M, Kraemer, B, Lee, PH, Liewald, DCM, Lopez, LM, Luciano, M, Macare, C, Marquand, AF, Matarin, M, Mather, KA, Mattheisen, M, McKay, DR, Milaneschi, Y, Maniega, SM, Nho, K, Nugent, AC, Nyquist, P, Loohuis, LMO, Oosterlaan, J, Papmeyer, M, Pirpamer, L, Puetz, B, Ramasamy, A, Richards, JS, Risacher, SL, Roiz-Santianez, R, Rommelse, N, Ropele, S, Rose, EJ, Royle, NA, Rundek, T, Saemann, PG, Saremi, A, Satizabal, CL, Schmaal, L, Schork, AJ, Shen, L, Shin, J, Shumskaya, E, Smith, AV, Sprooten, E, Strike, LT, Teumer, A, Tordesillas-Gutierrez, D, Toro, R, Trabzuni, D, Trompet, S, Vaidya, D, Van der Grond, J, Van der Lee, SJ, Van der Meer, D, Van Donkelaar, MMJ, Van Eijk, KR, Van Erp, TGM, Van Rooij, D, Walton, E, Westlye, LT, Whelan, CD, Windham, BG, Winkler, AM, Wittfeld, K, Woldehawariat, G, Wolf, C, Wolfers, T, Yanek, LR, Yang, J, Zijdenbos, A, Zwiers, MP, Agartz, I, Almasy, L, Ames, D, Amouyel, P, Andreassen, OA, Arepalli, S, Assareh, AA, Barral, S, Bastin, ME, Becker, DM, Becker, JT, Bennett, DA, Blangero, J, van Bokhoven, H, Boomsma, DI, Brodaty, H, Brouwer, RM, Brunner, HG, Buckner, RL, Buitelaar, JK, Bulayeva, KB, Cahn, W, Calhoun, VD, Cannon, DM, Cavalleri, GL, Cheng, C-Y, Cichon, S, Cookson, MR, Corvin, A, Crespo-Facorro, B, Curran, JE, Czisch, M, Dale, AM, Davies, GE, De Craen, AJM, De Geus, EJC, De Jager, PL, De Zubicaray, GI, Deary, IJ, Debette, S, DeCarli, C, Delanty, N, Depondt, C, DeStefano, A, Dillman, A, Djurovic, S, Donohoe, G, Drevets, WC, Duggirala, R, Dyer, TD, Enzinger, C, Erk, S, Espeseth, T, Fedko, IO, Fernandez, G, Ferrucci, L, Fisher, SE, Fleischman, DA, Ford, I, Fornage, M, Foroud, TM, Fox, PT, Francks, C, Fukunaga, M, Gibbs, JR, Glahn, DC, Gollub, RL, Goring, HHH, Green, RC, Gruber, O, Gudnason, V, Guelfi, S, Haberg, AK, Hansell, NK, Hardy, J, Hartman, CA, Hashimoto, R, Hegenscheid, K, Heinz, A, Le Hellard, S, Hernandez, DG, Heslenfeld, DJ, Ho, B-C, Hoekstra, PJ, Hoffmann, W, Hofman, A, Holsboer, F, Homuth, G, Hosten, N, Hottenga, J-J, Huentelman, M, Pol, HEH, Ikeda, M, Jack, CR, Jenkinson, M, Johnson, R, Joensson, EG, Jukema, JW, Kahn, RS, Kanai, R, Kloszewska, I, Knopman, DS, Kochunov, P, Kwok, JB, Lawrie, SM, Lemaitre, H, Liu, X, Longo, DL, Lopez, OL, Lovestone, S, Martinez, O, Martinot, J-L, Mattay, VS, McDonald, C, McIntosh, AM, McMahon, FJ, McMahon, KL, Mecocci, P, Melle, I, Meyer-Lindenberg, A, Mohnke, S, Montgomery, GW, Morris, DW, Mosley, TH, Muhleisen, TW, Mueller-Myhsok, B, Nalls, MA, Nauck, M, Nichols, TE, Niessen, WJ, Nothen, MM, Nyberg, L, Ohi, K, Olvera, RL, Ophoff, RA, Pandolfo, M, Paus, T, Pausova, Z, Penninx, BWJH, Pike, GB, Potkin, SG, Psaty, BM, Reppermund, S, Rietschel, M, Roffman, JL, Romanczuk-Seiferth, N, Rotter, JI, Ryten, M, Sacco, RL, Sachdev, PS, Saykin, AJ, Schmidt, R, Schmidt, H, Schofield, PR, Sigursson, S, Simmons, A, Singleton, A, Sisodiya, SM, Smith, C, Smoller, JW, Soininen, H, Steen, VM, Stott, DJ, Sussmann, JE, Thalamuthu, A, Toga, AW, Traynor, BJ, Troncoso, J, Tsolaki, M, Tzourio, C, Uitterlinden, AG, Hernandez, MCV, Van der Brug, M, van der Lugt, A, van der Wee, NJA, Van Haren, NEM, van't Ent, D, Van Tol, M-J, Vardarajan, BN, Vellas, B, Veltman, DJ, Voelzke, H, Walter, H, Wardlaw, JM, Wassink, TH, Weale, ME, Weinberger, DR, Weiner, MW, Wen, W, Westman, E, White, T, Wong, TY, Wright, CB, Zielke, RH, Zonderman, AB, Martin, NG, Van Duijn, CM, Wright, MJ, Longstreth, WT, Schumann, G, Grabe, HJ, Franke, B, Launer, LJ, Medland, SE, Seshadri, S, Thompson, PM, and Ikram, MA
Abstract: The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg=-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
Published: 2017

16. YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction.

Author: Gabriele, M, Vulto-van Silfhout, AT, Germain, P-L, Vitriolo, A, Kumar, R, Douglas, E, Haan, E, Kosaki, K, Takenouchi, T, Rauch, A, Steindl, K, Frengen, E, Misceo, D, Pedurupillay, CRJ, Stromme, P, Rosenfeld, JA, Shao, Y, Craigen, WJ, Schaaf, CP, Rodriguez-Buritica, D, Farach, L, Friedman, J, Thulin, P, McLean, SD, Nugent, KM, Morton, J, Nicholl, J, Andrieux, J, Stray-Pedersen, A, Chambon, P, Patrier, S, Lynch, SA, Kjaergaard, S, Tørring, PM, Brasch-Andersen, C, Ronan, A, van Haeringen, A, Anderson, PJ, Powis, Z, Brunner, HG, Pfundt, R, Schuurs-Hoeijmakers, JHM, van Bon, BWM, Lelieveld, S, Gilissen, C, Nillesen, WM, Vissers, LELM, Gecz, J, Koolen, DA, Testa, G, de Vries, BBA, Gabriele, M, Vulto-van Silfhout, AT, Germain, P-L, Vitriolo, A, Kumar, R, Douglas, E, Haan, E, Kosaki, K, Takenouchi, T, Rauch, A, Steindl, K, Frengen, E, Misceo, D, Pedurupillay, CRJ, Stromme, P, Rosenfeld, JA, Shao, Y, Craigen, WJ, Schaaf, CP, Rodriguez-Buritica, D, Farach, L, Friedman, J, Thulin, P, McLean, SD, Nugent, KM, Morton, J, Nicholl, J, Andrieux, J, Stray-Pedersen, A, Chambon, P, Patrier, S, Lynch, SA, Kjaergaard, S, Tørring, PM, Brasch-Andersen, C, Ronan, A, van Haeringen, A, Anderson, PJ, Powis, Z, Brunner, HG, Pfundt, R, Schuurs-Hoeijmakers, JHM, van Bon, BWM, Lelieveld, S, Gilissen, C, Nillesen, WM, Vissers, LELM, Gecz, J, Koolen, DA, Testa, G, and de Vries, BBA
Abstract: Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators.
Published: 2017

17. Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability

Author: Reijnders, M R F, Kousi, M, van Woerden, Geeske, Klein, M, Bralten, J, Verheijen - Mancini, Grazia, van Essen, T, Proietti-Onori, M, Smeets, EEJ, van Gastel, M, Stegmann, APA, Stevens, SJC, Lelieveld, SH, Gilissen, C, Pfundt, R, Tan, PL, Kleefstra, T, Franke, B, Elgersma, Ype, Katsanis, N, Brunner, HG, Reijnders, M R F, Kousi, M, van Woerden, Geeske, Klein, M, Bralten, J, Verheijen - Mancini, Grazia, van Essen, T, Proietti-Onori, M, Smeets, EEJ, van Gastel, M, Stegmann, APA, Stevens, SJC, Lelieveld, SH, Gilissen, C, Pfundt, R, Tan, PL, Kleefstra, T, Franke, B, Elgersma, Ype, Katsanis, N, and Brunner, HG
Published: 2017

18. The Role of Previous Miscarriages and Single Nucleotide Polymorphisms in Developmental Genes in the Etiology of Anorectal Malformations

Author: Van der Putte, R, Wijers, CHW, Blaauw, Ivo, Marcelis, CLM, Sloots, C.E.J., Brooks, A, Broens, PMA, Brunner, HG, van der Zanden, LFM, van Rooij, IALM, Roeleveld, N, and Pediatric Surgery
Published: 2015

19. Genetic influences on schizophrenia and subcortical brain volumes: Large-scale proof of concept

Author: Franke, B, van Hulzen, KJE, Arias-Vasquez, A, Bralten, J, Hoogman, M, Klein, M, van Donkelaar, MMJ, Hakobjan, MMH, Heister, AJGAM, Makkinje, RRR, Naber, MAM, van der Marel, SSL, Mostert, JC, Brunner, HG, van Bokhoven, H, Zwiers, MP, Buitelaar, JK, Fernández, G, Fisher, SE, Francks, C, Stein, JL, Hibar, DP, Thompson, PM, Ripke, S, Anttila, V, Neale, BM, Farh, KH, Bulik-Sullivan, B, Huang, H, Fromer, M, Goldstein, JI, Daly, MJ, Walters, RK, Smoller, JW, Lee, P, Belliveau, RA, Bergen, SE, Bevilacqua, E, Chambert, KD, Genovese, G, O'Dushlaine, C, Scolnick, EM, McCarroll, SA, Moran, JL, Palotie, A, Petryshen, TL, Erk, S, Heinz, A, Mohnke, S, Romanczuk-Seiferth, N, Walter, H, DeLisi, LE, McCarley, RW, Mesholam-Gately, RI, Seidman, LJ, Nichols, TE, Neale, MC, McIntosh, AM, Papmeyer, M, Sprooten, E, Lawrie, SM, Sussmann, JE, McMahon, FJ, Yao, Y, Meyer-Lindenberg, A, Schwarz, E, Grimm, O, Mattheisen, M, Agerbo, E, Demontis, D, Hansen, T, Mors, O, Olsen, L, Rasmussen, HB, Børglum, AD, Mortensen, PB, Werge, T, Andreassen, OA, Brown, AA, Athanasiu, L, Hartberg, CB, Haukvik, U, Melle, I, Gruber, O, Kraemer, B, Keil, M, Sachdev, PS, Mather, KA, Thalamuthu, A, Armstrong, NJ, Assareh, AA, Brodaty, H, Reppermund, S, Wen, W, Roiz-Santiañez, R, Perez-Iglesias, R, Saykin, AJ, Kim, S, Nho, K, Risacher, SL, Franke, B, van Hulzen, KJE, Arias-Vasquez, A, Bralten, J, Hoogman, M, Klein, M, van Donkelaar, MMJ, Hakobjan, MMH, Heister, AJGAM, Makkinje, RRR, Naber, MAM, van der Marel, SSL, Mostert, JC, Brunner, HG, van Bokhoven, H, Zwiers, MP, Buitelaar, JK, Fernández, G, Fisher, SE, Francks, C, Stein, JL, Hibar, DP, Thompson, PM, Ripke, S, Anttila, V, Neale, BM, Farh, KH, Bulik-Sullivan, B, Huang, H, Fromer, M, Goldstein, JI, Daly, MJ, Walters, RK, Smoller, JW, Lee, P, Belliveau, RA, Bergen, SE, Bevilacqua, E, Chambert, KD, Genovese, G, O'Dushlaine, C, Scolnick, EM, McCarroll, SA, Moran, JL, Palotie, A, Petryshen, TL, Erk, S, Heinz, A, Mohnke, S, Romanczuk-Seiferth, N, Walter, H, DeLisi, LE, McCarley, RW, Mesholam-Gately, RI, Seidman, LJ, Nichols, TE, Neale, MC, McIntosh, AM, Papmeyer, M, Sprooten, E, Lawrie, SM, Sussmann, JE, McMahon, FJ, Yao, Y, Meyer-Lindenberg, A, Schwarz, E, Grimm, O, Mattheisen, M, Agerbo, E, Demontis, D, Hansen, T, Mors, O, Olsen, L, Rasmussen, HB, Børglum, AD, Mortensen, PB, Werge, T, Andreassen, OA, Brown, AA, Athanasiu, L, Hartberg, CB, Haukvik, U, Melle, I, Gruber, O, Kraemer, B, Keil, M, Sachdev, PS, Mather, KA, Thalamuthu, A, Armstrong, NJ, Assareh, AA, Brodaty, H, Reppermund, S, Wen, W, Roiz-Santiañez, R, Perez-Iglesias, R, Saykin, AJ, Kim, S, Nho, K, and Risacher, SL
Abstract: Schizophrenia is a devastating psychiatric illness with high heritability. Brain structure and function differ, on average, between people with schizophrenia and healthy individuals. As common genetic associations are emerging for both schizophrenia and brain imaging phenotypes, we can now use genome-wide data to investigate genetic overlap. Here we integrated results from common variant studies of schizophrenia (33,636 cases, 43,008 controls) and volumes of several (mainly subcortical) brain structures (11,840 subjects). We did not find evidence of genetic overlap between schizophrenia risk and subcortical volume measures either at the level of common variant genetic architecture or for single genetic markers. These results provide a proof of concept (albeit based on a limited set of structural brain measures) and define a roadmap for future studies investigating the genetic covariance between structural or functional brain phenotypes and risk for psychiatric disorders.
Published: 2016

20. The ENIGMA Consortium: Large-scale collaborative analyses of neuroimaging and genetic data

Author: Thompson, PM, Stein, JL, Medland, SE, Hibar, DP, Vasquez, AA, Renteria, ME, Toro, R, Jahanshad, N, Schumann, G, Franke, B, Wright, MJ, Martin, NG, Agartz, I, Alda, M, Alhusaini, S, Almasy, L, Almeida, J, Alpert, K, Andreasen, NC, Andreassen, OA, Apostolova, LG, Appel, K, Armstrong, NJ, Aribisala, B, Bastin, ME, Bauer, M, Bearden, CE, Bergmann, Ø, Binder, EB, Blangero, J, Bockholt, HJ, Bøen, E, Bois, C, Boomsma, DI, Booth, T, Bowman, IJ, Bralten, J, Brouwer, RM, Brunner, HG, Brohawn, DG, Buckner, RL, Buitelaar, J, Bulayeva, K, Bustillo, JR, Calhoun, VD, Cannon, DM, Cantor, RM, Carless, MA, Caseras, X, Cavalleri, GL, Chakravarty, MM, Chang, KD, Ching, CRK, Christoforou, A, Cichon, S, Clark, VP, Conrod, P, Coppola, G, Crespo-Facorro, B, Curran, JE, Czisch, M, Deary, IJ, de Geus, EJC, den Braber, A, Delvecchio, G, Depondt, C, de Haan, L, de Zubicaray, GI, Dima, D, Dimitrova, R, and Djurovic, S
Subjects: endocrine system
Abstract: The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way. © 2014 The Author(s).
Published: 2014

