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1. A mutational hotspot in AMOTL1 defines a new syndrome of orofacial clefting, cardiac anomalies, and tall stature.

Author

Strong, A., Rao, S., Hardenberg, S. von, Li, D., Cox, L.L., Lee, P.C., Zhang, L.Q., Awotoye, W., Diamond, T., Gold, Jessica, Gooch, C., Gowans, L.J.J., Hakonarson, H., Hing, A., Loomes, K., Martin, N., Marazita, M.L., Mononen, T., Piccoli, D., Pfundt, R.P., Raskin, S., Scherer, S.W., Sobriera, N., Vaccaro, C., Wang, Xiang, Watson, D., Weksberg, R., Bhoj, E., Murray, J.C., Lidral, A.C., Butali, A., Buckley, M.F., Roscioli, T., Koolen, D.A., Seaver, L.H., Prows, C.A., Stottmann, R.W., Cox, T.C., Strong, A., Rao, S., Hardenberg, S. von, Li, D., Cox, L.L., Lee, P.C., Zhang, L.Q., Awotoye, W., Diamond, T., Gold, Jessica, Gooch, C., Gowans, L.J.J., Hakonarson, H., Hing, A., Loomes, K., Martin, N., Marazita, M.L., Mononen, T., Piccoli, D., Pfundt, R.P., Raskin, S., Scherer, S.W., Sobriera, N., Vaccaro, C., Wang, Xiang, Watson, D., Weksberg, R., Bhoj, E., Murray, J.C., Lidral, A.C., Butali, A., Buckley, M.F., Roscioli, T., Koolen, D.A., Seaver, L.H., Prows, C.A., Stottmann, R.W., and Cox, T.C.

Abstract

Item does not contain fulltext, AMOTL1 encodes angiomotin-like protein 1, an actin-binding protein that regulates cell polarity, adhesion, and migration. The role of AMOTL1 in human disease is equivocal. We report a large cohort of individuals harboring heterozygous AMOTL1 variants and define a core phenotype of orofacial clefting, congenital heart disease, tall stature, auricular anomalies, and gastrointestinal manifestations in individuals with variants in AMOTL1 affecting amino acids 157-161, a functionally undefined but highly conserved region. Three individuals with AMOTL1 variants outside this region are also described who had variable presentations with orofacial clefting and multi-organ disease. Our case cohort suggests that heterozygous missense variants in AMOTL1, most commonly affecting amino acid residues 157-161, define a new orofacial clefting syndrome, and indicates an important functional role for this undefined region.

Published
2023

3. An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome

Author

Choufani, S. (Sanaa), McNiven, V. (Vanda), Cytrynbaum, C. (Cheryl), Jangjoo, M. (Maryam), Adam, M. P. (Margaret P.), Bjornsson, H. T. (Hans T.), Harris, J. (Jacqueline), Dyment, D. A. (David A.), Graham, G. E. (Gail E.), Nezarati, M. M. (Marjan M.), Aul, R. B. (Ritu B.), Castiglioni, C. (Claudia), Breckpot, J. (Jeroen), Devriendt, K. (Koen), Stewart, H. (Helen), Banos-Pinero, B. (Benito), Mehta, S. (Sarju), Sandford, R. (Richard), Dunn, C. (Carolyn), Mathevet, R. (Remi), van Maldergem, L. (Lionel), Piard, J. (Juliette), Brischoux-Boucher, E. (Elise), Vitobello, A. (Antonio), Faivre, L. (Laurence), Bournez, M. (Marie), Tran-Mau, F. (Frederic), Maystadt, I. (Isabelle), Fernandez-Jaen, A. (Alberto), Alvarez, S. (Sara), Garcia-Prieto, I. D. (Irene Diez), Alkuraya, F. S. (Fowzan S.), Alsaif, H. S. (Hessa S.), Rahbeeni, Z. (Zuhair), El-Akouri, K. (Karen), Al-Mureikhi, M. (Mariam), Spillmann, R. C. (Rebecca C.), Shashi, V. (Vandana), Sanchez-Lara, P. A. (Pedro A.), Graham, J. M. (John M., Jr.), Roberts, A. (Amy), Chorin, O. (Odelia), Evrony, G. D. (Gilad D.), Kraatari-Tiri, M. (Minna), Dudding-Byth, T. (Tracy), Richardson, A. (Anamaria), Hunt, D. (David), Hamilton, L. (Laura), Dyack, S. (Sarah), Mendelsohn, B. A. (Bryce A.), Rodriguez, N. (Nicolas), Sanchez-Martinez, R. (Rosario), Tenorio-Castano, J. (Jair), Nevado, J. (Julian), Lapunzina, P. (Pablo), Tirado, P. (Pilar), Rodrigues, M. C. (Maria-Teresa Carminho Amaro), Quteineh, L. (Lina), Innes, A. M. (A. Micheil), Kline, A. D. (Antonie D.), Au, P. Y. (P. Y. Billie), Weksberg, R. (Rosanna), Choufani, S. (Sanaa), McNiven, V. (Vanda), Cytrynbaum, C. (Cheryl), Jangjoo, M. (Maryam), Adam, M. P. (Margaret P.), Bjornsson, H. T. (Hans T.), Harris, J. (Jacqueline), Dyment, D. A. (David A.), Graham, G. E. (Gail E.), Nezarati, M. M. (Marjan M.), Aul, R. B. (Ritu B.), Castiglioni, C. (Claudia), Breckpot, J. (Jeroen), Devriendt, K. (Koen), Stewart, H. (Helen), Banos-Pinero, B. (Benito), Mehta, S. (Sarju), Sandford, R. (Richard), Dunn, C. (Carolyn), Mathevet, R. (Remi), van Maldergem, L. (Lionel), Piard, J. (Juliette), Brischoux-Boucher, E. (Elise), Vitobello, A. (Antonio), Faivre, L. (Laurence), Bournez, M. (Marie), Tran-Mau, F. (Frederic), Maystadt, I. (Isabelle), Fernandez-Jaen, A. (Alberto), Alvarez, S. (Sara), Garcia-Prieto, I. D. (Irene Diez), Alkuraya, F. S. (Fowzan S.), Alsaif, H. S. (Hessa S.), Rahbeeni, Z. (Zuhair), El-Akouri, K. (Karen), Al-Mureikhi, M. (Mariam), Spillmann, R. C. (Rebecca C.), Shashi, V. (Vandana), Sanchez-Lara, P. A. (Pedro A.), Graham, J. M. (John M., Jr.), Roberts, A. (Amy), Chorin, O. (Odelia), Evrony, G. D. (Gilad D.), Kraatari-Tiri, M. (Minna), Dudding-Byth, T. (Tracy), Richardson, A. (Anamaria), Hunt, D. (David), Hamilton, L. (Laura), Dyack, S. (Sarah), Mendelsohn, B. A. (Bryce A.), Rodriguez, N. (Nicolas), Sanchez-Martinez, R. (Rosario), Tenorio-Castano, J. (Jair), Nevado, J. (Julian), Lapunzina, P. (Pablo), Tirado, P. (Pilar), Rodrigues, M. C. (Maria-Teresa Carminho Amaro), Quteineh, L. (Lina), Innes, A. M. (A. Micheil), Kline, A. D. (Antonie D.), Au, P. Y. (P. Y. Billie), and Weksberg, R. (Rosanna)

