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1. RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes

Author

Reijnders, M.R.F. (Margot R.F.), Ansor, N.M. (Nurhuda M.), Kousi, M. (Maria), Yue, W.W. (Wyatt W.), Tan, P.L. (Perciliz L.), Clarkson, K. (Katie), Clayton-Smith, J., Corning, K. (Ken), Jones, J.R. (Julie R.), Lam, W.W.K. (Wayne W.K.), Mancini, G.M.S. (Grazia), Marcelis, C.L.M. (Carlo), Mohammed, S. (Shabaz), Pfundt, R. (Rolph), Roifman, M. (Maian), Cohn, R.D., Chitayat, D. (David), Millard, T.H. (Tom H.), Katsanis, N. (Nicholas), Brunner, H.G., Banka, S. (Siddharth), Reijnders, M.R.F. (Margot R.F.), Ansor, N.M. (Nurhuda M.), Kousi, M. (Maria), Yue, W.W. (Wyatt W.), Tan, P.L. (Perciliz L.), Clarkson, K. (Katie), Clayton-Smith, J., Corning, K. (Ken), Jones, J.R. (Julie R.), Lam, W.W.K. (Wayne W.K.), Mancini, G.M.S. (Grazia), Marcelis, C.L.M. (Carlo), Mohammed, S. (Shabaz), Pfundt, R. (Rolph), Roifman, M. (Maian), Cohn, R.D., Chitayat, D. (David), Millard, T.H. (Tom H.), Katsanis, N. (Nicholas), Brunner, H.G., and Banka, S. (Siddharth)

Abstract

RAC1 is a widely studied Rho GTPase, a class of molecules that modulate numerous cellular functions essential for normal development. RAC1 is highly conserved across species and is under strict mutational constraint. We report seven individuals with distinct de novo missense RAC1 mutations and varying degrees of developmental delay, brain malformations, and additional phenotypes. Four individuals, each harboring one of c.53G>A (p.Cys18Tyr), c.116A>G (p.Asn39Ser), c.218C>T (p.Pro73Leu), and c.470G>A (p.Cys157Tyr) variants, were microcephalic, with head circumferences between −2.5 to −5 SD. In contrast, two individuals with c.151G>A (p.Val51Met) and c.151G>C (p.Val51Leu) alleles were macrocephalic with head circumferences of +4.16 and +4.5 SD. One individual harboring a c.190T>G (p.Tyr64Asp) allele had head circumference in the normal range. Collectively, we observed an extraordinary spread of ∼10 SD of head circumferences orchestrated by distinct mutations in the same gene. In silico modeling, mouse fibroblasts spreading assays, and in vivo overexpression assays using zebrafish as a surrogate model demonstrated that the p.Cys18Tyr and p.Asn39Ser RAC1 variants function as dominant-negative alleles and result in microcephaly, reduced neuronal proliferation, and cerebellar abnormalities in vivo. Conversely, the p.Tyr64Asp substitution is constitutively active. The remaining mutations are probably weakly dominant negative or their effects are context dependent. These findings highlight the importance of RAC1 in neuronal development. Along with TRIO and HACE1, a sub-category of rare developmental disorders is emerging with RAC1 as the central player. We show that ultra-rare disorders caused by private, non-recurrent missense mutations that result in varying phenotypes are challenging to dissect, but can be delineated through focused international collaboration.

Published
2017
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2. Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability

Author

Reijnders, M.R.F. (Margot R.F.), Kousi, M. (M.), Woerden, G.M. (Geeske) van, Klein, M. (Marieke), Bralten, L.B.C. (Linda), Mancini, G.M.S. (Grazia), Essen, T. (Ton) van, Proietti-Onori, M. (Martina), Smeets, E.E.J. (Eric E.J.), Van Gastel, M. (M.), Stegmann, A.P.A. (A. P.A.), Stevens, S.J.C. (S. J.C.), Lelieveld, S.H. (S. H.), Gilissen, C. (Christian), Pfundt, R. (Rolph), Tan, P.L. (P. L.), Kleefstra, T. (Tjitske), Franke, B. (Barbara), Elgersma, Y. (Ype), Katsanis, N. (Nicholas), Brunner, H.G., Reijnders, M.R.F. (Margot R.F.), Kousi, M. (M.), Woerden, G.M. (Geeske) van, Klein, M. (Marieke), Bralten, L.B.C. (Linda), Mancini, G.M.S. (Grazia), Essen, T. (Ton) van, Proietti-Onori, M. (Martina), Smeets, E.E.J. (Eric E.J.), Van Gastel, M. (M.), Stegmann, A.P.A. (A. P.A.), Stevens, S.J.C. (S. J.C.), Lelieveld, S.H. (S. H.), Gilissen, C. (Christian), Pfundt, R. (Rolph), Tan, P.L. (P. L.), Kleefstra, T. (Tjitske), Franke, B. (Barbara), Elgersma, Y. (Ype), Katsanis, N. (Nicholas), and Brunner, H.G.

Abstract

De novo mutations in specific mTOR pathway genes cause brain overgrowth in the context of intellectual disability (ID). By analyzing 101 mMTOR-related genes in a large ID patient cohort and two independent population cohorts, we show that these genes modulate brain growth in health and disease. We report the mTOR activator gene RHEB as an ID gene that is associated with megalencephaly when mutated. Functional testing of mutant RHEB in vertebrate animal models indicates pathway hyperactivation with a concomitant increase in cell and head size, aberrant neuronal migration, and induction of seizures, concordant with the human phenotype. This study reveals that tight control of brain volume is exerted through a large community of mTOR-related genes. Human brain volume can be altered, by either rare disruptive events causing hyperactivation of the pathway, or through the collective effects of common alleles.

Published
2017
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3. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants

Author

Fritsche, L.G. (Lars), Igl, W. (Wilmar), Cooke Bailey, J.N. (Jessica N.), Grassmann, F. (Felix), Sengupta, S. (Sebanti), Bragg-Gresham, J.L. (Jennifer L.), Burdon, K.P. (Kathryn P.), Hebbring, S.J. (Scott J.), Wen, C. (Cindy), Gorski, M. (Mathias), Kim, I.K. (Ivana), Cho, D. (David), Zack, D. (Donald), Souied, E.H. (Eric), Scholl, H.P.N. (Hendrik), Bala, E. (Elisa), ELee, K. (Kristine), Hunter, D. (David), Sardell, R.J. (Rebecca J.), Mitchell, P. (Paul), Merriam, J.E. (Joanna), Cipriani, F. (Francesco), Hoffman, J.D. (Joshua D.), Schick, T. (Tina), Lechanteur, Y.T.E. (Yara T. E.), Guymer, R.H. (Robyn), Johnson, M.P. (Matthew), Jiang, Y., Stanton, C.M. (Chloe), Buitendijk, G.H.S. (Gabrielle), Zhan, X. (Xiaowei), Kwong, A.M. (Alan M.), Boleda, A. (Alexis), Brooks, M. (Matthew), Gieser, L. (Linn), Ratna Priya, R. (Rinki), Branham, K.E. (Kari), Foerster, J.R. (Johanna R.), Heckenlively, J.R. (John), Othman, M.I. (Mohammad), Vote, B.J. (Brendan J.), Liang, H.H. (Helena Hai), Souzeau, E. (Emmanuelle), McAllister, I.L. (Ian L.), Isaacs, T. (Timothy), Hall, J. (Janette), Lake, S. (Stewart), Mackey, D.A. (David), Constable, I.J. (Ian J.), Craig, J.E. (Jamie E.), Kitchner, T.E. (Terrie E.), Yang, Z. (Zhenglin), Su, Z. (Zhiguang), Luo, H. (Hongrong), Chen, D. (Daniel), Ouyang, H. (Hong), Flagg, K. (Ken), Lin, D. (Danni), Mao, G. (Guanping), Ferreyra, H.A. (Henry), Stark, K. (Klaus), Strachwitz, C. (Claudia) von, Wolf, A. (Armin), Brandl, C. (Caroline), Rudolph, G. (Guenther), Olden, M. (Matthias), Morrison, M.A. (Margaux), Morgan, D.J. (Denise), Schu, M. (Matthew), Ahn, J. (Jeeyun), Silvestri, G. (Giuliana), Tsironi, E.E. (Evangelia), Park, K.H. (Kyu Hyung), Farrer, L.A. (Lindsay), Orlin, A. (Anton), Brucker, A. (Alexander), Curcio, C.A. (Christine A.), Mohand-Sa'd, S. (Saddek), Sahel, J.-A. (José-Alain), Audo, I. (Isabelle), Benchaboune, M. (Mustapha), Cree, A.J. (Angela), Rennie, C.A. (Christina A.), Goverdhan, S.V. (Srinivas V.), Grunin, M. (Michelle), Hagbi-Levi, S. (Shira), Campochiaro, B. (Betsy), Katsanis, N. (Nicholas), Holz, F.G. (Frank), Blond, F. (Frédéric), Blanché, H. (Hél'ne), Deleuze, J.-F. (Jean-Fran'ois), Igo Jr., R.P. (Robert), Truitt, B.J. (Barbara), Peachey, N.S. (Neal ), Meuer, S.M. (Stacy), Myers, C.E. (Chelsea), Moore, E.L. (Emily L.), Klein, R. (Ronald), Hauser, M.A. (Michael), Postel, E.A. (Eric), Courtenay, M.D. (Monique D.), Schwartz, S.M. (Stephen), Kovach, J.L. (Jaclyn), Scott, W.K. (William), Liew, G. (Gerald), Tan, A.G. (Ava G.), Gopinath, B. (Bamini), Smith, T. (Tim), Khan, J.C. (Jane), Shahid, M. (Mohammad), Moore, A.T. (Anthony), McGrath, J.A. (J Allie), Laux, R. (Reneé), Brantley, M.A. (Milam), Agarwal, A. (Anita), Ersoy, L. (Lebriz), Caramoy, A. (Albert), Langmann, T. (Thomas), Saksens, N.T.M. (Nicole T.), Jong, E.K. (Eiko Kde), Hoyng, C.B. (Carel), Cain, M.S. (Melinda), Richardson, A.J. (Andrea), Martin, T.M. (Tammy M.), Blangero, J. (John), Weeks, D.E. (Daniel), Dhillon, B. (Bal), Duijn, C.M. (Cornelia) van, Doheny, K.F. (Kimberly), Romm, J. (Jane), Klaver, C.C.W. (Caroline), Hayward, C. (Caroline), Gorin, M.B. (Michael B.), Klein, M.L. (Michael), Baird, P.N. (Paul), Hollander, A.I. (Anneke), Fauser, S. (Sascha), WYates, J.R. (John R.), Allikmets, R. (Rando), Wang, J.J. (Jie Jin), Schaumberg, D.A. (Debra), Klein, B.E.K. (Barbara), Hagstrom, S.A. (Stephanie), Chowers, Y. (Yehuda), Lotery, A.J. (Andrew), Léveillard, T. (Thierry), Zhang, K. (Kang), Brilliant, M.H. (Murray H.), Hewit, A.W. (Alex), Swaroop, A. (Anand), Chew, E.Y. (Emily Y.), Pericak-Vance, M.A. (Margaret), DeAngelis, M.M. (Margaret), Stambolian, D. (Dwight), Haines, J.L. (Jonathan), Iyengar, S.K. (Sudha), Weber, B.H.F. (Bernhard), Abecasis, G.R. (Gonçalo), Heid, I.M. (Iris), Li, M. (Mingyao), Fritsche, L.G. (Lars), Igl, W. (Wilmar), Cooke