21. A limited repertoire of mutations of the luteinizing hormone (LH) receptor gene in familial and sporadic patients with male LH-independent precocious puberty

Author: Kremer, H, Martens, Jwm, VAN REEN, M, VERHOEF POST, M, Wit, Jm, Otten, Bj, Drop, Sls, DELEMARRE VAN DE WAAL HA, POMBO ARIAS, M, DE LUCA, Filippo, Potau, N, Buckler, Jmh, Jansen, M, Parks, Js, Latif, Ha, Moll, Gw, Epping, W, Saggese, G, Mariman, Ecm, Themmen, Apn, and Brunner, Hg
Subjects: Male, Endocrinology, Diabetes and Metabolism, Biochemistry (medical), Clinical Biochemistry, DNA Mutational Analysis, Puberty, Precocious, Luteinizing Hormone, Receptors, LH, Biochemistry, Endocrinology, Mutation, Mechanistische en klinisch genetische aspecten van gonadotropine receptor mutaties, Cyclic AMP, Humans, Amino Acid Sequence, Mechanistic and clinical genetic aspects of gonadotropin receptor mutations, Child
Abstract: Herein, we report mutation analysis of the LH receptor gene in 17 males with LH-independent precocious puberty, of which 8 were familial and 9 had a negative family history. A total of 7 different mutations (all previously reported) were detected in 12 patients. Among 10 European familial male-limited precocious puberty (FMPP) patients who had a LH receptor gene mutation, none had the Asp578Gly mutation, which is responsible for the vast majority of cases in the U.S. The restricted number of activating mutations of the LH receptor observed in this and other studies of FMPP strongly suggests that an activating phenotype is associated with very specific sites in the receptor protein. Clinical follow-up of the 5 patients who did not have LH receptor mutations shows that such cases most likely do not have true FMPP. LH receptor mutation analysis provides a sensitive tool for distinguishing true FMPP from other causes of early-onset LH-independent puberty in males.
Published: 1999

22. Meier-Gorlin syndrome

Author: de Munnik, SA, Hoefsloot, EH, Roukema, J, Schoots, J, Knoers, NVAM, Brunner, HG, Jackson, AP, Bongers, EMHF, de Munnik, SA, Hoefsloot, EH, Roukema, J, Schoots, J, Knoers, NVAM, Brunner, HG, Jackson, AP, and Bongers, EMHF
Abstract: Meier-Gorlin syndrome (MGS) is a rare autosomal recessive primordial dwarfism disorder, characterized by microtia, patellar applasia/hypoplasia, and a proportionate short stature. Associated clinical features encompass feeding problems, congenital pulmonary emphysema, mammary hypoplasia in females and urogenital anomalies, such as cryptorchidism and hypoplastic labia minora and majora. Typical facial characteristics during childhood comprise a small mouth with full lips and micro-retrognathia. During ageing, a narrow, convex nose becomes more prominent. The diagnosis MGS should be considered in patients with at least two of the three features of the clinical triad of microtia, patellar anomalies, and pre- and postnatal growth retardation. In patients with short stature and/or microtia, the patellae should be assessed with care by ultrasonography before age 6 or radiography thereafter. Mutations in one of five genes (ORC1, ORC4, ORC6, CDT1, and CDC6) of the pre-replication complex, involved in DNA-replication, are detected in approximately 67-78 % of patients with MGS. Patients with ORC1 and ORC4 mutations appear to have the most severe short stature and microcephaly. Management should be directed towards in-depth investigation, treatment and prevention of associated problems, such as growth retardation, feeding problems, hearing loss, luxating patellae, knee pain, gonarthrosis, and possible pulmonary complications due to congenital pulmonary emphysema with or without broncho- or laryngomalacia. Growth hormone treatment is ineffective in most patients with MGS, but may be effective in patients in whom growth continues to decrease after the first year of life (usually growth velocity normalizes after the first year) and with low levels of IGF1. At present, few data is available about reproduction of females with MGS, but the risk of premature labor might be increased. Here, we propose experience-based guidelines for the regular care and treatment of MGS patients.
Published: 2015

23. (Waardenburg Anophthalmia) Syndrome in Humans and Mice

Author: Rainger, J, van Beusekom, E, Ramsay, JK, McKie, L, Al-Gazali, L, Pallotta, R, Saponari, A, Branney, P, Fisher, M, Morrison, H, Bicknell, L, Gautier, P, Perry, P, Sokhi, K, Sexton, D, Bardakjian, TM, Schneider, AS, Elcioglu, N, Ozkinay, F, Koenig, R, Megarbane, A, Semerci, CN, Khan, A, Zafar, S, Hennekam, R, Sousa, SB, Ramos, L, Garavelli, L, Furga, AS, Wischmeijer, A, Jackson, IJ, Gillessen-Kaesbach, G, Brunner, HG, Wieczorek, D, van Bokhoven, H, and FitzPatrick, DR
Abstract: Ophthalmo-acromelic syndrome (OAS), also known as Waardenburg Anophthalmia syndrome, is defined by the combination of eye malformations, most commonly bilateral anophthalmia, with post-axial oligosyndactyly. Homozygosity mapping and subsequent targeted mutation analysis of a locus on 14q24.2 identified homozygous mutations in SMOCI (SPARC-related modular calcium binding 1) in eight unrelated families. Four of these mutations are nonsense, two frame-shift, and two missense. The missense mutations are both in the second Thyroglobulin Type-1 (Tg1) domain of the protein. The orthologous gene in the mouse, Smoc1, shows site-and stage-specific expression during eye, limb, craniofacial, and somite development. We also report a targeted pre-conditional gene-trap mutation of SmoCI (Smoc(1tm1a)) that reduces mRNA to similar to 10% of wild-type levels. This gene-trap results in highly penetrant hindlimb post-axial oligosyndactyly in homozygous mutant animals (Smoc(1tm1a/tm1a)). Eye malformations, most commonly coloboma, and cleft palate occur in a significant proportion of Smoc(1tm1a/tm1a) embryos and pups. Thus partial loss of Smoc-1 results in a convincing phenocopy of the human disease. SMOC-1 is one of the two mammalian paralogs of Drosophila Pentagone, an inhibitor of decapentaplegic. The orthologous gene in Xenopus laevis, Smoc-1, also functions as a Bone Morphogenic Protein (BMP) antagonist in early embryogenesis. Loss of BMP antagonism during mammalian development provides a plausible explanation for both the limb and eye phenotype in humans and mice.
Published: 2011

24. Psychiatric Profile in Rubinstein-Taybi Syndrome A Review and Case Report

Author: Verhoeven, Willem, Tuinier, S, Kuijpers, HJH, Egger, JIM, Brunner, HG, and Psychiatry
Subjects: behavioral disciplines and activities
Abstract: Background: The diagnosis of Rubinstein-Taybi syndrome (RTS) is primarily clinical and based on the characteristic phenotype that is often combined with a variety of somatic anomalies and psychiatric disorders. Sampling and Methods: In this paper, a review is presented of the psychiatric and behavioural aspects of RTS. This is illustrated with a case report. Results: Behavioural aspects of about 150 patients are described, and include a variable degree of mental retardation, impulsivity, distractibility, instability of mood and stereotypies. In general, patients with RTS are described as sociable and friendly. Information about brain pathology is virtually absent. in about half of the cases, the syndrome is caused by a mutation or deletion of the CREB-binding protein (CBP) gene (16p13.3). The case report deals with an adult male who was referred for impulsivity and temper outbursts. A provisional diagnosis of atypical depression was made, and treatment with citalopram resulted in a remarkable amelioration of his mood and behaviour that persisted for more than 2 years (last observation). Conclusion: Patients with undetected genetic syndromes do occur in clinical psychiatry, and the clinician has to consider such disorders in cases with disturbed development, dysmorphias and somatic comorbidity. Copyright (C) 2009 S. Karger AG, Basel
Published: 2010