Abstract

Au-Kline syndrome (AKS) is a neurodevelopmental disorder associated with multiple malformations and a characteristic facial gestalt. The first individuals ascertained carried de novo loss-of-function (LoF) variants in HNRNPK. Here, we report 32 individuals with AKS (26 previously unpublished), including 13 with de novo missense variants. We propose new clinical diagnostic criteria for AKS that differentiate it from the clinically overlapping Kabuki syndrome and describe a significant phenotypic expansion to include individuals with missense variants who present with subtle facial features and few or no malformations. Many gene-specific DNA methylation (DNAm) signatures have been identified for neurodevelopmental syndromes. Because HNRNPK has roles in chromatin and epigenetic regulation, we hypothesized that pathogenic variants in HNRNPK may be associated with a specific DNAm signature. Here, we report a unique DNAm signature for AKS due to LoF HNRNPK variants, distinct from controls and Kabuki syndrome. This DNAm signature is also identified in some individuals with de novo HNRNPK missense variants, confirming their pathogenicity and the phenotypic expansion of AKS to include more subtle phenotypes. Furthermore, we report that some individuals with missense variants have an “intermediate” DNAm signature that parallels their milder clinical presentation, suggesting the presence of an epi-genotype phenotype correlation. In summary, the AKS DNAm signature may help elucidate the underlying pathophysiology of AKS. This DNAm signature also effectively supported clinical syndrome delineation and is a valuable aid for variant interpretation in individuals where a clinical diagnosis of AKS is unclear, particularly for mild presentations.

Published
2022

4. Phenotypic spectrum associated with PTCHD1 deletions and truncating mutations includes intellectual disability and autism spectrum disorder

Author

Chaudhry, A., Noor, A., Degagne, B., Baker, K., Bok, L. A., Brady, A. F., Chitayat, D., Chung, B. H., Cytrynbaum, C., Dyment, D., Filges, I., Helm, B., Hutchison, H. T., Jeng, L. J. B., Laumonnier, F., Marshall, C. R., Menzel, M., Parkash, S., Parker, M. J., Raymond, L. F., Rideout, A. L., Roberts, W., Rupps, R., Schanze, I., Schrander-Stumpel, C. T. R. M., Speevak, M. D., Stavropoulos, D. J., Stevens, S. J. C., Thomas, E. R. A., Toutain, A., Vergano, S., Weksberg, R., Scherer, S. W., Vincent, J. B., and Carter, M. T.

Published
2015
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5. Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature

Author

Rots, D., Chater-Diehl, E., Dingemans, A.J.M., Goodman, S.J., Siu, M.T., Cytrynbaum, C., Choufani, S., Hoang, N., Walker, S., Awamleh, Z., Charkow, J., Meyn, S., Pfundt, R.P., Rinne, T.K., Gardeitchik, T., Vries, B.B.A. de, Deden, A.C., Leenders, E.K.S.M., Kwint, M.P., Stumpel, C., Stevens, S.J.C., Vermeulen, J.R., Harssel, J.V.T. van, Bosch, D.G.M., Gassen, K.L.I. van, Binsbergen, E. van, Geus, C.M. de, Brackel, H., Hempel, M., Lessel, D., Denecke, J., Slavotinek, A., Strober, J., Crunk, A., Folk, L., Wentzensen, I.M., Yang, H., Zou, F., Millan, F., Person, R., Xie, Y., Liu, S., Ousager, L.B., Larsen, M., Schultz-Rogers, L., Morava, E., Klee, E.W., Berry, I.R., Campbell, J., Lindstrom, K., Pruniski, B., Neumeyer, A.M., Radley, J.A., Phornphutkul, C., Schmidt, B., Wilson, W.G., Õunap, K., Reinson, K., Pajusalu, S., Haeringen, A. van, Ruivenkamp, C., Cuperus, R., Santos-Simarro, F., Palomares-Bralo, M., Pacio-Míguez, M., Ritter, A., Bhoj, E., Tønne, E., Tveten, K., Cappuccio, G., Brunetti-Pierri, N., Rowe, L., Bunn, J., Saenz, M., Platzer, K., Mertens, M., Caluseriu, O., Nowaczyk, M.J., Cohn, R.D., Kannu, P., Alkhunaizi, E., Chitayat, D., Scherer, S.W., Brunner, H.G., Vissers, L.E., Kleefstra, T., Koolen, D.A., Weksberg, R., Rots, D., Chater-Diehl, E., Dingemans, A.J.M., Goodman, S.J., Siu, M.T., Cytrynbaum, C., Choufani, S., Hoang, N., Walker, S., Awamleh, Z., Charkow, J., Meyn, S., Pfundt, R.P., Rinne, T.K., Gardeitchik, T., Vries, B.B.A. de, Deden, A.C., Leenders, E.K.S.M., Kwint, M.P., Stumpel, C., Stevens, S.J.C., Vermeulen, J.R., Harssel, J.V.T. van, Bosch, D.G.M., Gassen, K.L.I. van, Binsbergen, E. van, Geus, C.M. de, Brackel, H., Hempel, M., Lessel, D., Denecke, J., Slavotinek, A., Strober, J., Crunk, A., Folk, L., Wentzensen, I.M., Yang, H., Zou, F., Millan, F., Person, R., Xie, Y., Liu, S., Ousager, L.B., Larsen, M., Schultz-Rogers, L., Morava, E., Klee, E.W., Berry, I.R., Campbell, J., Lindstrom, K., Pruniski, B., Neumeyer, A.M., Radley, J.A., Phornphutkul, C., Schmidt, B., Wilson, W.G., Õunap, K., Reinson, K., Pajusalu, S., Haeringen, A. van, Ruivenkamp, C., Cuperus, R., Santos-Simarro, F., Palomares-Bralo, M., Pacio-Míguez, M., Ritter, A., Bhoj, E., Tønne, E., Tveten, K., Cappuccio, G., Brunetti-Pierri, N., Rowe, L., Bunn, J., Saenz, M., Platzer, K., Mertens, M., Caluseriu, O., Nowaczyk, M.J., Cohn, R.D., Kannu, P., Alkhunaizi, E., Chitayat, D., Scherer, S.W., Brunner, H.G., Vissers, L.E., Kleefstra, T., Koolen, D.A., and Weksberg, R.

Abstract

Contains fulltext : 234078.pdf (Publisher’s version ) (Open Access), Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD." All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.

Published
2021

6. Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome

Author

Sheppard, SE, Campbell, IM, Harr, MH, Gold, N, Li, D, Bjornsson, HT, Cohen, JS, Fahrner, JA, Fatemi, A, Harris, JR, Nowak, C, Stevens, CA, Grand, K, Au, M, Graham, JM, Sanchez-Lara, PA, Del Campo, M, Jones, MC, Abdul-Rahman, O, Alkuraya, FS, Bassetti, JA, Bergstrom, K, Bhoj, E, Dugan, S, Kaplan, JD, Derar, N, Gripp, KW, Hauser, N, Innes, AM, Keena, B, Kodra, N, Miller, R, Nelson, B, Nowaczyk, MJ, Rahbeeni, Z, Ben-Shachar, S, Shieh, JT, Slavotinek, A, Sobering, AK, Abbott, M-A, Allain, DC, Amlie-Wolf, L, Au, PYB, Bedoukian, E, Beek, G, Barry, J, Berg, J, Bernstein, JA, Cytrynbaum, C, Chung, BH-Y, Donoghue, S, Dorrani, N, Eaton, A, Flores-Daboub, JA, Dubbs, H, Felix, CA, Fong, C-T, Fung, JLF, Gangaram, B, Goldstein, A, Greenberg, R, Ha, TK, Hersh, J, Izumi, K, Kallish, S, Kravets, E, Kwok, P-Y, Jobling, RK, Johnson, AEK, Kushner, J, Lee, BH, Levin, B, Lindstrom, K, Manickam, K, Mardach, R, McCormick, E, McLeod, DR, Mentch, FD, Minks, K, Muraresku, C, Nelson, SF, Porazzi, P, Pichurin, PN, Powell-Hamilton, NN, Powis, Z, Ritter, A, Rogers, C, Rohena, L, Ronspies, C, Schroeder, A, Stark, Z, Starr, L, Stoler, J, Suwannarat, P, Velinov, M, Weksberg, R, Wilnai, Y, Zadeh, N, Zand, DJ, Falk, MJ, Hakonarson, H, Zackai, EH, Quintero-Rivera, F, Sheppard, SE, Campbell, IM, Harr, MH, Gold, N, Li, D, Bjornsson, HT, Cohen, JS, Fahrner, JA, Fatemi, A, Harris, JR, Nowak, C, Stevens, CA, Grand, K, Au, M, Graham, JM, Sanchez-Lara, PA, Del Campo, M, Jones, MC, Abdul-Rahman, O, Alkuraya, FS, Bassetti, JA, Bergstrom, K, Bhoj, E, Dugan, S, Kaplan, JD, Derar, N, Gripp, KW, Hauser, N, Innes, AM, Keena, B, Kodra, N, Miller, R, Nelson, B, Nowaczyk, MJ, Rahbeeni, Z, Ben-Shachar, S, Shieh, JT, Slavotinek, A, Sobering, AK, Abbott, M-A, Allain, DC, Amlie-Wolf, L, Au, PYB, Bedoukian, E, Beek, G, Barry, J, Berg, J, Bernstein, JA, Cytrynbaum, C, Chung, BH-Y, Donoghue, S, Dorrani, N, Eaton, A, Flores-Daboub, JA, Dubbs, H, Felix, CA, Fong, C-T, Fung, JLF, Gangaram, B, Goldstein, A, Greenberg, R, Ha, TK, Hersh, J, Izumi, K, Kallish, S, Kravets, E, Kwok, P-Y, Jobling, RK, Johnson, AEK, Kushner, J, Lee, BH, Levin, B, Lindstrom, K, Manickam, K, Mardach, R, McCormick, E, McLeod, DR, Mentch, FD, Minks, K, Muraresku, C, Nelson, SF, Porazzi, P, Pichurin, PN, Powell-Hamilton, NN, Powis, Z, Ritter, A, Rogers, C, Rohena, L, Ronspies, C, Schroeder, A, Stark, Z, Starr, L, Stoler, J, Suwannarat, P, Velinov, M, Weksberg, R, Wilnai, Y, Zadeh, N, Zand, DJ, Falk, MJ, Hakonarson, H, Zackai, EH, and Quintero-Rivera, F