Bailey, J.N. (Jessica N.), Grassmann, F. (Felix), Sengupta, S. (Sebanti), Bragg-Gresham, J.L. (Jennifer L.), Burdon, K.P. (Kathryn P.), Hebbring, S.J. (Scott J.), Wen, C. (Cindy), Gorski, M. (Mathias), Kim, I.K. (Ivana), Cho, D. (David), Zack, D. (Donald), Souied, E.H. (Eric), Scholl, H.P.N. (Hendrik), Bala, E. (Elisa), ELee, K. (Kristine), Hunter, D. (David), Sardell, R.J. (Rebecca J.), Mitchell, P. (Paul), Merriam, J.E. (Joanna), Cipriani, F. (Francesco), Hoffman, J.D. (Joshua D.), Schick, T. (Tina), Lechanteur, Y.T.E. (Yara T. E.), Guymer, R.H. (Robyn), Johnson, M.P. (Matthew), Jiang, Y., Stanton, C.M. (Chloe), Buitendijk, G.H.S. (Gabrielle), Zhan, X. (Xiaowei), Kwong, A.M. (Alan M.), Boleda, A. (Alexis), Brooks, M. (Matthew), Gieser, L. (Linn), Ratna Priya, R. (Rinki), Branham, K.E. (Kari), Foerster, J.R. (Johanna R.), Heckenlively, J.R. (John), Othman, M.I. (Mohammad), Vote, B.J. (Brendan J.), Liang, H.H. (Helena Hai), Souzeau, E. (Emmanuelle), McAllister, I.L. (Ian L.), Isaacs, T. (Timothy), Hall, J. (Janette), Lake, S. (Stewart), Mackey, D.A. (David), Constable, I.J. (Ian J.), Craig, J.E. (Jamie E.), Kitchner, T.E. (Terrie E.), Yang, Z. (Zhenglin), Su, Z. (Zhiguang), Luo, H. (Hongrong), Chen, D. (Daniel), Ouyang, H. (Hong), Flagg, K. (Ken), Lin, D. (Danni), Mao, G. (Guanping), Ferreyra, H.A. (Henry), Stark, K. (Klaus), Strachwitz, C. (Claudia) von, Wolf, A. (Armin), Brandl, C. (Caroline), Rudolph, G. (Guenther), Olden, M. (Matthias), Morrison, M.A. (Margaux), Morgan, D.J. (Denise), Schu, M. (Matthew), Ahn, J. (Jeeyun), Silvestri, G. (Giuliana), Tsironi, E.E. (Evangelia), Park, K.H. (Kyu Hyung), Farrer, L.A. (Lindsay), Orlin, A. (Anton), Brucker, A. (Alexander), Curcio, C.A. (Christine A.), Mohand-Sa'd, S. (Saddek), Sahel, J.-A. (José-Alain), Audo, I. (Isabelle), Benchaboune, M. (Mustapha), Cree, A.J. (Angela), Rennie, C.A. (Christina A.), Goverdhan, S.V. (Srinivas V.), Grunin, M. (Michelle), Hagbi-Levi, S. (Shira), Campochiaro, B. (Betsy), Katsanis, N. (Nicholas), Holz, F.G. (Frank), Blond, F. (Frédéric), Blanché, H. (Hél'ne), Deleuze, J.-F. (Jean-Fran'ois), Igo Jr., R.P. (Robert), Truitt, B.J. (Barbara), Peachey, N.S. (Neal ), Meuer, S.M. (Stacy), Myers, C.E. (Chelsea), Moore, E.L. (Emily L.), Klein, R. (Ronald), Hauser, M.A. (Michael), Postel, E.A. (Eric), Courtenay, M.D. (Monique D.), Schwartz, S.M. (Stephen), Kovach, J.L. (Jaclyn), Scott, W.K. (William), Liew, G. (Gerald), Tan, A.G. (Ava G.), Gopinath, B. (Bamini), Smith, T. (Tim), Khan, J.C. (Jane), Shahid, M. (Mohammad), Moore, A.T. (Anthony), McGrath, J.A. (J Allie), Laux, R. (Reneé), Brantley, M.A. (Milam), Agarwal, A. (Anita), Ersoy, L. (Lebriz), Caramoy, A. (Albert), Langmann, T. (Thomas), Saksens, N.T.M. (Nicole T.), Jong, E.K. (Eiko Kde), Hoyng, C.B. (Carel), Cain, M.S. (Melinda), Richardson, A.J. (Andrea), Martin, T.M. (Tammy M.), Blangero, J. (John), Weeks, D.E. (Daniel), Dhillon, B. (Bal), Duijn, C.M. (Cornelia) van, Doheny, K.F. (Kimberly), Romm, J. (Jane), Klaver, C.C.W. (Caroline), Hayward, C. (Caroline), Gorin, M.B. (Michael B.), Klein, M.L. (Michael), Baird, P.N. (Paul), Hollander, A.I. (Anneke), Fauser, S. (Sascha), WYates, J.R. (John R.), Allikmets, R. (Rando), Wang, J.J. (Jie Jin), Schaumberg, D.A. (Debra), Klein, B.E.K. (Barbara), Hagstrom, S.A. (Stephanie), Chowers, Y. (Yehuda), Lotery, A.J. (Andrew), Léveillard, T. (Thierry), Zhang, K. (Kang), Brilliant, M.H. (Murray H.), Hewit, A.W. (Alex), Swaroop, A. (Anand), Chew, E.Y. (Emily Y.), Pericak-Vance, M.A. (Margaret), DeAngelis, M.M. (Margaret), Stambolian, D. (Dwight), Haines, J.L. (Jonathan), Iyengar, S.K. (Sudha), Weber, B.H.F. (Bernhard), Abecasis, G.R. (Gonçalo), Heid, I.M. (Iris), and Li, M. (Mingyao)