25. MLL2 mutation detection in 86 patients with Kabuki syndrome: A genotype-phenotype study

Author: Makrythanasis, P, van Bon, BW, Steehouwer, M, Rodríguez-Santiago, B, Simpson, M, Dias, P, Anderlid, BM, Arts, P, Bhat, M, Augello, B, Biamino, E, Bongers, EMHF, del Campo, M, Cordeiro, I, Cueto-González, AM, Cuscó, I, Deshpande, C, Frysira, E, Izatt, L, Flores, R, Galán, E, Gener, B, Gilissen, C, Granneman, SM, Hoyer, J, Yntema, HG, Kets, CM, Koolen, DA, Marcelis, CL, Medeira, A, Micale, L, Mohammed, S, de Munnik, SA, Nordgren, A, Psoni, S, Reardon, W, Revencu, N, Roscioli, T, Ruiterkamp-Versteeg, M, Santos, HG, Schoumans, J, Schuurs-Hoeijmakers, JHM, Silengo, MC, Toledo, L, Vendrell, T, van der Burgt, I, van Lier, B, Zweier, C, Reymond, A, Trembath, RC, Perez-Jurado, L, Dupont, J, de Vries, BBA, Brunner, HG, Veltman, JA, Merla, G, Antonarakis, SE, Hoischen, A, Makrythanasis, P, van Bon, BW, Steehouwer, M, Rodríguez-Santiago, B, Simpson, M, Dias, P, Anderlid, BM, Arts, P, Bhat, M, Augello, B, Biamino, E, Bongers, EMHF, del Campo, M, Cordeiro, I, Cueto-González, AM, Cuscó, I, Deshpande, C, Frysira, E, Izatt, L, Flores, R, Galán, E, Gener, B, Gilissen, C, Granneman, SM, Hoyer, J, Yntema, HG, Kets, CM, Koolen, DA, Marcelis, CL, Medeira, A, Micale, L, Mohammed, S, de Munnik, SA, Nordgren, A, Psoni, S, Reardon, W, Revencu, N, Roscioli, T, Ruiterkamp-Versteeg, M, Santos, HG, Schoumans, J, Schuurs-Hoeijmakers, JHM, Silengo, MC, Toledo, L, Vendrell, T, van der Burgt, I, van Lier, B, Zweier, C, Reymond, A, Trembath, RC, Perez-Jurado, L, Dupont, J, de Vries, BBA, Brunner, HG, Veltman, JA, Merla, G, Antonarakis, SE, and Hoischen, A
Abstract: Recently, pathogenic variants in the MLL2 gene were identified as the most common cause of Kabuki (Niikawa-Kuroki) syndrome (MIM#147920). To further elucidate the genotype-phenotype correlation, we studied a large cohort of 86 clinically defined patients with Kabuki syndrome (KS) for mutations in MLL2. All patients were assessed using a standardized phenotype list and all were scored using a newly developed clinical score list for KS (MLL2-Kabuki score 0-10). Sequencing of the full coding region and intron-exon boundaries of MLL2 identified a total of 45 likely pathogenic mutations (52%): 31 nonsense, 10 missense and four splice-site mutations, 34 of which were novel. In five additional patients, novel, i.e. non-dbSNP132 variants of clinically unknown relevance, were identified. Patients with likely pathogenic nonsense or missense MLL2 mutations were usually more severely affected (median 'MLL2-Kabuki score' of 6) as compared to the patients without MLL2 mutations (median 'MLL2-Kabuki score' of 5), a significant difference (p<0.0014). Several typical facial features such as large dysplastic ears, arched eyebrows with sparse lateral third, blue sclerae, a flat nasal tip with a broad nasal root, and a thin upper and a full lower lip were observed more often in mutation positive patients. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Published: 2013

26. MLL2 mutation detection in 86 patients with Kabuki syndrome: a genotype-phenotype study

Author: UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Centre de génétique médicale UCL, Makrythanasis, P, van Bon, Bw, Steehouwer, M, Rodríguez-Santiago, B, Simpson, M, Dias, P, Anderlid, Bm, Arts, P, Bhat, M, Augello, B, Biamino, E, Bongers, Emhf, Del Campo, M, Cordeiro, I, Cueto-González, Am, Cuscó, I, Deshpande, C, Frysira, E, Izatt, L, Flores, R, Galán, E, Gener, B, Gilissen, C, Granneman, Sm, Hoyer, J, Yntema, Hg, Kets, Cm, Koolen, DA, Marcelis, Cl, Medeira, A, Micale, L, Mohammed, S, de Munnik, Sa, Nordgren, A, Psoni, S, Reardon, W, Revencu, Nicole, Roscioli, T, Ruiterkamp-Versteeg, M, Santos, Hg, Schoumans, J, Schuurs-Hoeijmakers, Jhm, Silengo, Mc, Toledo, L, Vendrell, T, van der Burgt, I, van Lier, B, Zweier, C, Reymond, A, Trembath, Rc, Perez-Jurado, L, Dupont, J, de Vries, Bba, Brunner, Hg, Veltman, Ja, Merla, G, Antonarakis, Se, Hoischen, A, UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Centre de génétique médicale UCL, Makrythanasis, P, van Bon, Bw, Steehouwer, M, Rodríguez-Santiago, B, Simpson, M, Dias, P, Anderlid, Bm, Arts, P, Bhat, M, Augello, B, Biamino, E, Bongers, Emhf, Del Campo, M, Cordeiro, I, Cueto-González, Am, Cuscó, I, Deshpande, C, Frysira, E, Izatt, L, Flores, R, Galán, E, Gener, B, Gilissen, C, Granneman, Sm, Hoyer, J, Yntema, Hg, Kets, Cm, Koolen, DA, Marcelis, Cl, Medeira, A, Micale, L, Mohammed, S, de Munnik, Sa, Nordgren, A, Psoni, S, Reardon, W, Revencu, Nicole, Roscioli, T, Ruiterkamp-Versteeg, M, Santos, Hg, Schoumans, J, Schuurs-Hoeijmakers, Jhm, Silengo, Mc, Toledo, L, Vendrell, T, van der Burgt, I, van Lier, B, Zweier, C, Reymond, A, Trembath, Rc, Perez-Jurado, L, Dupont, J, de Vries, Bba, Brunner, Hg, Veltman, Ja, Merla, G, Antonarakis, Se, and Hoischen, A
Abstract: Recently, pathogenic variants in the MLL2 gene were identified as the most common cause of Kabuki (Niikawa-Kuroki) syndrome (MIM#147920). To further elucidate the genotype-phenotype correlation, we studied a large cohort of 86 clinically defined patients with Kabuki syndrome (KS) for mutations in MLL2. All patients were assessed using a standardized phenotype list and all were scored using a newly developed clinical score list for KS (MLL2-Kabuki score 0-10). Sequencing of the full coding region and intron-exon boundaries of MLL2 identified a total of 45 likely pathogenic mutations (52%): 31 nonsense, 10 missense and four splice-site mutations, 34 of which were novel. In five additional patients, novel, i.e. non-dbSNP132 variants of clinically unknown relevance, were identified. Patients with likely pathogenic nonsense or missense MLL2 mutations were usually more severely affected (median 'MLL2-Kabuki score' of 6) as compared to the patients without MLL2 mutations (median 'MLL2-Kabuki score' of 5), a significant difference (p < 0.0014). Several typical facial features such as large dysplastic ears, arched eyebrows with sparse lateral third, blue sclerae, a flat nasal tip with a broad nasal root, and a thin upper and a full lower lip were observed more often in mutation positive patients.
Published: 2013

