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18 results on '"Benke, P.J."'

1. The clinical and molecular spectrum of the KDM6B-related neurodevelopmental disorder.

Author

Rots, D., Jakub, T.E., Keung, C., Jackson, A., Banka, S., Pfundt, R.P., Vries, B.B.A. de, Jaarsveld, R.H. van, Hopman, S.M.J., Binsbergen, E. van, Valenzuela, I., Hempel, M., Bierhals, T., Kortüm, F., Lecoquierre, F., Goldenberg, A., Hertz, J.M., Andersen, C.B., Kibæk, M., Prijoles, E.J., Stevenson, R.E., Everman, D.B., Patterson, W.G., Meng, L., Gijavanekar, C., Dios, K. De, Lakhani, S., Levy, T., Wagner, M., Wieczorek, D., Benke, P.J., Lopez Garcia, M.S., Perrier, R., Sousa, S.B., Almeida, P.M., Simões, M.J., Isidor, B., Deb, W., Schmanski, A.A., Abdul-Rahman, O., Philippe, C., Bruel, A.L., Faivre, L., Vitobello, A., Thauvin, C., Smits, J.J., Garavelli, L., Caraffi, S.G., Peluso, F., Davis-Keppen, L., Platt, D., Royer, E., Leeuwen, L van, Sinnema, M., Stegmann, A.P.A., Stumpel, C.T., Tiller, G.E., Bosch, D.G.M., Potgieter, S.T., Joss, S., Splitt, M., Holden, S., Prapa, M., Foulds, N., Douzgou, S., Puura, K., Waltes, R., Chiocchetti, A.G., Freitag, C.M., Satterstrom, F.K., Rubeis, S. de, Buxbaum, J., Gelb, B.D., Branko, A., Kushima, I., Howe, J., Scherer, S.W., Arado, A., Baldo, C., Patat, O., Bénédicte, D., Lopergolo, D., Santorelli, F.M., Haack, T.B., Dufke, A., Bertrand, M., Falb, R.J., Rieß, A., Krieg, P., Spranger, S., Bedeschi, M.F., Iascone, M., Josephi-Taylor, S., Roscioli, T., Buckley, M.F., Liebelt, J., Dagli, A.I., Aten, E., Hurst, A.C.E., Hicks, A., Suri, M., Aliu, E., Naik, S., Sidlow, R., Coursimault, J., Nicolas, G., Küpper, H., Petit, F., Ibrahim, V., Top, D., Cara, F. Di, Louie, R.J., Stolerman, E., Brunner, H.G., Vissers, L.E.L.M., Kramer, J.M., Kleefstra, T., Rots, D., Jakub, T.E., Keung, C., Jackson, A., Banka, S., Pfundt, R.P., Vries, B.B.A. de, Jaarsveld, R.H. van, Hopman, S.M.J., Binsbergen, E. van, Valenzuela, I., Hempel, M., Bierhals, T., Kortüm, F., Lecoquierre, F., Goldenberg, A., Hertz, J.M., Andersen, C.B., Kibæk, M., Prijoles, E.J., Stevenson, R.E., Everman, D.B., Patterson, W.G., Meng, L., Gijavanekar, C., Dios, K. De, Lakhani, S., Levy, T., Wagner, M., Wieczorek, D., Benke, P.J., Lopez Garcia, M.S., Perrier, R., Sousa, S.B., Almeida, P.M., Simões, M.J., Isidor, B., Deb, W., Schmanski, A.A., Abdul-Rahman, O., Philippe, C., Bruel, A.L., Faivre, L., Vitobello, A., Thauvin, C., Smits, J.J., Garavelli, L., Caraffi, S.G., Peluso, F., Davis-Keppen, L., Platt, D., Royer, E., Leeuwen, L van, Sinnema, M., Stegmann, A.P.A., Stumpel, C.T., Tiller, G.E., Bosch, D.G.M., Potgieter, S.T., Joss, S., Splitt, M., Holden, S., Prapa, M., Foulds, N., Douzgou, S., Puura, K., Waltes, R., Chiocchetti, A.G., Freitag, C.M., Satterstrom, F.K., Rubeis, S. de, Buxbaum, J., Gelb, B.D., Branko, A., Kushima, I., Howe, J., Scherer, S.W., Arado, A., Baldo, C., Patat, O., Bénédicte, D., Lopergolo, D., Santorelli, F.M., Haack, T.B., Dufke, A., Bertrand, M., Falb, R.J., Rieß, A., Krieg, P., Spranger, S., Bedeschi, M.F., Iascone, M., Josephi-Taylor, S., Roscioli, T., Buckley, M.F., Liebelt, J., Dagli, A.I., Aten, E., Hurst, A.C.E., Hicks, A., Suri, M., Aliu, E., Naik, S., Sidlow, R., Coursimault, J., Nicolas, G., Küpper, H., Petit, F., Ibrahim, V., Top, D., Cara, F. Di, Louie, R.J., Stolerman, E., Brunner, H.G., Vissers, L.E.L.M., Kramer, J.M., and Kleefstra, T.

Abstract

Item does not contain fulltext, De novo variants are a leading cause of neurodevelopmental disorders (NDDs), but because every monogenic NDD is different and usually extremely rare, it remains a major challenge to understand the complete phenotype and genotype spectrum of any morbid gene. According to OMIM, heterozygous variants in KDM6B cause "neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities." Here, by examining the molecular and clinical spectrum of 85 reported individuals with mostly de novo (likely) pathogenic KDM6B variants, we demonstrate that this description is inaccurate and potentially misleading. Cognitive deficits are seen consistently in all individuals, but the overall phenotype is highly variable. Notably, coarse facies and distal skeletal anomalies, as defined by OMIM, are rare in this expanded cohort while other features are unexpectedly common (e.g., hypotonia, psychosis, etc.). Using 3D protein structure analysis and an innovative dual Drosophila gain-of-function assay, we demonstrated a disruptive effect of 11 missense/in-frame indels located in or near the enzymatic JmJC or Zn-containing domain of KDM6B. Consistent with the role of KDM6B in human cognition, we demonstrated a role for the Drosophila KDM6B ortholog in memory and behavior. Taken together, we accurately define the broad clinical spectrum of the KDM6B-related NDD, introduce an innovative functional testing paradigm for the assessment of KDM6B variants, and demonstrate a conserved role for KDM6B in cognition and behavior. Our study demonstrates the critical importance of international collaboration, sharing of clinical data, and rigorous functional analysis of genetic variants to ensure correct disease diagnosis for rare disorders.