Abstract

Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non-LoF variants. This study identifies genotype-phenotype correlations as well as race-facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long-term outcomes in individuals with WSS.

Published
2021

7. De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects

Author

Manole, A, Efthymiou, S, O'Connor, E, Mendes, MI, Jennings, M, Maroofian, R, Davagnanam, I, Mankad, K, Lopez, MR, Salpietro, V, Harripaul, R, Badalato, L, Walia, J, Francklyn, CS, Athanasiou-Fragkouli, A, Sullivan, R, Desai, S, Baranano, K, Zafar, F, Rana, N, Ilyas, M, Horga, A, Kara, M, Mattioli, F, Goldenberg, A, Griffin, H, Piton, A, Henderson, LB, Kara, B, Aslanger, AD, Raaphorst, J, Pfundt, R, Portier, R, Shinawi, M, Kirby, A, Christensen, KM, Wang, L, Rosti, RO, Paracha, SA, Sarwar, MT, Jenkins, D, SYNAPS Study Group, Ahmed, J, Santoni, FA, Ranza, E, Iwaszkiewicz, J, Cytrynbaum, C, Weksberg, R, Wentzensen, IM, Guillen Sacoto, MJ, Si, Y, Telegrafi, A, Andrews, MV, Baldridge, D, Gabriel, H, Mohr, J, Oehl-Jaschkowitz, B, Debard, S, Senger, B, Fischer, F, van Ravenwaaij, C, Fock, AJM, Stevens, SJC, Bähler, J, Nasar, A, Mantovani, JF, Manzur, A, Sarkozy, A, Smith, DEC, Salomons, GS, Ahmed, ZM, Riazuddin, S, Usmani, MA, Seibt, A, Ansar, M, Antonarakis, SE, Vincent, JB, Ayub, M, Grimmel, M, Jelsig, AM, Hjortshøj, TD, Karstensen, HG, Hummel, M, Haack, TB, Jamshidi, Y, Distelmaier, F, Horvath, R, Gleeson, JG, Becker, H, Mandel, J-L, Koolen, DA, and Houlden, H

Abstract

Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function.

Published
2020

8. DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes

Author

Choufani, S, Gibson, WT, Turinsky, AL, Chung, BHY, Wang, T, Garg, K, Vitriolo, A, Cohen, ASA, Cyrus, S, Goodman, S, Chater-Diehl, E, Brzezinski, J, Brudno, M, Ming, LH, White, SM, Lynch, SA, Clericuzio, C, Temple, IK, Flinter, F, McConnell, V, Cushing, T, Bird, LM, Splitt, M, Kerr, B, Scherer, SW, Machado, J, Imagawa, E, Okamoto, N, Matsumoto, N, Testa, G, Iascone, M, Tenconi, R, Caluseriu, O, Mendoza-Londono, R, Chitayat, D, Cytrynbaum, C, Tatton-Brown, K, Weksberg, R, Choufani, S, Gibson, WT, Turinsky, AL, Chung, BHY, Wang, T, Garg, K, Vitriolo, A, Cohen, ASA, Cyrus, S, Goodman, S, Chater-Diehl, E, Brzezinski, J, Brudno, M, Ming, LH, White, SM, Lynch, SA, Clericuzio, C, Temple, IK, Flinter, F, McConnell, V, Cushing, T, Bird, LM, Splitt, M, Kerr, B, Scherer, SW, Machado, J, Imagawa, E, Okamoto, N, Matsumoto, N, Testa, G, Iascone, M, Tenconi, R, Caluseriu, O, Mendoza-Londono, R, Chitayat, D, Cytrynbaum, C, Tatton-Brown, K, and Weksberg, R

Abstract

Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase EZH2, which encodes a core component of the Polycomb repressive complex-2 (PRC2). Using genome-wide DNA methylation (DNAm) data for 187 individuals with OGID and 969 control subjects, we show that pathogenic variants in EZH2 generate a highly specific and sensitive DNAm signature reflecting the phenotype of WS. This signature can be used to distinguish loss-of-function from gain-of-function missense variants and to detect somatic mosaicism. We also show that the signature can accurately classify sequence variants in EED and SUZ12, which encode two other core components of PRC2, and predict the presence of pathogenic variants in undiagnosed individuals with OGID. The discovery of a functionally relevant signature with utility for diagnostic classification of sequence variants in EZH2, EED, and SUZ12 supports the emerging paradigm shift for implementation of DNAm signatures into diagnostics and translational research.