27. Cellular interference in craniofrontonasal syndrome: males mosaic for mutations in the X-linked EFNB1 gene are more severely affected than true hemizygotes

Author: Twigg, SRF, Babbs, C, Elzen, Marijke, Goriely, A, Taylor, S, McGowan, SJ, Giannoulatou, E, Lonie, L, Ragoussis, J, Akha, ES, Knight, SJL, Zechi-Ceide, RM, Hoogeboom, JAM, Pober, BR, Toriello, HV, Wall, SA, Passos-Bueno, MR, Brunner, HG, Mathijssen, Irene, Wilkie, AOM, Twigg, SRF, Babbs, C, Elzen, Marijke, Goriely, A, Taylor, S, McGowan, SJ, Giannoulatou, E, Lonie, L, Ragoussis, J, Akha, ES, Knight, SJL, Zechi-Ceide, RM, Hoogeboom, JAM, Pober, BR, Toriello, HV, Wall, SA, Passos-Bueno, MR, Brunner, HG, Mathijssen, Irene, and Wilkie, AOM
Abstract: Craniofrontonasal syndrome (CFNS), an X-linked disorder caused by loss-of-function mutations of EFNB1, exhibits a paradoxical sex reversal in phenotypic severity: females characteristically have frontonasal dysplasia, craniosynostosis and additional minor malformations, but males are usually more mildly affected with hypertelorism as the only feature. X-inactivation is proposed to explain the more severe outcome in heterozygous females, as this leads to functional mosaicism for cells with differing expression of EPHRIN-B1, generating abnormal tissue boundariesua process that cannot occur in hemizygous males. Apparently challenging this model, males occasionally present with a more severe female-like CFNS phenotype. We hypothesized that such individuals might be mosaic for EFNB1 mutations and investigated this possibility in multiple tissue samples from six sporadically presenting males. Using denaturing high performance liquid chromatography, massively parallel sequencing and multiplex-ligation-dependent probe amplification (MLPA) to increase sensitivity above standard dideoxy sequencing, we identified mosaic mutations of EFNB1 in all cases, comprising three missense changes, two gene deletions and a novel point mutation within the 5 untranslated region (UTR). Quantification by Pyrosequencing and MLPA demonstrated levels of mutant cells between 15 and 69. The 5 UTR variant mutates the stop codon of a small upstream open reading frame that, using a dual-luciferase reporter construct, was demonstrated to exacerbate interference with translation of the wild-type protein. These results demonstrate a more severe outcome in mosaic than in constitutionally deficient males in an X-linked dominant disorder and provide further support for the cellular interference mechanism, normally related to X-inactivation in females.
Published: 2013

28. The ABCA4 2588G>C Stargardt mutation: single origin and increasing frequency from South-West to North-East Europe

Author: Maugeri A, Flothmann K, Hemmrich N, Ingvast S, Jorge P, Paloma E, Patel R, Rozet JM, Tammur J, Testa F, Balcells S, Bird AC, Brunner HG, Hoyng CB, Metspalu A, Simonelli F, Allikmets R, Bhattacharya SS, D'Urso M, Gonzalez-Duarte R, and Kaplan J
Abstract: Inherited retinal dystrophies represent the most important cause of vision impairment in adolescence, affecting approximately 1 out of 3000 individuals. Mutations of the photoreceptor-specific gene ABCA4 (ABCR) are a common cause of retinal dystrophy. A number of mutations have been repeatedly reported for this gene, notably the 2588G>C mutation which is frequent in both patients and controls. Here we ascertained the frequency of the 2588G>C mutation in a total of 2343 unrelated random control individuals from 11 European countries and 241 control individuals from the US, as well as in 614 patients with STGD both from Europe and the US. We found an overall carrier frequency of 1 out of 54 in Europe, compared with 1 out of 121 in the US, confirming that the 2588G>C ABCA4 mutation is one of the most frequent autosomal recessive mutations in the European population. Carrier frequencies show an increasing gradient in Europe from South-West to North-East. The lowest carrier frequency, 0 out of 199 (0%), was found in Portugal; the highest, 11 out of 197 (5.5%), was found in Sweden. Haplotype analysis in 16 families segregating the 2588G>C mutation showed four intragenic polymorphisms invariably present in all 16 disease chromosomes and sharing of the same allele for several markers flanking the ABCA4 locus in most of the disease chromosomes. These results indicate a single origin of the 2588G>C mutation which, to our best estimate, occurred between 2400 and 3000 years ago.
Published: 2002

29. Abnormal processing of mutant LH receptors is causing the signalling deficiency in two new mutations identified in a patient with complete Leydig cell hypoplasia

Author: Martens, John, Lumbroso, S, Verhoef-Post, M, Richter - Unruh, A, Szarras-Czapnik, M, Romer, TE, Brunner, HG, Themmen, Axel, Sultan, C, and Developmental Biology
Published: 2002

30. Leydig cell hypoplasia: cases with new mutations, new polymorphisms and cases without mutations in the Luteinizing Hormone receptor gene

Author: Richter - Unruh, A, Martens, John, Verhoef-Post, M, Wessels, HT (H.), Kors, WA, Sinneckers, GHG, Boehmer, Annemie, Drop, Sten, Toledo, SPA, Brunner, HG, Themmen, Axel, and Developmental Biology
Published: 2002