Published
2023

2. Genotype-phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders

Author

Mannucci, I., Dang, N.D.P., Huber, H, Murry, J.B., Abramson, J., Althoff, T., Banka, S., Baynam, G., Bearden, D., Beleza-Meireles, A., Benke, P.J., Berland, S., Bierhals, T., Bilan, F., Bindoff, Laurence, Braathen, G.J., Busk, O.L., Chenbhanich, J., Denecke, J., Escobar, L.F., Estes, C., Fleischer, J., Groepper, D., Haaxma, C.A., Hempel, M., Holler-Managan, Y., Houge, G., Jackson, A., Kellogg, L., Keren, B., Kiraly-Borri, C., Kraus, C., Kubisch, C., Guyader, G. Le, Ljungblad, U.W., Brenman, L.M., Martinez-Agosto, J.A., Might, M., Miller, D.T., Minks, K.Q., Moghaddam, B., Nava, C., Nelson, S.F., Parant, J.M., Prescott, T., Rajabi, F., Randrianaivo, H., Reiter, S.F., Schuurs-Hoeijmakers, J.H.M., Shieh, P.B., Slavotinek, A., Smithson, S., Stegmann, A.P.A., Tomczak, K., Tveten, K., Wang, J, Whitlock, J.H., Zweier, C., McWalter, K., Juusola, J., Quintero-Rivera, F., Fischer, U., Yeo, N.C., Kreienkamp, H.J., Lessel, D., Mannucci, I., Dang, N.D.P., Huber, H, Murry, J.B., Abramson, J., Althoff, T., Banka, S., Baynam, G., Bearden, D., Beleza-Meireles, A., Benke, P.J., Berland, S., Bierhals, T., Bilan, F., Bindoff, Laurence, Braathen, G.J., Busk, O.L., Chenbhanich, J., Denecke, J., Escobar, L.F., Estes, C., Fleischer, J., Groepper, D., Haaxma, C.A., Hempel, M., Holler-Managan, Y., Houge, G., Jackson, A., Kellogg, L., Keren, B., Kiraly-Borri, C., Kraus, C., Kubisch, C., Guyader, G. Le, Ljungblad, U.W., Brenman, L.M., Martinez-Agosto, J.A., Might, M., Miller, D.T., Minks, K.Q., Moghaddam, B., Nava, C., Nelson, S.F., Parant, J.M., Prescott, T., Rajabi, F., Randrianaivo, H., Reiter, S.F., Schuurs-Hoeijmakers, J.H.M., Shieh, P.B., Slavotinek, A., Smithson, S., Stegmann, A.P.A., Tomczak, K., Tveten, K., Wang, J, Whitlock, J.H., Zweier, C., McWalter, K., Juusola, J., Quintero-Rivera, F., Fischer, U., Yeo, N.C., Kreienkamp, H.J., and Lessel, D.

Abstract

Contains fulltext : 245060.pdf (Publisher’s version ) (Open Access), BACKGROUND: We aimed to define the clinical and variant spectrum and to provide novel molecular insights into the DHX30-associated neurodevelopmental disorder. METHODS: Clinical and genetic data from affected individuals were collected through Facebook-based family support group, GeneMatcher, and our network of collaborators. We investigated the impact of novel missense variants with respect to ATPase and helicase activity, stress granule (SG) formation, global translation, and their effect on embryonic development in zebrafish. SG formation was additionally analyzed in CRISPR/Cas9-mediated DHX30-deficient HEK293T and zebrafish models, along with in vivo behavioral assays. RESULTS: We identified 25 previously unreported individuals, ten of whom carry novel variants, two of which are recurrent, and provide evidence of gonadal mosaicism in one family. All 19 individuals harboring heterozygous missense variants within helicase core motifs (HCMs) have global developmental delay, intellectual disability, severe speech impairment, and gait abnormalities. These variants impair the ATPase and helicase activity of DHX30, trigger SG formation, interfere with global translation, and cause developmental defects in a zebrafish model. Notably, 4 individuals harboring heterozygous variants resulting either in haploinsufficiency or truncated proteins presented with a milder clinical course, similar to an individual harboring a de novo mosaic HCM missense variant. Functionally, we established DHX30 as an ATP-dependent RNA helicase and as an evolutionary conserved factor in SG assembly. Based on the clinical course, the variant location, and type we establish two distinct clinical subtypes. DHX30 loss-of-function variants cause a milder phenotype whereas a severe phenotype is caused by HCM missense variants that, in addition to the loss of ATPase and helicase activity, lead to a detrimental gain-of-function with respect to SG formation. Behavioral characterization of dhx30-deficient

Published
2021

3. Biallelic variants in PPP1R13L cause paediatric dilated cardiomyopathy

Author

Robinson, H.K., primary, Zaklyazminskaya, E., additional, Povolotskaya, I., additional, Surikova, Y., additional, Mallin, L., additional, Armstrong, C., additional, Mabin, D., additional, Benke, P.J., additional, Chrisant, M.R., additional, McDonald, M., additional, Marboe, C.C., additional, Agre, K.E., additional, Deyle, D.R., additional, McWalter, K., additional, Douglas, G., additional, Balashova, M.S., additional, Kaimonov, V., additional, Shirokova, N., additional, Pomerantseva, E., additional, Turner, C.L., additional, and Ellard, S., additional

Published
2020
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4. Genome-wide Association Study of Change in Fasting Glucose over time in 13,807 non-diabetic European Ancestry Individuals

Author

Liu, C.-T. (Ching-Ti), Merino, J. (Jordi), Rybin, D. (Denis), DiCorpo, D. (Daniel), Benke, P.J. (Paul), Bragg-Gresham, J.L. (Jennifer L.), Canouil, M. (Mickaël), Corre, T. (Tanguy), Grallert, H. (Harald), Isaacs, A.J. (Aaron), Kutalik, Z. (Zoltán), Lahti, J. (Jari), Marullo, L. (Letizia), Marzi, C. (Carola), Rasmussen-Torvik, L.J. (Laura), Rocheleau, G. (Ghislain), Rueedi, R. (Rico), Scapoli, C. (Chiara), Verweij, N. (Niek), Vogelzangs, N. (Nicole), Willems, S.M. (Sara), Yengo, L. (Loic), Bakker, S.J.L. (Stephan), Beilby, J.P. (John), Hui, J. (Jennie), Kajantie, E. (Eero), Müller-Nurasyid, M. (Martina), Rathmann, W. (Wolfgang), Balkau, B. (Beverley), Bergmann, S.M. (Sven), Hagen, K. (Knut), Florez, J.C. (Jose), Froguel, P. (Philippe), Harris, T.B. (Tamara), Hung, J. (Joseph), James, A. (Alan), Kavousi, M. (Maryam), Miljkovic, I. (Iva), Musk, A.W. (Arthur W.), Palmer, L.J. (Lyle J.), Peters, A. (Annette), Roussel, R. (Ronan), Harst, P. (Pim) van der, Duijn, C.M. (Cornelia) van, Vollenweider, P. (Peter), Barroso, I.E. (Inês), Prokopenko, I. (Inga), Amin, N. (Najaf), Meigs, J.B. (James), Bouatia-Naji, N. (Nabila), Liu, C.-T. (Ching-Ti), Merino, J. (Jordi), Rybin, D. (Denis), DiCorpo, D. (Daniel), Benke, P.J. (Paul), Bragg-Gresham, J.L. (Jennifer L.), Canouil, M. (Mickaël), Corre, T. (Tanguy), Grallert, H. (Harald), Isaacs, A.J. (Aaron), Kutalik, Z. (Zoltán), Lahti, J. (Jari), Marullo, L. (Letizia), Marzi, C. (Carola), Rasmussen-Torvik, L.J. (Laura), Rocheleau, G. (Ghislain), Rueedi, R. (Rico), Scapoli, C. (Chiara), Verweij, N. (Niek), Vogelzangs, N. (Nicole), Willems, S.M. (Sara), Yengo, L. (Loic), Bakker, S.J.L. (Stephan), Beilby, J.P. (John), Hui, J. (Jennie), Kajantie, E. (Eero), Müller-Nurasyid, M. (Martina), Rathmann, W. (Wolfgang), Balkau, B. (Beverley), Bergmann, S.M. (Sven), Hagen, K. (Knut), Florez, J.C. (Jose), Froguel, P. (Philippe), Harris, T.B. (Tamara), Hung, J. (Joseph), James, A. (Alan), Kavousi, M. (Maryam), Miljkovic, I. (Iva), Musk, A.W. (Arthur W.), Palmer, L.J. (Lyle J.), Peters, A. (Annette), Roussel, R. (Ronan), Harst, P. (Pim) van der, Duijn, C.M. (Cornelia) van, Vollenweider, P. (Peter), Barroso, I.E. (Inês), Prokopenko, I. (Inga), Amin, N. (Najaf), Meigs, J.B. (James), and Bouatia-Naji, N. (Nabila)