Published
2020

11. Mapping of a new SGBS locus to chromosome Xp22 in a family with a severe form of Simpson-Golabi-Behmel syndrome

Author

Brzustowicz, L.M., Farrell, S., Khan, M.B., and Weksberg, R.

Subjects
Genetic disorders -- Research, Chromosome mapping -- Usage, Intestines -- Abnormalities, Skeleton -- Abnormalities, X chromosome -- Abnormalities, Syndromes in children -- Genetic aspects, Biological sciences
Abstract

Mapping of a new Simpson-Golabi-Behmel syndrome (SGBS) locus to chromosome Xp22 has been carried out in a family with a severe form of the syndrome an X-linked overgrowth syndrome with visceral/skeletal abnormalities associated. Not all of those with SGBS have demonstrated disruptions of the glypican-3 gene (GPB3) locus. Alterations in this gene, located on Xq26, are implicated in etiology of the more mild forms of the disorder. A second SGBS locus is on Xp22. The mapping project used 25 simple tandem-repeat polymorphism markers all across the X chromosome.

Published
1999

13. HIST1H1E heterozygous protein-truncating variants cause a recognizable syndrome with intellectual disability and distinctive facial gestalt: A study to clarify the HIST1H1E syndrome phenotype in 30 individuals

Author

Burkardt, DD, Zachariou, A, Loveday, C, Allen, CL, Amor, DJ, Ardissone, A, Banka, S, Bourgois, A, Coubes, C, Cytrynbaum, C, Faivre, L, Marion, G, Horton, R, Kotzot, D, Lay-Son, G, Lees, M, Low, K, Luk, H-M, Mark, P, McConkie-Rosell, A, McDonald, M, Pappas, J, Phillipe, C, Shears, D, Skotko, B, Stewart, F, Stewart, H, Temple, IK, Mau-Them, FT, Verdugo, RA, Weksberg, R, Zarate, YA, Graham, JM, Tatton-Brown, K, Burkardt, DD, Zachariou, A, Loveday, C, Allen, CL, Amor, DJ, Ardissone, A, Banka, S, Bourgois, A, Coubes, C, Cytrynbaum, C, Faivre, L, Marion, G, Horton, R, Kotzot, D, Lay-Son, G, Lees, M, Low, K, Luk, H-M, Mark, P, McConkie-Rosell, A, McDonald, M, Pappas, J, Phillipe, C, Shears, D, Skotko, B, Stewart, F, Stewart, H, Temple, IK, Mau-Them, FT, Verdugo, RA, Weksberg, R, Zarate, YA, Graham, JM, and Tatton-Brown, K

Abstract

Histone Gene Cluster 1 Member E, HIST1H1E, encodes Histone H1.4, is one of a family of epigenetic regulator genes, acts as a linker histone protein, and is responsible for higher order chromatin structure. HIST1H1E syndrome (also known as Rahman syndrome, OMIM #617537) is a recently described intellectual disability (ID) syndrome. Since the initial description of five unrelated individuals with three different heterozygous protein-truncating variants (PTVs) in the HIST1H1E gene in 2017, we have recruited 30 patients, all with HIST1H1E PTVs that result in the same shift in frame and that cluster to a 94-base pair region in the HIST1H1E carboxy terminal domain. The identification of 30 patients with HIST1H1E variants has allowed the clarification of the HIST1H1E syndrome phenotype. Major findings include an ID and a recognizable facial appearance. ID was reported in all patients and is most frequently of moderate severity. The facial gestalt consists of a high frontal hairline and full lower cheeks in early childhood and, in later childhood and adulthood, affected individuals have a strikingly high frontal hairline, frontal bossing, and deep-set eyes. Other associated clinical features include hypothyroidism, abnormal dentition, behavioral issues, cryptorchidism, skeletal anomalies, and cardiac anomalies. Brain magnetic resonance imaging (MRI) is frequently abnormal with a slender corpus callosum a frequent finding.

Published
2019

14. To look or not to look during vaccination: A pilot randomized trial

Author

Mithal, Priyanjali, Simmons, Pamela, Cornelissen, Tessa, Wong, Horace, Pillai Riddell, Rebecca, McMurtry, C. Meghan, Burry, Lisa, Stephens, Derek, Lou, Anna, Nicolson, R., Georgiades, S., Szatmari, P., Anagnostou, E., Scherer, S. W., Choufani, S., Brudno, M., and Weksberg, R.