31. CNS involvement in OFD1 syndrome: a clinical, molecular, and neuroimaging study

Author: Del Giudice, E, Macca, M, Imperati, F, D'Amico, A, Parent, P, Pasquier, L, Layet, V, Lyonnet, S, Stamboul Darmency, V, Thauvin Robinet, C, Franco, B, OFD1 Collaborative Group including Bankier A, Oral Facial Digital Type I., White, S, Collins, F, Gardner, M, Keeling, Sl, Tan, T, Mcgaughran, J, Mckenzie, F, Lhotta, K, Abdulla, F, Destree, A, Devriendt, K, Matthijs, G, Ferrier, R, Mcleod, Dr, Friedman, Jm, Heran, H, Graham, Ge, Klatt, R, Teebi, A, Jensen, P, Gilbert, B, Marlin, S, Trousseau, A, Toutain, A, David, A, Odent, S, Héron, D, Burglen, L, Rio, M, Jouk, Ps, Plessis, G, Lespinasse, J, Giuliano, F, Turc Carel, C, Betz, Rc, Heim, S, Klehr Martinelli, M, Kotzot, D, Minnerop, M, Schell Apacik, C, Gal, A, Orth, U, Gillessen Kaesbach, G, Zoll, B, Mucke, J, Tzschach, A, Godde, E, Carmi, R, Brunetti, N, Scarcella, A, Castelluccio, P, Castellan, C, Gerola, O, Bigoni, S, Zelante, L, Foggia, S, Sabato, A, Bianchini, G, Nuova, As, Virdis, R, Ferrero, Giovanni Battista, Selicorni, A, Gurrieri, F, Cuore, S, Megarbane, A, Chiong, Ma, Cutiongco, Em, Obersztyn, E, Kutkowska Kazmierczak, A, Mota, Cr, de Magalhaes, D, Stevanovic, G, Del Pozo JS, Barcina, Mg, Iwarsson, E, Graber, V, Okhowat, R, Shinzel, A, Brunner, Hg, Krapels, I, Hovers, V, Beemer, Fa, Terhal, P, Rump, P, Elcioglu, N, Toprak, O, Burn, J, Henderson, A, Jones, E, Dean, J, Castle, B, Macdonald, F, Farndon, P, Williams, D, Homfray, T, Lees, M, Loughlin, S, Raymond, Fl, Trump, D, Whittaker, J, Smithson, S, Rankin, J, Turner, C, Bird, L, Chibuk, J, Masser Frye, D, Sell, S, Amy, S, Schafer, I, Bartoshesky, Le, Jenny, K, Benke, P, Curry, C, Swenerton, A, Treisman, T, Dunlap, Jw, Shashi, V, Reich, E, Reimschisel, T, Pfau, R, Pober, B, Robertson, J, Roggenbuck, J, Thiese, H., DEL GIUDICE, Ennio, M., Macca, F., Imperati, A., D’Amico, P., Parent, L., Pasquier, V., Layet, S., Lyonnet, V., Stamboul Darmency, C., Thauvin Robinet, Franco, Brunella, and Oral Facial Digital Type, I. Collaborative G. r. o. u. p.
Subjects: Central nervous system, Neuroimaging, Neuropsychological Tests, Pharmacology, Bioinformatics, Settore MED/03 - GENETICA MEDICA, Ciliopathies, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Central Nervous System Diseases, medicine, Humans, Genetics(clinical), Pharmacology (medical), Orofaciodigital type 1, Neurodevelopmental phenotype, OFD1, Female, Magnetic Resonance Imaging, Mutation, Orofaciodigital Syndromes, Medicine (all), Genetics (clinical), Agenesis of the corpus callosum, 030304 developmental biology, Medicine(all), 0303 health sciences, business.industry, Research, Cilium, Neuropsychology, Cognition, General Medicine, medicine.disease, central nervous system, Porencephaly, 3. Good health, medicine.anatomical_structure, business, 030217 neurology & neurosurgery
Abstract: Background Oral-facial-digital type 1 syndrome (OFD1; OMIM 311200) belongs to the expanding group of disorders ascribed to ciliary dysfunction. With the aim of contributing to the understanding of the role of primary cilia in the central nervous system (CNS), we performed a thorough characterization of CNS involvement observed in this disorder. Methods A cohort of 117 molecularly diagnosed OFD type I patients was screened for the presence of neurological symptoms and/or cognitive/behavioral abnormalities on the basis of the available information supplied by the collaborating clinicians. Seventy-one cases showing CNS involvement were further investigated through neuroimaging studies and neuropsychological testing. Results Seventeen patients were molecularly diagnosed in the course of this study and five of these represent new mutations never reported before. Among patients displaying neurological symptoms and/or cognitive/behavioral abnormalities, we identified brain structural anomalies in 88.7%, cognitive impairment in 68%, and associated neurological disorders and signs in 53% of cases. The most frequently observed brain structural anomalies included agenesis of the corpus callosum and neuronal migration/organisation disorders as well as intracerebral cysts, porencephaly and cerebellar malformations. Conclusions Our results support recent published findings indicating that CNS involvement in this condition is found in more than 60% of cases. Our findings correlate well with the kind of brain developmental anomalies described in other ciliopathies. Interestingly, we also described specific neuropsychological aspects such as reduced ability in processing verbal information, slow thought process, difficulties in attention and concentration, and notably, long-term memory deficits which may indicate a specific role of OFD1 and/or primary cilia in higher brain functions.
Published: 2014
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32. Genotype versus phenotype in families with androgen insensitivity syndrome

Author: Boehmer, Annemie, Brüggenwirth, Hennie, van Assendelft, C, Otten, BJ, Mooijman, Marja, Niermeijer, Martinus, Brunner, HG, Rouwe, CW, Waelkens, J, Oostdijk, W (Wilma), Kleijer, W, Kwast, Theodorus, de Vroede, MA, Drop, Sten, Pediatrics, Developmental Biology, and Clinical Genetics
Subjects: RECEPTOR GENE-MUTATIONS, DOMAIN, CELLS, 17-BETA-HYDROXYSTEROID DEHYDROGENASE-3 DEFICIENCY, NOVO MUTATIONS, STEROID BINDING, MOSAICISM
Abstract: Androgen insensitivity syndrome encompasses a wide range of phenotypes, which are caused by numerous different mutations in the AR gene. Detailed information on the genotype/ phenotype relationship in androgen insensitivity syndrome is important for sex assignment, treatment of androgen insensitivity syndrome patients, genetic counseling of their families, and insight into the functional domains of the AR. The commonly accepted concept of dependence on fetal androgens of the development of Wolffian ducts was studied in complete androgen insensitivity syndrome (CAIS) patients. In a nationwide survey in The Netherlands, all cases (n = 49) with the presumptive diagnosis androgen insensitivity syndrome known to pediatric endocrinologists and clinical geneticists were studied. After studying the clinical phenotype, mutation analysis and functional analysis of mutant receptors were performed using genital skin fibroblasts and in vitro expression studies. Here we report the findings in families with multiple affected cases. Fifty-nine percent of androgen insensitivity syndrome patients had other affected relatives. A total of 17 families were studied, seven families with CAIS (IS patients), nine families with partial androgen insensitivity (24 patients), and one family with female prepubertal phenotypes (two patients). No phenotypic variation was observed in families with CAIS. However, phenotypic variation was observed in one-third of families with partial androgen insensitivity resulting in different sex of rearing and differences in requirement of reconstructive surgery. Intrafamilial phenotypic variation was observed for mutations R846H, M771I, and deletion of amino acid N682. Four newly identified mutations were found. Follow-up in families with different AR gene mutations provided information on residual androgen action in vivo and the development of the prepubertal and adult phenotype. Patients with a functional complete defective AR had some pubic hair, Tanner stage P2, and vestigial Wolffian duct derivatives despite absence of AR expression. Vaginal length was functional in most but not all CAIS patients. The minimal incidence of androgen insensitivity syndrome in The Netherlands, based on patients with molecular proof of the diagnosis is 1:99,000. Phenotypic variation was absent in families with CAIS, but distinct phenotypic variation was observed relatively frequent in families with partial androgen insensitivity. Molecular observations suggest that phenotypic variation had different etiologies among these families. Sex assignment of patients with partial androgen insensitivity cannot be based on a specific identified AR gene mutation because distinct phenotypic variation in partial androgen insensitivity families is relatively frequent. In genetic counseling of partial androgen insensitivity families, this frequent occurrence of variable expression resulting in differences in sex of rearing and/or requirement of reconstructive surgery is important information. During puberty or normal dose androgen therapy, no or only minimal virilization may occur even in patients with significant (but still deficient) prenatal virilization. Wolffian duct remnants remain detectable but differentiation does not occur in the absence of a functional AR. In many CAIS patients, surgical elongation of the vagina is not indicated.
Published: 2001

33. Assignment of X-linked hydrocephalus to Xq28 by linkage analysis

Author: Willems PJ, Dijkstra I, Van der Auwera BJ, Vits L, Coucke P, Raeymaekers P, Van Broeckhoven C, CONSALEZ , GIAN GIACOMO, Freeman SB, Warren ST, Brouwer OF, Brunner HG, Renier WO, Van Elsen AF, Dumon JE, Willems, Pj, Dijkstra, I, Van der Auwera, Bj, Vits, L, Coucke, P, Raeymaekers, P, Van Broeckhoven, C, Consalez, GIAN GIACOMO, Freeman, Sb, Warren, St, Brouwer, Of, Brunner, Hg, Renier, Wo, Van Elsen, Af, and Dumon, Je
Published: 1990