Abstract

Type 2 diabetes (T2D) affects the health of millions of people worldwide. The identification of genetic determinants associated with changes in glycemia over time might illuminate biological features that precede the development of T2D. Here we conducted a genome-wide association study of longitudinal fasting glucose changes in up to 13,807 non-diabetic individuals of European descent from nine cohorts. Fasting glucose change over time was defined as the slope of the line defined by multiple fasting glucose measurements obtained over up to 14 years of observation. We tested for associations of genetic variants with inverse-normal transformed fasting glucose change over time adjusting for age at baseline, sex, and principal components of genetic variation. We found no genome-wide significant association (P < 5 × 10−8) with fasting glucose change over time. Seven loci previously associated with T2D, fasting glucose or HbA1c were nominally (P < 0.05) associated with fasting glucose change over time. Limited power influences unambiguous interpretation, but these dat

Published
2019
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5. PORCN mutations in focal dermal hypoplasia: coping with lethality

Author

Bornholdt, D., Oeffner, F., Konig, A., Happle, R.H.G., Alanay, Y., Ascherman, J., Benke, P.J., Boente Mdel, C., Burgt, I. van der, Chassaing, N., Ellis, I., Francisco, C.R., Giovanna, P. Della, Hamel, B.C.J., Has, C., Heinelt, K., Janecke, A., Kastrup, W., Loeys, B.L., Lohrisch, I., Marcelis, C.L.M., Mehraein, Y., Nicolas, M.E., Pagliarini, D., Paradisi, M., Patrizi, A., Piccione, M., Piza-Katzer, H., Prager, B., Prescott, K., Strien, J., Utine, G.E., Zeller, M.S., Grzeschik, K.H., Bornholdt, D, Oeffner, F, König, A, Happle, R, Alanay, Y, Ascherman, J, Benke, PJ, Boente Mdel C, van der Burgt I, Chassaing, N, Ellis, I, Francisco, CR, Della Giovanna P, Hamel, B, Has, C, Heinelt, K, Janecke, A, Kastrup, W, Loeys, B, Lohrisch, I, Marcelis, C, Mehraein, Y, Nicolas, ME, Pagliarini, D, Paradisi, M, Patrizi, A, Piccione, M, Piza-Katzer, H, Prager, B, Prescott, K, Strien, J, Utine, GE, Zeller, MS, Grzeschik, KH, Bornholdt D, Oeffner F, König A, Happle R, Alanay Y, Ascherman J, Benke PJ, Chassaing N, Ellis I, Francisco CR, Hamel B, Has C, Heinelt K, Janecke A, Kastrup W, Loeys B, Lohrisch I, Marcelis C, Mehraein Y, Nicolas ME, Pagliarini D, Paradisi M, Patrizi A, Piccione M, Piza-Katzer H, Prager B, Prescott K, Strien J, Utine GE, Zeller MS, and Grzeschik KH

Subjects
Adult, Male, Adolescent, Base Sequence, DNA Mutational Analysis, Molecular Sequence Data, Infant, Newborn, Infant, Membrane Proteins, Genomic disorders and inherited multi-system disorders [IGMD 3], Focal Dermal Hypoplasia, Settore MED/38 - Pediatria Generale E Specialistica, Settore MED/03 - Genetica Medica, Child, Preschool, Mutation, Goltz syndrome, FDH, PORCN, WNT, skewed X-inactivation, postzygotic mosaic, Humans, Protein Isoforms, Female, Amino Acid Sequence, Child, Acyltransferases
Abstract

Contains fulltext : 81709.pdf (Publisher’s version ) (Closed access) The X-linked dominant trait focal dermal hypoplasia (FDH, Goltz syndrome) is a developmental defect with focal distribution of affected tissues due to a block of Wnt signal transmission from cells carrying a detrimental PORCN mutation on an active X-chromosome. Molecular characterization of 24 unrelated patients from different ethnic backgrounds revealed 23 different mutations of the PORCN gene in Xp11.23. Three were microdeletions eliminating PORCN and encompassing neighboring genes such as EBP, the gene associated with Conradi-Hunermann-Happle syndrome (CDPX2). 12/24 patients carried nonsense mutations resulting in loss of function. In one case a canonical splice acceptor site was mutated, and 8 missense mutations exchanged highly conserved amino acids. FDH patients overcome the consequences of potentially lethal X-chromosomal mutations by extreme skewing of X-chromosome inactivation in females, enabling transmission of the trait in families, or by postzygotic mosaicism both in male and female individuals. Molecular characterization of the PORCN mutations in cases diagnosed as Goltz syndrome is particularly relevant for genetic counseling of patients and their families since no functional diagnostic test is available and carriers of the mutation might otherwise be overlooked due to considerable phenotypic variability associated with the mosaic status.

Published
2009

6. High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies

Author

Hamdan, F.F., Myers, C.T., Cossette, P., Lemay, P., Spiegelman, D., Laporte, A.D., Nassif, C., Diallo, O., Monlong, J., Cadieux-Dion, M., Dobrzeniecka, S., Meloche, C., Retterer, K., Cho, M.T., Rosenfeld, J.A., Bi, W., Massicotte, C., Miguet, M., Brunga, L., Regan, B.M., Mo, K., Tam, C., Schneider, A., Hollingsworth, G., FitzPatrick, D.R., Donaldson, A., Canham, N., Blair, E., Kerr, B., Fry, A.E., Thomas, R.H., Shelagh, J., Hurst, J.A., Brittain, H., Blyth, M., Lebel, R.R., Gerkes, E.H., Davis-Keppen, L., Stein, Q., Chung, W.K., Dorison, S.J., Benke, P.J., Fassi, E., Corsten-Janssen, N., Kamsteeg, E.J., Mau-Them, F.T., Bruel, A.L., Verloes, A., Ounap, K., Wojcik, M.H., Albert, D.V.F., Venkateswaran, S., Ware, T., Jones, D., Liu, Y.C., Mohammad, S.S., Bizargity, P., Bacino, C.A., Leuzzi, V., Martinelli, S., Dallapiccola, B., Tartaglia, M., Blumkin, L., Wierenga, K.J., Purcarin, G., O'Byrne, J.J., Stockler, S., Lehman, A., Keren, B., Nougues, M.C., Mignot, C., Auvin, S., Nava, C., Hiatt, S.M., Bebin, M., Shao, Y., Scaglia, F., Lalani, S.R., Frye, R.E., Jarjour, I.T., Jacques, S., Boucher, R.M., Riou, E., Srour, M., Carmant, L., Lortie, A., Major, P., Diadori, P., Dubeau, F., D'Anjou, G., Bourque, G., Berkovic, S.F., Sadleir, L.G., Campeau, P.M., Kibar, Z., Lafreniere, R.G., Girard, S.L., Mercimek-Mahmutoglu, S., Boelman, C., Rouleau, G.A., et al., Hamdan, F.F., Myers, C.T., Cossette, P., Lemay, P., Spiegelman, D., Laporte, A.D., Nassif, C., Diallo, O., Monlong, J., Cadieux-Dion, M., Dobrzeniecka, S., Meloche, C., Retterer, K., Cho, M.T., Rosenfeld, J.A., Bi, W., Massicotte, C., Miguet, M., Brunga, L., Regan, B.M., Mo, K., Tam, C., Schneider, A., Hollingsworth, G., FitzPatrick, D.R., Donaldson, A., Canham, N., Blair, E., Kerr, B., Fry, A.E., Thomas, R.H., Shelagh, J., Hurst, J.A., Brittain, H., Blyth, M., Lebel, R.R., Gerkes, E.H., Davis-Keppen, L., Stein, Q., Chung, W.K., Dorison, S.J., Benke, P.J., Fassi, E., Corsten-Janssen, N., Kamsteeg, E.J., Mau-Them, F.T., Bruel, A.L., Verloes, A., Ounap, K., Wojcik, M.H., Albert, D.V.F., Venkateswaran, S., Ware, T., Jones, D., Liu, Y.C., Mohammad, S.S., Bizargity, P., Bacino, C.A., Leuzzi, V., Martinelli, S., Dallapiccola, B., Tartaglia, M., Blumkin, L., Wierenga, K.J., Purcarin, G., O'Byrne, J.J., Stockler, S., Lehman, A., Keren, B., Nougues, M.C., Mignot, C., Auvin, S., Nava, C., Hiatt, S.M., Bebin, M., Shao, Y., Scaglia, F., Lalani, S.R., Frye, R.E., Jarjour, I.T., Jacques, S., Boucher, R.M., Riou, E., Srour, M., Carmant, L., Lortie, A., Major, P., Diadori, P., Dubeau, F., D'Anjou, G., Bourque, G., Berkovic, S.F., Sadleir, L.G., Campeau, P.M., Kibar, Z., Lafreniere, R.G., Girard, S.L., Mercimek-Mahmutoglu, S., Boelman, C., and Rouleau, G.A., et al.