Subjects
medicine.medical_specialty, business.industry, Original Articles, vaccination, Influenza vaccinations, Preference, law.invention, Vaccination, 03 medical and health sciences, 0302 clinical medicine, Anesthesiology and Pain Medicine, looking preference, Randomized controlled trial, needle, law, 030225 pediatrics, Physical therapy, Medicine, fear, pain, Analysis of variance, business, 030217 neurology & neurosurgery, Research Article
Abstract

Background Clinicians commonly advise patients to look away from the needle during vaccinations; however, this recommendation is not evidence based. Aim The aim of this study was to determine whether looking at the needle versus looking away affects pain and fear during vaccinations in adults. Methods This was a pilot randomized two-group parallel trial with university students receiving influenza vaccinations. Participants were stratified according to their initial needle-looking preference and randomly assigned to either look at versus away from the needle. Participants self-reported their pain and fear during vaccination. Results Of the 184 subjects who agreed to participate, 160 were enrolled; 66% were female. A three-way analysis of variance (ANOVA; Looking allocation assignment × Looking preference × Sex) revealed a significant main effect of looking allocation assignment on fear (P = 0.025); those who were randomized to look had higher fear scores than those who were randomized to look away. There was also a significant main effect of looking preference on fear (P

Published
2018

17. Chromosomal contacts connect loci associated with autism, BMI and head circumference phenotypes

Author

Loviglio, M. N, Leleu, M., Männik, K., Passeggeri, M., Giannuzzi, G., van der Werf, I., Waszak, S. M., Zazhytska, M., Roberts Caldeira, I., Gheldof, N., Migliavacca, E., Alfaiz, A. A., Hippolyte, L., Maillard, A. M., van Dijck, A., Kooy, R. F., Sanlaville, D., Rosenfeld, J. A., Shaffer, L. G., Andrieux, J., Marshall, C., Scherer, S. W., Shen, Y., Gusella, J. F., Thorsteinsdottir, U., Thorleifsson, G., Dermitzakis, E. T., Deplancke, B., Beckmann, J. S., Rougemont, J., Jacquemont, S., Reymond, A., Collaborators: Loviglio MN, Männik, K, van der Werf, I, Giannuzzi, G, Zazhytska, M, Gheldof, N, Migliavacca, E, Alfaiz, Aa, Roberts Caldeira, I, Hippolyte, L, Maillard, Am, Ferrarini, A, Butschi, Fn, Conrad, B, Addor, Mc, Belfiore, M, Roetzer, K, Dijck, Av, Blaumeiser, B, Kooy, F, Roelens, F, Dheedene, A, Chiaie, Bd, Menten, B, Oostra, A, Caberg, Jh, Carter, M, Kellam, B, Stavropoulos, Dj, Marshall, C, Scherer, Sw, Weksberg, R, Cytrynbaum, C, Bassett, A, Lowther, C, Gillis, J, Mackay, S, Bache, I, Ousager, Lb, Smerdel, Mp, Graakjaer, J, Kjaergaard, S, Metspalu, A, Mathieu, M, Bonneau, D, Guichet, A, Parent, P, Férec, C, Gerard, M, Plessis, G, Lespinasse, J, Masurel, A, Marle, N, Faivre, L, Callier, P, Layet, V, Meur, Nl, Le Goff, C, Duban Bedu, B, Sukno, S, Boute, O, Andrieux, J, Blanchet, P, Geneviève, D, Puechberty, J, Schneider, A, Leheup, B, Jonveaux, P, Mercier, S, David, A, Le Caignec, C, de Pontual, L, Pipiras, E, Jacquette, A, Keren, B, Gilbert Dussardier, B, Bilan, F, Goldenberg, A, Chambon, P, Toutain, A, Till, M, Sanlaville, D, Leube, B, Royer Pokora, B, Grabe, Hj, Schmidt, Co, Schurmann, C, Homuth, G, Thorleifsson, G, Thorsteinsdottir, U, Bernardini, L, Novelli, A, Micale, L, Merla, G, Zollino, M, Mari, Francesca, Rizzo, Cl, Renieri, Alessandra, Silengo, M, Vulto van Silfhout AT, Schouten, M, Pfundt, R, de Leeuw, N, Vansenne, F, Maas, Sm, Barge Schaapveld DQ, Knegt, Ac, Stadheim, B, Rodningen, O, Houge, G, Price, S, Hawkes, L, Campbell, C, Kini, U, Vogt, J, Walters, R, Blakemore, A, Gusella, Jf, Shen, Y, Scott, D, Bacino, Ca, Tsuchiya, K, Ladda, R, Sell, S, Asamoah, A, Hamati, Ai, Rosenfeld, Ja, Shaffer, Lg, Mitchell, E, Hodge, Jc, Beckmann, Js, Jacquemont, S, Reymond, A, Ewans, Lj, Mowat, D, Walker, J, Amor, Dj, Esch, Hv, Leroy, P, Bamforth, Js, Babu, D, Isidor, B, Didonato, N, Hackmann, K, Passeggeri, M, Haeringen, Av, Smith, R, Ellingwood, S, Farber, Dm, Puri, V, Zadeh, N, Weaver, Dd, Miller, M, Wilks, T, Jorgez, Cj, Lafayette, D, Blaumeiser, Bettina, 2p15 Consortium, 16p11.2 Consortium, Loviglio, M.N., Männik, K., van der Werf, I., Giannuzzi, G., Zazhytska, M., Gheldof, N., Migliavacca, E., Alfaiz, A.A., Roberts-Caldeira, I., Hippolyte, L., Maillard, A.M., Ferrarini, A., Butschi, F.N., Conrad, B., Addor, M.C., Belfiore, M., Roetzer, K., Dijck, A.V., Blaumeiser, B., Kooy, F., Roelens, F., Dheedene, A., Chiaie, B.D., Menten, B., Oostra, A., Caberg, J.H., Carter, M., Kellam, B., Stavropoulos, D.J., Marshall, C., Scherer, S.W., Weksberg, R., Cytrynbaum, C., Bassett, A., Lowther, C., Gillis, J., MacKay, S., Bache, I., Ousager, L.B., Smerdel, M.P., Graakjaer, J., Kjaergaard, S., Metspalu, A., Mathieu, M., Bonneau, D., Guichet, A., Parent, P., Férec, C., Gerard, M., Plessis, G., Lespinasse, J., Masurel, A., Marle, N., Faivre, L., Callier, P., Layet, V., Meur, N.L., Le Goff, C., Duban-Bedu, B., Sukno, S., Boute, O., Andrieux, J., Blanchet, P., Geneviève, D., Puechberty, J., Schneider, A., Leheup, B., Jonveaux, P., Mercier, S., David, A., Le Caignec, C., de Pontual, L., Pipiras, E., Jacquette, A., Keren, B., Gilbert-Dussardier, B., Bilan, F., Goldenberg, A., Chambon, P., Toutain, A., Till, M., Sanlaville, D., Leube, B., Royer-Pokora, B., Grabe, H.J., Schmidt, C.O., Schurmann, C., Homuth, G., Thorleifsson, G., Thorsteinsdottir, U., Bernardini, L., Novelli, A., Micale, L., Merla, G., Zollino, M., Mari, F., Rizzo, C.L., Renieri, A., Silengo, M., Vulto-van Silfhout, A.T., Schouten, M., Pfundt, R., de Leeuw, N., Vansenne, F., Maas, S.M., Barge-Schaapveld, D.Q., Knegt, A.C., Stadheim, B., Rodningen, O., Houge, G., Price, S., Hawkes, L., Campbell, C., Kini, U., Vogt, J., Walters, R., Blakemore, A., Gusella, J.F., Shen, Y., Scott, D., Bacino, C.A., Tsuchiya, K., Ladda, R., Sell, S., Asamoah, A., Hamati, A.I., Rosenfeld, J.A., Shaffer, L.G., Mitchell, E., Hodge, J.C., Beckmann, J.S., Jacquemont, S., Reymond, A., Ewans, L.J., Mowat, D., Walker, J., Amor, D.J., Esch, H.V., Leroy, P., Bamforth, J.S., Babu, D., Isidor, B., DiDonato, N., Hackmann, K., Passeggeri, M., Haeringen, A.V., Smith, R., Ellingwood, S., Farber, D.M., Puri, V., Zadeh, N., Weaver, D.D., Miller, M., Wilks, T., Jorgez, C.J., Lafayette, D., Other departments, and Human Genetics