34. Bohring syndrome

Author: Brunner, HG, van Tintelen, JP, de Boer, RJ, Other departments, and Cardiovascular Centre (CVC)
Subjects: Clinical description and delineation of genetic syndromes, Klinische beschrijving en moleculaire definiëring van genetische syndromen, Genetics (clinical)
Abstract: Item does not contain fulltext
Published: 2000

35. Testing for inherited susceptibility to breast and ovarian cancer

Author: Brunner, HG, Ligtenberg, MJL, and Faculteit Medische Wetenschappen/UMCG
Subjects: MUTATIONS, WOMEN, BRCA1, POPULATION, FAMILIES
Published: 1999

36. Comments: A limited repertoire of mutations of the luteinizing hormone (LH) receptor gene in familial and sporadic patients with male LH-independent precocious puberty

Author: Kremer, H, Martens, John, van Reen, M, Verhoef-Post, M, Wit, JM, Otten, BJ, Drop, Sten, Delemarre- van de Waal, HA, Pombo-Arias, M, de Luca, F, Potau, N, Buckler, JMH, Jansen, M, Parks, JS, Latif, HA, Moll, GW, Epping, W, Saggese, G, Mariman, ECM, Themmen, Axel, Brunner, HG, and Developmental Biology
Published: 1999

37. Comments: Analysis of mutations in genes of the follicle-stimulating hormone receptor signaling pathway in ovarian granulosa cell tumors

Author: Ligtenberg, MJ, Siers, M, Themmen, Axel, Hanselaar, TG, Willemsen, W, Brunner, HG, and Developmental Biology
Published: 1999

38. Identity-by-descent filtering of exome sequence data identifies PIGV mutations in hyperphosphatasia mental retardation syndrome

Author: Krawitz, PM, Schweiger, MR, Rödelsperger, C, Marcelis, C, Kölsch, U, Meisel, C, Stephani, F, Kinoshita, T, Murakami, Y, Bauer, S, Isau, M, Fischer, A, Dahl, A, Kerick, M, Hecht, J, Köhler, S, Jäger, M, Grünhagen, J, De Condor, BJ, Doelken, S, Brunner, HG, Meinecke, P, Passarge, E, Thompson, MD, Cole, DE, Horn, D, Roscioli, T, Mundlos, S, Robinson, PN, Krawitz, PM, Schweiger, MR, Rödelsperger, C, Marcelis, C, Kölsch, U, Meisel, C, Stephani, F, Kinoshita, T, Murakami, Y, Bauer, S, Isau, M, Fischer, A, Dahl, A, Kerick, M, Hecht, J, Köhler, S, Jäger, M, Grünhagen, J, De Condor, BJ, Doelken, S, Brunner, HG, Meinecke, P, Passarge, E, Thompson, MD, Cole, DE, Horn, D, Roscioli, T, Mundlos, S, and Robinson, PN
Abstract: Hyperphosphatasia mental retardation (HPMR) syndrome is an autosomal recessive form of mental retardation with distinct facial features and elevated serum alkaline phosphatase. We performed whole-exome sequencing in three siblings of a nonconsanguineous union with HPMR and performed computational inference of regions identical by descent in all siblings to establish PIGV, encoding a member of the GPI-anchor biosynthesis pathway, as the gene mutated in HPMR. We identified homozygous or compound heterozygous mutations in PIGV in three additional families. © 2010 Nature America, Inc. All rights reserved.
Published: 2010

39. Genome-wide profiling of p63 DNA-binding sites identifies an element that regulates gene expression during limb development in the 7q21 shfm1 locus

Author: Kouwenhoven, EN, va Heeringen, SJ, Tena, JJ, Oti, M, Dutilh, BE, Alonso, ME, de la Elisa, CM, Smeenk, L, Rinne, T, Parsaulian, L, Bolat, E, Jurgelenaite, R, Huynen, MA, Hoischen, A, Veltman, JA, Brunner, HG, Roscioli, T, Oates, E, Wilson, M, Manzanares, M, José, LGS, Stunnenberg, HG, Lohrum, M, van Bokhoven, H, Zhou, H, Kouwenhoven, EN, va Heeringen, SJ, Tena, JJ, Oti, M, Dutilh, BE, Alonso, ME, de la Elisa, CM, Smeenk, L, Rinne, T, Parsaulian, L, Bolat, E, Jurgelenaite, R, Huynen, MA, Hoischen, A, Veltman, JA, Brunner, HG, Roscioli, T, Oates, E, Wilson, M, Manzanares, M, José, LGS, Stunnenberg, HG, Lohrum, M, van Bokhoven, H, and Zhou, H
Abstract: Heterozygous mutations in p63 are associated with split hand/foot malformations (SHFM), orofacial clefting, and ectodermal abnormalities. Elucidation of the p63 gene network that includes target genes and regulatory elements may reveal new genes for other malformation disorders. We performed genome-wide DNA-binding profiling by chromatin immunoprecipitation (ChIP), followed by deep sequencing (ChIP-seq) in primary human keratinocytes, and identified potential target genes and regulatory elements controlled by p63. We show that p63 binds to an enhancer element in the SHFM1 locus on chromosome 7q and that this element controls expression of DLX6 and possibly DLX5, both of which are important for limb development. A unique micro-deletion including this enhancer element, but not the DLX5/DLX6 genes, was identified in a patient with SHFM. Our study strongly indicates disruption of a non-coding cis-regulatory element located more than 250 kb from the DLX5/DLX6 genes as a novel disease mechanism in SHFM1. These data provide a proof-of-concept that the catalogue of p63 binding sites identified in this study may be of relevance to the studies of SHFM and other congenital malformations that resemble the p63-associated phenotypes. © 2010 Kouwenhoven et al.
Published: 2010

40. A homozygous mutation in the luteinizing hormone receptor causes partial leydig cell hypoplasia: correlation between receptor activity and phenotype

Author: Martens, John, Verhoef-Post, M, Abelin, N, Ezabella, M, Toledo, SPA, Brunner, HG, Themmen, Axel, and Developmental Biology
Published: 1998

41. MLL2mutation detection in 86 patients with Kabuki syndrome: a genotype-phenotype study

Author: Makrythanasis, P, primary, van Bon, BW, additional, Steehouwer, M, additional, Rodríguez-Santiago, B, additional, Simpson, M, additional, Dias, P, additional, Anderlid, BM, additional, Arts, P, additional, Bhat, M, additional, Augello, B, additional, Biamino, E, additional, Bongers, EMHF, additional, del Campo, M, additional, Cordeiro, I, additional, Cueto-González, AM, additional, Cuscó, I, additional, Deshpande, C, additional, Frysira, E, additional, Izatt, L, additional, Flores, R, additional, Galán, E, additional, Gener, B, additional, Gilissen, C, additional, Granneman, SM, additional, Hoyer, J, additional, Yntema, HG, additional, Kets, CM, additional, Koolen, DA, additional, Marcelis, CL, additional, Medeira, A, additional, Micale, L, additional, Mohammed, S, additional, de Munnik, SA, additional, Nordgren, A, additional, Psoni, S, additional, Reardon, W, additional, Revencu, N, additional, Roscioli, T, additional, Ruiterkamp-Versteeg, M, additional, Santos, HG, additional, Schoumans, J, additional, Schuurs-Hoeijmakers, JHM, additional, Silengo, MC, additional, Toledo, L, additional, Vendrell, T, additional, van der Burgt, I, additional, van Lier, B, additional, Zweier, C, additional, Reymond, A, additional, Trembath, RC, additional, Perez-Jurado, L, additional, Dupont, J, additional, de Vries, BBA, additional, Brunner, HG, additional, Veltman, JA, additional, Merla, G, additional, Antonarakis, SE, additional, and Hoischen, A, additional
Published: 2013
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42. Intragenic deletion in DYRK1A leads to mental retardation and primary microcephaly