Abstract

Item does not contain fulltext, Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy.

Published
2017

7. GWAS of 126,559 individuals identifies genetic variants associated with educational attainment

Author

Rietveld, C.A. (Niels), Medland, S.E. (Sarah), Derringer, J., Yang, J. (Joanna), Esko, T. (Tõnu), Martin, N.W. (Nicolas), Westra, H.J. (Harm-Jan), Shakhbazov, K. (Konstantin), Abdellaoui, A. (Abdel), Agrawal, A. (Arpana), Albrecht, E. (Eva), Alizadeh, B.Z. (Behrooz), Amin, N. (Najaf), Barnard, J. (John), Baumeister, S.E. (Sebastian), Benke, P.J. (Paul), Bielak, L.F. (Lawrence F.), Boatman, J.A. (Jeffrey), Boyle, P.A. (Patricia), Davies, G. (Gail), Leeuw, C. (Christiaan) de, Eklund, N. (Niina), Evans, D.S. (Daniel), Ferhmann, R. (Rudolf), Fischer, K. (Krista), Gieger, C. (Christian), Gjessing, H.K. (Håkon), Hägg, S. (Sara), Harris, J.R. (Jennifer), Hayward, C. (Caroline), Holzapfel, C. (Christina), Ibrahim-Verbaas, C.A. (Carla), Ingelsson, E. (Erik), Jacobsson, B. (Bo), Joshi, P.K. (Peter), Juqessur, A. (Astanand), Kaakinen, M. (Marika), Kanoni, S. (Stavroula), Karjalainen, J. (Juha), Kolcic, I. (Ivana), Kristiansson, K. (Kati), Kutalik, Z. (Zoltán), Lahti, J. (Jari), Lee, S.H. (Sang Hong), Lin, P. (Peng), Lind, P.A. (Penelope), Liu, Y. (YongMei), Lohman, K. (Kurt), Loitfelder, M. (Marisa), Mcmahon, G. (George), Marques-Vidal, P. (Pedro), Meirelles, O., Milani, L. (Lili), Myhre, R. (Ronny), Nuotio, M.-L. (Marja-Liisa), Oldmeadow, C. (Christopher), Petrovic, K. (Katja), Peyrot, W.J. (Wouter ), Polasek, O. (Ozren), Quaye, L. (Lydia), Reinmaa, E. (Eva), Rice, J.P. (John), Rizzi, T.S. (Thais), Schmidt, H. (Helena), Schmidt, R. (Reinhold), Smith, A.V. (Davey), Smith, J.A. (Jennifer A), Tanaka, T. (Toshiko), Terracciano, A., Loos, M.J.H.M. (Matthijs) van der, Vitart, V. (Veronique), Völzke, H. (Henry), Wellmann, J. (Jürgen), Yu, L. (Lei), Zhao, W. (Wei), Allik, J., Attia, J. (John), Bandinelli, S. (Stefania), Bastardot, F. (Francois), Beauchamp, J.P. (Jonathan), Bennett, D.A. (David), Berger, K. (Klaus), Bierut, L.J. (Laura), Boomsma, D.I. (Dorret), Bültmann, U. (Ute), Campbell, H. (Harry), Chabris, C.F. (Christopher F.), Cherkas, L. (Lynn), Chung, M.K. (Mina), Cucca, F. (Francesco), Andrade, M. (Mariza) de, Jager, P.L. (Philip) de, Neve, J.E. (Jan-Emmanuel) de, Deary, I.J. (Ian), Dedoussis, G.V. (George), Deloukas, P. (Panagiotis), Dimitriou, M. (Maria), Eiríksdóttir, G. (Guoný), Elderson, M.F. (Martin), Eriksson, J.G. (Johan), Evans, D.M. (David), Faul, J.D. (Jessica), Ferrucci, L. (Luigi), Garcia, M. (Melissa), Grönberg, H. (Henrik), Guonason, V. (Vilmundur), Hall, P. (Per), Harris, J.M. (Juliette), Harris, T.B. (Tamara), Hastie, N. (Nick), Heath, A.C. (Andrew), Hernandez, D.G. (Dena), Hoffmann, W. (Wolfgang), Holle, R. (Rolf), Holliday, E.G. (Elizabeth), Hottenga, J.J. (Jouke Jan), Iacono, W.G. (William), Illig, T. (Thomas), Jarvelin, M.-R. (Marjo-Riitta), Kähönen, M. (Mika), Kaprio, J. (Jaakko), Kirkpatrick, R.M. (Robert), Kowgier, M. (Matthew), Latvala, A. (Antti), Launer, L.J. (Lenore), Lawlor, D.A. (Debbie), Lehtimäki, T. (Terho), Li, J. (Jingmei), Lichtenstein, P. (Paul), Lichtner, P. (Peter), Liewald, D.C.M. (David), Madden, P.A. (Pamela), Magnusson, P.K. (Patrik), Mäkinen, T. (Tuukka), Masala, G. (Giovanna), McGue, M. (Matt), Metspalu, A. (Andres), Mielck, A. (Andreas), Miller, M. (Michael), Montgomery, G.W. (Grant), Mukherjee, S. (Sutapa), Nyholt, D.R. (Dale), Oostra, B.A. (Ben), Palmer, C. (Cameron), Palotie, A. (Aarno), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Peyser, P.A. (Patricia A.), Preisig, M. (Martin), Räikkönen, K. (Katri), Raitakari, O. (Olli), Realo, A. (Anu), Ring, S.M. (Susan), Ripatti, S. (Samuli), Rivadeneira Ramirez, F. (Fernando), Rudan, I. (Igor), Rustichini, A. (Aldo), Salomaa, V. (Veikko), Sarin, A.-P., Schlessinger, D., Scott, R.J. (Rodney), Snieder, H. (Harold), St Pourcain, B. (Beate), Starr, J.M. (John), Sul, J.H. (Jae Hoon), Surakka, I. (Ida), Svento, R. (Rauli), Teumer, A. (Alexander), Tiemeier, H.W. (Henning), Rooij, F.J.A. (Frank) van, Wagoner, D.R. (David) van, Vartiainen, E. (Erkki), Viikari, J. (Jorma), Vollenweider, P. (Peter), Vonk, J.M. (Judith), Waeber, G. (Gérard), Weir, D.R. (David), Wichmann, H.E. (Heinz Erich), Widen, E. (Elisabeth), Willemsen, G.A.H.M. (Gonneke), Wilson, J.F. (James), Wright, A.F. (Alan), Conley, D. (Dalton), Davey-Smith, G. (George), Franke, L. (Lude), Groenen, P.J.F. (Patrick), Hofman, A. (Albert), Johannesson, M. (Magnus), Kardia, S.L.R. (Sharon), Krueger, R.F., Laibson, D. (David), Martin, N.G. (Nicholas), Meyer, M.N. (Michelle), Posthuma, D. (Danielle), Thurik, A.R. (Roy), Timpson, N.J. (Nicholas), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, Visscher, P.M. (Peter), Benjamin, D.J. (Daniel