Abstract

Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10 -8) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10 -10). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.

Published
2016
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4. Mutations in LRRC50 Predispose Zebrafish and Humans to Seminomas

Author

Basten, S.G. (Sander G.), Davis, E.E. (Erica), Gillis, A.J.M. (Ad), Rooijen, E. (Ellen) van, Stoop, J.A. (Hans), Babala, N. (Nikolina), Logister, I. (Ive), Heath, Z.G. (Zachary G.), Jonges, T.N. (Trudy N.), Katsanis, N. (Nicholas), Voest, E.E. (Emile), van Eeden, F.J. (Freek J.), Medema, R.H. (Rene), Ketting, R.F. (René), Schulte-Merker, S. (Stefan), Looijenga, L.H.J. (Leendert), Giles, R.H., Basten, S.G. (Sander G.), Davis, E.E. (Erica), Gillis, A.J.M. (Ad), Rooijen, E. (Ellen) van, Stoop, J.A. (Hans), Babala, N. (Nikolina), Logister, I. (Ive), Heath, Z.G. (Zachary G.), Jonges, T.N. (Trudy N.), Katsanis, N. (Nicholas), Voest, E.E. (Emile), van Eeden, F.J. (Freek J.), Medema, R.H. (Rene), Ketting, R.F. (René), Schulte-Merker, S. (Stefan), Looijenga, L.H.J. (Leendert), and Giles, R.H.

Published
2013
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5. Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration

Author

Yu, Y. (Yi), Bhangale, T. (Tushar), Fagerness, J. (Jesen), Ripke, S. (Stephan), Thorleifsson, G. (Gudmar), Tan, P.L. (Perciliz), Souied, E.H. (Eric), Richardson, A.J. (Andrea), Merriam, J.E. (Joanna), Buitendijk, G.H.S. (Gabrielle), Reynolds, R. (Robyn), Raychaudhuri, S. (Soumya), Chin, K.A. (Kimberly), Sobrin, L. (Lucia), Evangelou, E. (Evangelos), Lee, P.H. (Phil), Leveziel, N. (Nicolas), Zack, D.J. (Donald), Campochiaro, B. (Betsy), Smith, R.T. (Theodore), Barile, G.R. (Gaetano), Guymer, R.H. (Robyn), Hogg, R. (Ruth), Chakravarthy, U. (Usha), Robman, L.D. (Luba), Gustafsson, O. (Omar), Sigurdsson, H. (Haraldur), Ortmann, W. (Ward), Behrens, T.W. (Timothy), Stefansson, K. (Kari), Uitterlinden, A.G. (André), Tikka-Kleemola, P. (Päivi), Vingerling, J.R. (Hans), Klaver, C.C.W. (Caroline), Allikmets, R. (Rando), Brantley, M.A. (Milam), Baird, P.N. (Paul), Katsanis, N. (Nicholas), Thorsteinsdottir, U. (Unnur), Ioannidis, J.P.A. (John), Daly, M.J. (Mark), Graham, R.R. (Robert), Seddon, J.M. (Johanna), Yu, Y. (Yi), Bhangale, T. (Tushar), Fagerness, J. (Jesen), Ripke, S. (Stephan), Thorleifsson, G. (Gudmar), Tan, P.L. (Perciliz), Souied, E.H. (Eric), Richardson, A.J. (Andrea), Merriam, J.E. (Joanna), Buitendijk, G.H.S. (Gabrielle), Reynolds, R. (Robyn), Raychaudhuri, S. (Soumya), Chin, K.A. (Kimberly), Sobrin, L. (Lucia), Evangelou, E. (Evangelos), Lee, P.H. (Phil), Leveziel, N. (Nicolas), Zack, D.J. (Donald), Campochiaro, B. (Betsy), Smith, R.T. (Theodore), Barile, G.R. (Gaetano), Guymer, R.H. (Robyn), Hogg, R. (Ruth), Chakravarthy, U. (Usha), Robman, L.D. (Luba), Gustafsson, O. (Omar), Sigurdsson, H. (Haraldur), Ortmann, W. (Ward), Behrens, T.W. (Timothy), Stefansson, K. (Kari), Uitterlinden, A.G. (André), Tikka-Kleemola, P. (Päivi), Vingerling, J.R. (Hans), Klaver, C.C.W. (Caroline), Allikmets, R. (Rando), Brantley, M.A. (Milam), Baird, P.N. (Paul), Katsanis, N. (Nicholas), Thorsteinsdottir, U. (Unnur), Ioannidis, J.P.A. (John), Daly, M.J. (Mark), Graham, R.R. (Robert), and Seddon, J.M. (Johanna)

Abstract

Despite significant progress in the identification of genetic loci for age-related macular degeneration (AMD), not all of the heritability has been explained. To identify variants which contribute to the remaining genetic susceptibility, we performed the largest meta-analysis of genome-wide association studies to date for advanced AMD. We imputed 6 036 699 single-nucleotide polymorphisms with the 1000 Genomes Project reference genotypes on 2594 cases and 4134 controls with follow-up replication of top signals in 5640 cases and 52 174 controls. We identified two new common susceptibility alleles, rs1999930 on 6q21-q22.3 near FRK/COL10A1 [odds ratio (OR) 0.87; P 5 1.1 × 10-8] and rs4711751 on 6p12 near VEGFA (OR 1.15; P 5 8.7 × 10-9). In addition to the two novel loci, 10 previously reported loci in ARMS2/HTRA1 (rs10490924), CFH (rs1061170, and rs1410996), CFB (rs641153), C3 (rs2230199), C2 (rs9332739), CFI (rs10033900), LIPC (rs10468017), TIMP3 (rs9621532) and CETP (rs3764261) were confirmed with genomewide significant signals in this large study. Loci in the recently reported genes ABCA1 and COL8A1 were also detected with suggestive evidence of association with advanced AMD. The novel variants identified in this study suggest that angiogenesis (VEGFA) and extracellular collagen matrix (FRK/COL10A1) pathways contribute to the development of advanced AMD.

Published
2011
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