Subjects
0301 basic medicine, Male, Microcephaly, Autism Spectrum Disorder, Obesity/genetics, Settore MED/03 - GENETICA MEDICA, Body Mass Index, Microcephaly/genetics, Gene duplication, Chromosome Duplication, ddc:576.5, Copy-number variation, Child, In Situ Hybridization, In Situ Hybridization, Fluorescence, Genetics, medicine.diagnostic_test, Chromosome Mapping, Middle Aged, Phenotype, Chromatin, Chemistry, Psychiatry and Mental Health, Child, Preschool, Female, Original Article, Chromosomes, Human, Pair 16/genetics, Megalencephaly/genetics, Chromosome Deletion, Autistic Disorder/genetics, Molecular Biology, Cellular and Molecular Neuroscience, Human, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Adult, Adolescent, DNA Copy Number Variations, Locus (genetics), DNA Copy Number Variations/genetics, Biology, Aged, Autistic Disorder, Chromosomes, Human, Pair 16, Humans, Infant, Intellectual Disability, Megalencephaly, Obesity, Chromosomes, Fluorescence, Chromatin/metabolism, 03 medical and health sciences, medicine, Preschool, Gene, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Pair 16, medicine.disease, Intellectual Disability/genetics, Autism Spectrum Disorder/genetics, 030104 developmental biology, Human medicine, Chromosome Mapping/methods, Fluorescence in situ hybridization
Abstract

Contains fulltext : 174530.pdf (Publisher’s version ) (Open Access) Copy number variants (CNVs) are major contributors to genomic imbalance disorders. Phenotyping of 137 unrelated deletion and reciprocal duplication carriers of the distal 16p11.2 220 kb BP2-BP3 interval showed that these rearrangements are associated with autism spectrum disorders and mirror phenotypes of obesity/underweight and macrocephaly/microcephaly. Such phenotypes were previously associated with rearrangements of the non-overlapping proximal 16p11.2 600 kb BP4-BP5 interval. These two CNV-prone regions at 16p11.2 are reciprocally engaged in complex chromatin looping, as successfully confirmed by 4C-seq, fluorescence in situ hybridization and Hi-C, as well as coordinated expression and regulation of encompassed genes. We observed that genes differentially expressed in 16p11.2 BP4-BP5 CNV carriers are concomitantly modified in their chromatin interactions, suggesting that disruption of chromatin interplays could participate in the observed phenotypes. We also identified cis- and trans-acting chromatin contacts to other genomic regions previously associated with analogous phenotypes. For example, we uncovered that individuals with reciprocal rearrangements of the trans-contacted 2p15 locus similarly display mirror phenotypes on head circumference and weight. Our results indicate that chromosomal contacts' maps could uncover functionally and clinically related genes.

Published
2015

18. Prenatal molecular testing for Beckwith-Wiedemann and Silver-Russell syndromes: A challenge for molecular analysis and genetic counseling.