J.), Cesarini, D. (David), Koellinger, Ph.D. (Philipp), Rietveld, C.A. (Niels), Medland, S.E. (Sarah), Derringer, J., Yang, J. (Joanna), Esko, T. (Tõnu), Martin, N.W. (Nicolas), Westra, H.J. (Harm-Jan), Shakhbazov, K. (Konstantin), Abdellaoui, A. (Abdel), Agrawal, A. (Arpana), Albrecht, E. (Eva), Alizadeh, B.Z. (Behrooz), Amin, N. (Najaf), Barnard, J. (John), Baumeister, S.E. (Sebastian), Benke, P.J. (Paul), Bielak, L.F. (Lawrence F.), Boatman, J.A. (Jeffrey), Boyle, P.A. (Patricia), Davies, G. (Gail), Leeuw, C. (Christiaan) de, Eklund, N. (Niina), Evans, D.S. (Daniel), Ferhmann, R. (Rudolf), Fischer, K. (Krista), Gieger, C. (Christian), Gjessing, H.K. (Håkon), Hägg, S. (Sara), Harris, J.R. (Jennifer), Hayward, C. (Caroline), Holzapfel, C. (Christina), Ibrahim-Verbaas, C.A. (Carla), Ingelsson, E. (Erik), Jacobsson, B. (Bo), Joshi, P.K. (Peter), Juqessur, A. (Astanand), Kaakinen, M. (Marika), Kanoni, S. (Stavroula), Karjalainen, J. (Juha), Kolcic, I. (Ivana), Kristiansson, K. (Kati), Kutalik, Z. (Zoltán), Lahti, J. (Jari), Lee, S.H. (Sang Hong), Lin, P. (Peng), Lind, P.A. (Penelope), Liu, Y. (YongMei), Lohman, K. (Kurt), Loitfelder, M. (Marisa), Mcmahon, G. (George), Marques-Vidal, P. (Pedro), Meirelles, O., Milani, L. (Lili), Myhre, R. (Ronny), Nuotio, M.-L. (Marja-Liisa), Oldmeadow, C. (Christopher), Petrovic, K. (Katja), Peyrot, W.J. (Wouter ), Polasek, O. (Ozren), Quaye, L. (Lydia), Reinmaa, E. (Eva), Rice, J.P. (John), Rizzi, T.S. (Thais), Schmidt, H. (Helena), Schmidt, R. (Reinhold), Smith, A.V. (Davey), Smith, J.A. (Jennifer A), Tanaka, T. (Toshiko), Terracciano, A., Loos, M.J.H.M. (Matthijs) van der, Vitart, V. (Veronique), Völzke, H. (Henry), Wellmann, J. (Jürgen), Yu, L. (Lei), Zhao, W. (Wei), Allik, J., Attia, J. (John), Bandinelli, S. (Stefania), Bastardot, F. (Francois), Beauchamp, J.P. (Jonathan), Bennett, D.A. (David), Berger, K. (Klaus), Bierut, L.J. (Laura), Boomsma, D.I. (Dorret), Bültmann, U. (Ute), Campbell, H. (Harry), Chabris, C.F. (Christopher F.), Cherkas, L. (Lynn), Chung, M.K. (Mina), Cucca, F. (Francesco), Andrade, M. (Mariza) de, Jager, P.L. (Philip) de, Neve, J.E. (Jan-Emmanuel) de, Deary, I.J. (Ian), Dedoussis, G.V. (George), Deloukas, P. (Panagiotis), Dimitriou, M. (Maria), Eiríksdóttir, G. (Guoný), Elderson, M.F. (Martin), Eriksson, J.G. (Johan), Evans, D.M. (David), Faul, J.D. (Jessica), Ferrucci, L. (Luigi), Garcia, M. (Melissa), Grönberg, H. (Henrik), Guonason, V. (Vilmundur), Hall, P. (Per), Harris, J.M. (Juliette), Harris, T.B. (Tamara), Hastie, N. (Nick), Heath, A.C. (Andrew), Hernandez, D.G. (Dena), Hoffmann, W. (Wolfgang), Holle, R. (Rolf), Holliday, E.G. (Elizabeth), Hottenga, J.J. (Jouke Jan), Iacono, W.G. (William), Illig, T. (Thomas), Jarvelin, M.-R. (Marjo-Riitta), Kähönen, M. (Mika), Kaprio, J. (Jaakko), Kirkpatrick, R.M. (Robert), Kowgier, M. (Matthew), Latvala, A. (Antti), Launer, L.J. (Lenore), Lawlor, D.A. (Debbie), Lehtimäki, T. (Terho), Li, J. (Jingmei), Lichtenstein, P. (Paul), Lichtner, P. (Peter), Liewald, D.C.M. (David), Madden, P.A. (Pamela), Magnusson, P.K. (Patrik), Mäkinen, T. (Tuukka), Masala, G. (Giovanna), McGue, M. (Matt), Metspalu, A. (Andres), Mielck, A. (Andreas), Miller, M. (Michael), Montgomery, G.W. (Grant), Mukherjee, S. (Sutapa), Nyholt, D.R. (Dale), Oostra, B.A. (Ben), Palmer, C. (Cameron), Palotie, A. (Aarno), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Peyser, P.A. (Patricia A.), Preisig, M. (Martin), Räikkönen, K. (Katri), Raitakari, O. (Olli), Realo, A. (Anu), Ring, S.M. (Susan), Ripatti, S. (Samuli), Rivadeneira Ramirez, F. (Fernando), Rudan, I. (Igor), Rustichini, A. (Aldo), Salomaa, V. (Veikko), Sarin, A.-P., Schlessinger, D., Scott, R.J. (Rodney), Snieder, H. (Harold), St Pourcain, B. (Beate), Starr, J.M. (John), Sul, J.H. (Jae Hoon), Surakka, I. (Ida), Svento, R. (Rauli), Teumer, A. (Alexander), Tiemeier, H.W. (Henning), Rooij, F.J.A. (Frank) van, Wagoner, D.R. (David) van, Vartiainen, E. (Erkki), Viikari, J. (Jorma), Vollenweider, P. (Peter), Vonk, J.M. (Judith), Waeber, G. (Gérard), Weir, D.R. (David), Wichmann, H.E. (Heinz Erich), Widen, E. (Elisabeth), Willemsen, G.A.H.M. (Gonneke), Wilson, J.F. (James), Wright, A.F. (Alan), Conley, D. (Dalton), Davey-Smith, G. (George), Franke, L. (Lude), Groenen, P.J.F. (Patrick), Hofman, A. (Albert), Johannesson, M. (Magnus), Kardia, S.L.R. (Sharon), Krueger, R.F., Laibson, D. (David), Martin, N.G. (Nicholas), Meyer, M.N. (Michelle), Posthuma, D. (Danielle), Thurik, A.R. (Roy), Timpson, N.J. (Nicholas), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, Visscher, P.M. (Peter), Benjamin, D.J. (Daniel J.), Cesarini, D. (David), and Koellinger, Ph.D. (Philipp)