Author: van Bon, BWM, primary, Hoischen, A, additional, Hehir-Kwa, J, additional, de Brouwer, APM, additional, Ruivenkamp, C, additional, Gijsbers, ACJ, additional, Marcelis, CL, additional, de Leeuw, N, additional, Veltman, JA, additional, Brunner, HG, additional, and de Vries, BBA, additional
Published: 2011
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43. Familial Kleefstra syndrome due to maternal somatic mosaicism for interstitial 9q34.3 microdeletions

Author: Willemsen, MH, primary, Beunders, G, additional, Callaghan, M, additional, de Leeuw, N, additional, Nillesen, WM, additional, Yntema, HG, additional, van Hagen, JM, additional, Nieuwint, AWM, additional, Morrison, N, additional, Keijzers-Vloet, STM, additional, Hoischen, A, additional, Brunner, HG, additional, Tolmie, J, additional, and Kleefstra, T, additional
Published: 2011
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44. A homozygous FKRP start codon mutation is associated with Walker–Warburg syndrome, the severe end of the clinical spectrum

Author: Van Reeuwijk, J, primary, Olderode‐Berends, MJW, additional, Van Den Elzen, C, additional, Brouwer, OF, additional, Roscioli, T, additional, Van Pampus, MG, additional, Scheffer, H, additional, Brunner, HG, additional, Van Bokhoven, H, additional, and Hol, FA, additional
Published: 2010
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45. Deletions encompassing 1q41q42.1 and clinical features of autosomal dominant Robinow syndrome

Author: Mazzeu, JF, primary, Vianna-Morgante, AM, additional, Krepischi, ACV, additional, Oudakker, A, additional, Rosenberg, C, additional, Szuhai, K, additional, McGill, J, additional, MacCraughan, J, additional, van Bokhoven, H, additional, and Brunner, HG, additional
Published: 2010
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46. The ABCA4 2588G>C Stargardt mutation: single origin and increasingfrequency from South-West to North-East Europe.

Author: Maugeri, A, Flothmann, K, Hemmrich, N, Ingvast, S, Jorge, P, Paloma, E, Patel, R, Rozet, JM, Tammur, J, Testa, F, Balcells, S, Bird, AC, Brunner, HG, Hoyng, CB, Metspalu, A, Simonelli, F, Allikmets, R, Bhattacharya, SS, D'Urso, M, Gonzalez-Duarte, R, Kaplan, J, te Meerman, GJ, Santos, R, Schwartz, M, Van Camp, G, Wadelius, C, Weber, BH, Cremers, FP, Maugeri, A, Flothmann, K, Hemmrich, N, Ingvast, S, Jorge, P, Paloma, E, Patel, R, Rozet, JM, Tammur, J, Testa, F, Balcells, S, Bird, AC, Brunner, HG, Hoyng, CB, Metspalu, A, Simonelli, F, Allikmets, R, Bhattacharya, SS, D'Urso, M, Gonzalez-Duarte, R, Kaplan, J, te Meerman, GJ, Santos, R, Schwartz, M, Van Camp, G, Wadelius, C, Weber, BH, and Cremers, FP
Published: 2002

47. Dominant versus recessive traits conveyed by allelic mutations - to what extent is nonsense-mediated decay involved?

Author: Ben-Shachar, S, primary, Khajavi, M, additional, Withers, MA, additional, Shaw, CA, additional, van Bokhoven, H, additional, Brunner, HG, additional, and Lupski, JR, additional
Published: 2009
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48. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome

Author: Tartaglia, Marco, Mehler, El, Goldberg, R, Zampino, Giuseppe, Brunner, Hg, Kremer, H, Van Der Burgt, I, Crosby, Ah, Ion, A, Jeffery, S, Kalidas, K, Patton, Ma, Kucherlapati, R, Gelb, Bd, Zampino, Giuseppe (ORCID:0000-0003-3865-3253), Tartaglia, Marco, Mehler, El, Goldberg, R, Zampino, Giuseppe, Brunner, Hg, Kremer, H, Van Der Burgt, I, Crosby, Ah, Ion, A, Jeffery, S, Kalidas, K, Patton, Ma, Kucherlapati, R, Gelb, Bd, and Zampino, Giuseppe (ORCID:0000-0003-3865-3253)
Abstract: Noonan syndrome (MIM 163950) is an autosomal dominant disorder characterized by dysmorphic facial features, proportionate short stature and heart disease (most commonly pulmonic stenosis and hypertrophic cardiomyopathy). Webbed neck, chest deformity, cryptorchidism, mental retardation and bleeding diatheses also are frequently associated with this disease. This syndrome is relatively common, with an estimated incidence of 1 in 1,000-2,500 live births. It has been mapped to a 5-cM region (NS1) [corrected] on chromosome 12q24.1, and genetic heterogeneity has also been documented. Here we show that missense mutations in PTPN11 (MIM 176876)-a gene encoding the nonreceptor protein tyrosine phosphatase SHP-2, which contains two Src homology 2 (SH2) domains-cause Noonan syndrome and account for more than 50% of the cases that we examined. All PTPN11 missense mutations cluster in interacting portions of the amino N-SH2 domain and the phosphotyrosine phosphatase domains, which are involved in switching the protein between its inactive and active conformations. An energetics-based structural analysis of two N-SH2 mutants indicates that in these mutants there may be a significant shift of the equilibrium favoring the active conformation. This implies that they are gain-of-function changes and that the pathogenesis of Noonan syndrome arises from excessive SHP-2 activity.
Published: 2001

49. CHD7 mutations in patients initially diagnosed with Kallmann syndrome – the clinical overlap with CHARGE syndrome

Author: Jongmans, MCJ, primary, Van Ravenswaaij‐Arts, CMA, additional, Pitteloud, N, additional, Ogata, T, additional, Sato, N, additional, Claahsen‐van der Grinten, HL, additional, Van Der Donk, K, additional, Seminara, S, additional, Bergman, JEH, additional, Brunner, HG, additional, Crowley, WF, additional, and Hoefsloot, LH, additional
Published: 2008
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50. INTESTINAL PSEUDOOBSTRUCTION IN MYOTONIC-DYSTROPHY

Author: BRUNNER, HG, HAMEL, BCJ, RIEU, P, HOWELER, CJ, and PETERS, FTM
Subjects: SENSORY NEUROPATHY, HEREDITARY MOTOR, LOCUS, FIBROSIS, CARDIAC INVOLVEMENT, NORMAL-PRESSURE HYDROCEPHALUS, MUSCULAR-DYSTROPHY, DISEASE, PILOMATRICOMAS, FAMILY
Abstract: We describe four myotonic dystrophy (DM) patients who developed recurrent intestinal pseudo-obstruction. Some episodes were associated with gastroenteritis, while abdominal crowding may have occurred in one case during the third trimester of pregnancy. In most instances, however, no apparent cause could be identified. Intestinal pseudo-obstruction may occur at any stage of DM. In one of our cases intestinal pseudo-obstruction preceded significant muscle weakness by IS years. Intestinal pseudo-obstruction is usually treated effectively with conservative measures. These include restriction of oral intake, intravenous fluids, and multiple enemas or colonoscopy. Improved intestinal function was noted in one case treated with the prokinetic agent cisapride. A partial sigmoid resection was performed in three cases with dolichomegacolon. No abnormalities were reported on histological examination. Since intestinal pseudo-obstruction is a rare complication of DM, it is of interest that two of our cases are sibs. Review of published reports showed several reports of familial occurrence of specific complications. These include cardiac conduction disturbances, focal myocarditis, mitral valve prolapse, pilomatrixomas, polyneuropathy, normal pressure hydrocephalus, and dilatation of the urinary tract. Myotonic dystrophy may show a tendency to familial clustering of organ specific involvement.
Published: 1992

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