Published
2013
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8. Common variants at 6q22 and 17q21 are associated with intracranial volume

Author

Ikram, M.A. (Arfan), Fornage, M. (Myriam), Smith, A.V. (Davey), Seshadri, S. (Sudha), Schmidt, R. (Reinhold), Debette, S. (Stéphanie), Vrooman, H.A. (Henri), Sigurdsson, S. (Stefan), Ropele, S. (Stefan), Taal, H.R. (Rob), Mook-Kanamori, D.O. (Dennis), Coker, L.H. (Laura), Longstreth Jr, W.T., Niessen, W.J. (Wiro), DeStefano, A.L. (Anita), Beiser, A. (Alexa), Zijdenbos, A.P., Struchalin, M.V. (Maksim), Jack Jr., C.R. (Clifford), Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A.G. (André), Knopman, D.S. (David), Hartikainen, A.L., Pennell, C.E. (Craig), Thiering, E. (Eelisabeth), Steegers, E.A.P. (Eric), Hakonarson, H. (Hakon), Heinrich, J. (Joachim), Palmer, C. (Cameron), Jarvelin, M.-R. (Marjo-Riitta), McCarthy, M.I. (Mark), Grant, S.F.A. (Struan), Pourcain, B.S. (Beate), Timpson, N.J. (Nicholas), Sovio, U. (Ulla), Nalls, M.A. (Michael), Au, R. (Rhoda), Hofman, A. (Albert), Gudnason, H. (Haukur), Lugt, A. (Aad) van der, Harris, T.B. (Tamara), Meeks, W.M. (William), Vernooij, M.W. (Meike), Buchem, M.A. (Mark) van, Catellier, D.J. (Diane), Jaddoe, V.W.V. (Vincent), Gudnason, V. (Vilmundur), Windham, B.G. (Gwen), Wolf, P.A. (Philip), Duijn, C.M. (Cornelia) van, Mosley, T.H. (Thomas), Launer, L.J. (Lenore), Breteler, M.M.B. (Monique), DeCarli, C. (Charles), Adair, L.S. (Linda), Ang, W.Q. (Wei), Atalay, M. (Mustafa), Beijsterveldt, C.E.M. (Toos) van, Bergen, N.E. (Nienke), Benke, P.J. (Paul), Berry, D. (Diane), Coin, L. (Lachlan), Davis, O.S.P. (Oliver S.), Elliott, P. (Paul), Flexeder, C. (Claudia), Frayling, T.M. (Timothy), Gaillard, R. (Romy), Groen-Blokhuis, M. (Maria), Goh, L.-K., Haworth, C.M.A. (Claire M.), Hadley, D. (David), Hedebrand, J. (Johannes), Hinney, A. (Anke), Hirschhorn, J.N. (Joel), Holloway, J.W. (John), Holst, J.J., Hottenga, J.J. (Jouke Jan), Horikoshi, M. (Momoko), Huikari, V. (Ville), Hypponen, E. (Elina), Kilpeläinen, T.O. (Tuomas), Kirin, M. (Mirna), Kowgier, M. (Matthew), Lakka, T.A. (Timo), Lange, L.A. (Leslie), Lawlor, D.A. (Debbie), Lehtimäki, T. (Terho), Lewin, A. (Alex), Lindgren, C.M. (Cecilia), Lindi, V. (Virpi), Maggi, R. (Reedik), Marsh, J.A. (Julie), Middeldorp, C.M. (Christel), Millwood, I.Y. (Iona), Murray, J.C. (Jeffrey), Nivard, M. (Michel), Nohr, C. (Christian), Ntalla, I. (Ioanna), Oken, E. (Emily), Panoutsopoulou, K. (Kalliope), Pararajasingham, J. (Jennifer), Rodriguez, A. (Alfredo Chapin), Salem, R.M. (Rany), Sebert, S. (Sylvain), Siitonen, N. (Niina), Strachan, D.P. (David), Teo, Y.Y. (Yik Ying), Valcárcel, B. (Beatriz), Willemsen, G.A.H.M. (Gonneke), Zeggini, E. (Eleftheria), Boomsma, D.I. (Dorret), Cooper, C. (Charles), Gillman, M.H. (Matthew), Hocher, B. (Berthold), Mohlke, K.L. (Karen), Dedoussis, G.V. (George), Ong, K.K. (Ken), Pearson, E. (Ewan), Price, T.S. (Thomas), Power, C. (Christopher), Raitakari, O. (Olli), Saw, S-M. (Seang-Mei), Scherag, A. (Andre), Simell, O. (Olli), Sørensen, T.I.A. (Thorkild), Wilson, J.F. (James), Ikram, M.A. (Arfan), Fornage, M. (Myriam), Smith, A.V. (Davey), Seshadri, S. (Sudha), Schmidt, R. (Reinhold), Debette, S. (Stéphanie), Vrooman, H.A. (Henri), Sigurdsson, S. (Stefan), Ropele, S. (Stefan), Taal, H.R. (Rob), Mook-Kanamori, D.O. (Dennis), Coker, L.H. (Laura), Longstreth Jr, W.T., Niessen, W.J. (Wiro), DeStefano, A.L. (Anita), Beiser, A. (Alexa), Zijdenbos, A.P., Struchalin, M.V. (Maksim), Jack Jr., C.R. (Clifford), Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A.G. (André), Knopman, D.S. (David), Hartikainen, A.L., Pennell, C.E. (Craig), Thiering, E. (Eelisabeth), Steegers, E.A.P. (Eric), Hakonarson, H. (Hakon), Heinrich, J. (Joachim), Palmer, C. (Cameron), Jarvelin, M.-R. (Marjo-Riitta), McCarthy, M.I. (Mark), Grant, S.F.A. (Struan), Pourcain, B.S. (Beate), Timpson, N.J. (Nicholas), Sovio, U. (Ulla), Nalls, M.A. (Michael), Au, R. (Rhoda), Hofman, A. (Albert), Gudnason, H. (Haukur), Lugt, A. (Aad) van der, Harris, T.B. (Tamara), Meeks, W.M. (William), Vernooij, M.W. (Meike), Buchem, M.A. (Mark) van, Catellier, D.J. (Diane), Jaddoe, V.W.V. (Vincent), Gudnason, V. (Vilmundur), Windham, B.G. (Gwen), Wolf, P.A. (Philip), Duijn, C.M. (Cornelia) van, Mosley, T.H. (Thomas), Launer, L.J. (Lenore), Breteler, M.M.B. (Monique), DeCarli, C. (Charles), Adair, L.S. (Linda), Ang, W.Q. (Wei), Atalay, M. (Mustafa), Beijsterveldt, C.E.M. (Toos) van, Bergen, N.E. (Nienke), Benke, P.J. (Paul), Berry, D. (Diane), Coin, L. (Lachlan), Davis, O.S.P. (Oliver S.), Elliott, P. (Paul), Flexeder, C. (Claudia), Frayling, T.M. (Timothy), Gaillard, R. (Romy), Groen-Blokhuis, M. (Maria), Goh, L.-K., Haworth, C.M.A. (Claire M.), Hadley, D. (David), Hedebrand, J. (Johannes), Hinney, A. (Anke), Hirschhorn, J.N. (Joel), Holloway, J.W. (John), Holst, J.J., Hottenga, J.J. (Jouke Jan), Horikoshi, M. (Momoko), Huikari, V. (Ville), Hypponen, E. (Elina), Kilpeläinen, T.O. (Tuomas), Kirin, M. (Mirna), Kowgier, M. (Matthew), Lakka, T.A. (Timo), Lange, L.A. (Leslie), Lawlor, D.A. (Debbie), Lehtimäki, T. (Terho), Lewin, A. (Alex), Lindgren, C.M. (Cecilia), Lindi, V. (Virpi), Maggi, R. (Reedik), Marsh, J.A. (Julie), Middeldorp, C.M. (Christel), Millwood, I.Y. (Iona), Murray, J.C. (Jeffrey), Nivard, M. (Michel), Nohr, C. (Christian), Ntalla, I. (Ioanna), Oken, E. (Emily), Panoutsopoulou, K. (Kalliope), Pararajasingham, J. (Jennifer), Rodriguez, A. (Alfredo Chapin), Salem, R.M. (Rany), Sebert, S. (Sylvain), Siitonen, N. (Niina), Strachan, D.P. (David), Teo, Y.Y. (Yik Ying), Valcárcel, B. (Beatriz), Willemsen, G.A.H.M. (Gonneke), Zeggini, E. (Eleftheria), Boomsma, D.I. (Dorret), Cooper, C. (Charles), Gillman, M.H. (Matthew), Hocher, B. (Berthold), Mohlke, K.L. (Karen), Dedoussis, G.V. (George), Ong, K.K. (Ken), Pearson, E. (Ewan), Price, T.S. (Thomas), Power, C. (Christopher), Raitakari, O. (Olli), Saw, S-M. (Seang-Mei), Scherag, A. (Andre), Simell, O. (Olli), Sørensen, T.I.A. (Thorkild), and Wilson, J.F. (James)

Abstract

During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 × 10 -8) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 × 10 -11), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 × 10 -12), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 × 10 -3 for 6q22 and 1.2 × 10 -3 for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size.

Published
2012
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9. Array-based FMR1 sequencing and deletion analysis in patients with a fragile X syndrome-like phenotype

Author

Collins, S.C. (Stephen), Coffee, B. (Brad), Benke, P.J. (Paul), Berry-Kravis, E.M. (Elizabeth), Gilbert, F. (Fred), Oostra, B.A. (Ben), Halley, D. (Dicky), Zwick, M.E. (Michael), Cutler, D.J. (David), Warren, S.T. (Stephen), Collins, S.C. (Stephen), Coffee, B. (Brad), Benke, P.J. (Paul), Berry-Kravis, E.M. (Elizabeth), Gilbert, F. (Fred), Oostra, B.A. (Ben), Halley, D. (Dicky), Zwick, M.E. (Michael), Cutler, D.J. (David), and Warren, S.T. (Stephen)

Abstract

Background: Fragile X syndrome (FXS) is caused by loss of function mutations in the FMR1 gene. Trinucleotide CGG-repeat expansions, resulting in FMR1 gene silencing, are the most common mutations observed at this locus. Even though the repeat expansion mutation is a functional null mutation, few conventional mutations have been identified at this locus, largely due to the clinical laboratory focus on the repeat tract. Methodology/Principal Findings: To more thoroughly evaluate the frequency of conventional mutations in FXS-like patients, we used an array-based method to sequence FMR1 in 51 unrelated males exhibiting several features characteristic of FXS but with normal CGG-repeat tracts of FMR1. One patient was identified with a deletion in FMR1, but none of the patients were found to have other conventional mutations. Conclusions/Significance: These data suggest that missense mutations in FMR1 are not a common cause of the FXS phenotype in patients who have normal-length CGG-repeat tracts. However, screening for small deletions of FMR1 may be of clinically utility.

Published
2010
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10. Mutational spectrum of the oral-facial-digital type I syndrome: a study on a large collection of patients.

Author

Prattichizzo, C., Macca, M., Novelli, V., Giorgio, G., Barra, A., Franco, B., Abdulla, F., Abramowicz, M., Amy, S., Schafer, I., Bankier, A., White, S., Barcina, M.G., Bartoshesky, L.E., Jenny, K., Beemer, F.A., Benke, P.J., Betz, R.C., Bianchini, G., Garavelli, L., Bigoni, S., Bird, L., Chibuk, J., Masser-Frye, D., Brunetti, N., Scarcella, A., Brunner, H.G., Burn, J., Carmi, R., Castellan, C., Castelluccio, P., Castle, B., Chiong, M.A., Cutiongco, E.M., Collins, F., Couchon, E., Curry, A., Pastore, M., Curry, C.J., Swenerton, A., Treisman, T., Dean, J., Devriendt, K., Matthijs, G., Dunlap, J.W., Shashi, V., Elcioglu, N., Farndon, P., Ferrero, G.B., Ferrier, R., Foulds, N., Friedman, J., Gal, A., Orth, U., Gardner, M., Gerola, O., Gillessen-Kaesbach, G., Giuliano, F., Turc-Carel, C., Godde, E., Graber, V., Graham, G.E., Gurrieri, F., Harbour, L., Henderson, A., Jones, E., Heran, H., Homfrey, T., Taylor, R., Iwarsson, E., Jensen, P.S., Jezela-Stanek, A., Joss, S., Taylor, G., Keeling, S.l., Klatt, R., Teebi, A., Klehr-Martinelli, M., Kotzot, D., Lees, M., Loughlin, S., Lhotta, K., Macdonald, F., Mari, F., Renieri, A., Marlin, S., McGaughran, J., McKenzie, F., McLeod, D.R., Megarbane, A., Mota, C.R., Mucke, J., Tzschach, A., Obersztyn, E., Okhowat, R., Shinzel, A., Pfau, R., Pober, B., Raymond, F.L., Prattichizzo, C., Macca, M., Novelli, V., Giorgio, G., Barra, A., Franco, B., Abdulla, F., Abramowicz, M., Amy, S., Schafer, I., Bankier, A., White, S., Barcina, M.G., Bartoshesky, L.E., Jenny, K., Beemer, F.A., Benke, P.J., Betz, R.C., Bianchini, G., Garavelli, L., Bigoni, S., Bird, L., Chibuk, J., Masser-Frye, D., Brunetti, N., Scarcella, A., Brunner, H.G., Burn, J., Carmi, R., Castellan, C., Castelluccio, P., Castle, B., Chiong, M.A., Cutiongco, E.M., Collins, F., Couchon, E., Curry, A., Pastore, M., Curry, C.J., Swenerton, A., Treisman, T., Dean, J., Devriendt, K., Matthijs, G., Dunlap, J.W., Shashi, V., Elcioglu, N., Farndon, P., Ferrero, G.B., Ferrier, R., Foulds, N., Friedman, J., Gal, A., Orth, U., Gardner, M., Gerola, O., Gillessen-Kaesbach, G., Giuliano, F., Turc-Carel, C., Godde, E., Graber, V., Graham, G.E., Gurrieri, F., Harbour, L., Henderson, A., Jones, E., Heran, H., Homfrey, T., Taylor, R., Iwarsson, E., Jensen, P.S., Jezela-Stanek, A., Joss, S., Taylor, G., Keeling, S.l., Klatt, R., Teebi, A., Klehr-Martinelli, M., Kotzot, D., Lees, M., Loughlin, S., Lhotta, K., Macdonald, F., Mari, F., Renieri, A., Marlin, S., McGaughran, J., McKenzie, F., McLeod, D.R., Megarbane, A., Mota, C.R., Mucke, J., Tzschach, A., Obersztyn, E., Okhowat, R., Shinzel, A., Pfau, R., Pober, B., and Raymond, F.L.

Abstract

Contains fulltext : 70803.pdf (publisher's version ) (Closed access), Oral-facial-digital type I (OFDI) syndrome is a male-lethal X-linked dominant developmental disorder belonging to the heterogeneous group of oral-facial-digital syndromes (OFDS). OFDI is characterized by malformations of the face, oral cavity, and digits. Central nervous system (CNS) abnormalities and cystic kidney disease can also be part of this condition. This rare genetic disorder is due to mutations in the OFD1 gene that encodes a centrosome/basal body protein necessary for primary cilium assembly and for left-right axis determination, thus ascribing OFDI to the growing number of disorders associated to ciliary dysfunction. We now report a mutation analysis study in a cohort of 100 unrelated affected individuals collected worldwide. Putative disease-causing mutations were identified in 81 patients (81%). We describe 67 different mutations, 64 of which represent novel mutations, including 36 frameshift, nine missense, 11 splice-site, and 11 nonsense mutations. Most of them concentrate in exons 3, 8, 9, 12, 13, and 16, suggesting that these exons may represent mutational hotspots. Phenotypic characterization of the patients provided a better definition of the clinical features of OFDI syndrome. Our results indicate that renal cystic disease is present in 60% of cases >18 years of age. Genotype-phenotype correlation did not reveal significant associations apart for the high-arched/cleft palate most frequently associated to missense and splice-site mutations. Our results contribute to further expand our knowledge on the molecular basis of OFDI syndrome.

Published
2008

11. NaV1.7 gain-of-function mutations as a continuum: A1632E displays physiological changes associated with erythromelalgia and paroxysmal extreme pain disorder mutations and produces symptoms of both disorders.

Author

Estacion, M., Dib-Hajj, S.D., Benke, P.J., Morsche, R.H.M. te, Eastman, E.M., Macala, L., Drenth, J.P.H., Waxman, S.G., Estacion, M., Dib-Hajj, S.D., Benke, P.J., Morsche, R.H.M. te, Eastman, E.M., Macala, L., Drenth, J.P.H., and Waxman, S.G.

Abstract

Contains fulltext : 70933.pdf (publisher's version ) (Open Access), Gain-of-function mutations of Na(V)1.7 have been shown to produce two distinct disorders: Na(V)1.7 mutations that enhance activation produce inherited erythromelalgia (IEM), characterized by burning pain in the extremities; Na(V)1.7 mutations that impair inactivation produce a different, nonoverlapping syndrome, paroxysmal extreme pain disorder (PEPD), characterized by rectal, periocular, and perimandibular pain. Here we report a novel Na(V)1.7 mutation associated with a mixed clinical phenotype with characteristics of IEM and PEPD, with an alanine 1632 substitution by glutamate (A1632E) in domain IV S4-S5 linker. Patch-clamp analysis shows that A1632E produces changes in channel function seen in both IEM and PEPD mutations: A1632E hyperpolarizes (-7 mV) the voltage dependence of activation, slows deactivation, and enhances ramp responses, as observed in Na(V)1.7 mutations that produce IEM. A1632E depolarizes (+17mV) the voltage dependence of fast inactivation, slows fast inactivation, and prevents full inactivation, resulting in persistent inward currents similar to PEPD mutations. Using current clamp, we show that A1632E renders dorsal root ganglion (DRG) and trigeminal ganglion neurons hyperexcitable. These results demonstrate a Na(V)1.7 mutant with biophysical characteristics common to PEPD (impaired fast inactivation) and IEM (hyperpolarized activation, slow deactivation, and enhanced ramp currents) associated with a clinical phenotype with characteristics of both IEM and PEPD and show that this mutation renders DRG and trigeminal ganglion neurons hyperexcitable. These observations indicate that IEM and PEPD mutants are part of a physiological continuum that can produce a continuum of clinical phenotypes.

Published
2008

17. Black children deficient in galactose 1-phosphate uridyltransferase: Correlation of activity and immunoreactive protein in erythrocytes and leukocytes

Author

Landt, M., Ritter, D., Lai, K., Benke, P.J., Elsas, L.J., and Steiner, R.D.

Abstract

A recent study found a high prevalence of a missense mutation (S135L) in the gene for galactose 1-phosphate uridyltransferase (GALT) in black children with galactosemia (J Pediatr 1996;128:89-95). In the present study, GALT activity and GALT protein content were measured in erythrocytes and leukocytes of eight black and seven white galactosemic (GALT-deficient) children, for correlation with the presence of the S135L and Q188R (highly prevalent in white galactosemic children) missense mutations. The S135L mutation was found in 9 of 16 alleles of black children but not in white children; the Q188R mutation was found in 10 of 14 alleles examined in white galactosemic children and in 4 of 16 alleles in black galactosemic children. The GALT activity was near zero in the erythrocytes of white and black galactosemic children (0.26 +/- 0.28 vs 0.33 +/- 0.25 @mmol/hr per gram of hemoglobin, respectively; p = 0.61) (normal 17 to 26 @mmol/hr per gram), and no correlation of erythrocyte activity with genotype was observed. The GALT activity was higher in the leukocytes of black galactosemic children compared with white children (5 +/- 6 vs 1 +/- 2 @mmol/hr per gram, respectively) (normal 172 to 374 @mmol/hr per gram), but the difference was not statistically significant ( p = 0.11). Analysis by genotype revealed that the two S135L homozygotes had much more leukocyte activity (9 and 17 @mmol/hr per gram) than Q188R homozygotes or than all non-S135L allelic genotypes. Compound heterozygotes (S135L/G) had intermediate activity. The GALT protein was not detectable by Western blot in the erythrocytes of either white or black galactosemic children, as determined by antibodies specific for both C- and N-terminal sequences. The GALT protein was undetectable in the leukocytes of white galactosemic children, but leukocytes from black galactosemic children with the S135L mutation contained reduced but readily detectable GALT protein. Erythrocyte galactose 1-phosphate levels were significantly lower in galactosemic children with an S135L mutant allele (1.1 +/- 0.2 gm/dl) compared with children who had other mutations (3.1 +/- 0.9 mg/dl; p = 0.0001). The correlation of protein content data with activity levels in the blood cells suggests that the S135L missense mutation affects the stability of GALT protein to produce a deficiency state. (J Pediatr 1997;130:972-80)

Published
1997
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