Author

Prawitt D., Begemann M., Soellner L., Eggermann K., Tenorio J., Nevado J., Moore G.E., Mackay D.J.G., Temple K., Gillessen-Kaesbach G., Ogata T., Weksberg R., Algar E., Lapunzina P., Eggermann T., Brioude F., Russo S., Lombardi M.P., Bliek J., Maher E.R., Larizza L., Netchine I., Gonzales M., Gronskov K., Tumer Z., Monk D., Mannens M., Chrzanowska K., Walasek M.K., Prawitt D., Begemann M., Soellner L., Eggermann K., Tenorio J., Nevado J., Moore G.E., Mackay D.J.G., Temple K., Gillessen-Kaesbach G., Ogata T., Weksberg R., Algar E., Lapunzina P., Eggermann T., Brioude F., Russo S., Lombardi M.P., Bliek J., Maher E.R., Larizza L., Netchine I., Gonzales M., Gronskov K., Tumer Z., Monk D., Mannens M., Chrzanowska K., and Walasek M.K.

Abstract

Beckwith-Wiedemann and Silver-Russell syndromes (BWS/SRS) are two imprinting disorders (IDs) associated with disturbances of the 11p15.5 chromosomal region. In BWS, epimutations and genomic alterations within 11p15.5 are observed in >70% of patients, whereas in SRS they are observed in about 60% of the cases. In addition, 10% of the SRS patients carry a maternal uniparental disomy of chromosome 7 11p15.5. There is an increasing demand for prenatal testing of these disorders owing to family history, indicative prenatal ultrasound findings or aberrations involving chromosomes 7 and 11. The complex molecular findings underlying these disorders are a challenge not only for laboratories offering these tests but also for geneticists counseling affected families. The scope of counseling must consider the range of detectable disturbances and their origin, the lack of precise quantitative knowledge concerning the inheritance and recurrence risks for the epigenetic abnormalities, which are hallmarks of these developmental disorders. In this paper, experts in the field of BWS and SRS, including members of the European network of congenital IDs (EUCID.net; www.imprinting-disorders.eu), put together their experience and work in the field of 11p15.5-Associated IDs with a focus on prenatal testing. Altogether, prenatal tests of 160 fetuses (122 referred for BWS, 38 for SRS testing) from 5 centers were analyzed and reviewed. We summarize the current knowledge on BWS and SRS with respect to diagnostic testing, the consequences for prenatal genetic testing and counseling and our cumulative experience in dealing with these disorders.Copyright © 2016 Macmillan Publishers Limited.

Published
2016

19. EMQN best practice guidelines for the molecular genetic testing and reporting of chromosome 11p15 imprinting disorders: Silver-Russell and Beckwith-Wiedemann syndrome.

Author

MacKay D.J., Riccio A., Weksberg R., Lapunzina P., Gronskov K., Eggermann T., Eggermann K., Bliek J., Brioude F., Algar E., Buiting K., Russo S., Tumer Z., Monk D., Moore G., Antoniadi T., MacDonald F., Netchine I., Lombardi P., Soellner L., Begemann M., Prawitt D., Maher E.R., Mannens M., MacKay D.J., Riccio A., Weksberg R., Lapunzina P., Gronskov K., Eggermann T., Eggermann K., Bliek J., Brioude F., Algar E., Buiting K., Russo S., Tumer Z., Monk D., Moore G., Antoniadi T., MacDonald F., Netchine I., Lombardi P., Soellner L., Begemann M., Prawitt D., Maher E.R., and Mannens M.

Abstract

Molecular genetic testing for the 11p15-associated imprinting disorders Silver-Russell and Beckwith-Wiedemann syndrome (SRS, BWS) is challenging because of the molecular heterogeneity and complexity of the affected imprinted regions. With the growing knowledge on the molecular basis of these disorders and the demand for molecular testing, it turned out that there is an urgent need for a standardized molecular diagnostic testing and reporting strategy. Based on the results from the first external pilot quality assessment schemes organized by the European Molecular Quality Network (EMQN) in 2014 and in context with activities of the European Network of Imprinting Disorders (EUCID.net) towards a consensus in diagnostics and management of SRS and BWS, best practice guidelines have now been developed. Members of institutions working in the field of SRS and BWS diagnostics were invited to comment, and in the light of their feedback amendments were made. The final document was ratified in the course of an EMQN best practice guideline meeting and is in accordance with the general SRS and BWS consensus guidelines, which are in preparation. These guidelines are based on the knowledge acquired from peer-reviewed and published data, as well as observations of the authors in their practice. However, these guidelines can only provide a snapshot of current knowledge at the time of manuscript submission and readers are advised to keep up with the literature.Copyright © 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

Published
2016

20. EMQN best practice guidelines for the molecular genetic testing and reporting of chromosome 11p15 imprinting disorders: Silver-Russell and Beckwith-Wiedemann syndrome

Author

Eggermann, K, Bliek, J, Brioude, F, Algar, E, Buiting, K, Russo, S, Tumer, Z, Monk, D, Moore, G, Antoniadi, T, Macdonald, F, Netchine, I, Lombardi, P, Soellner, L, Begemann, M, Prawitt, D, Maher, ER, Mannens, M, Riccio, A, Weksberg, R, Lapunzina, P, Gronskov, K, Mackay, DJG, Eggermann, T, Eggermann, K, Bliek, J, Brioude, F, Algar, E, Buiting, K, Russo, S, Tumer, Z, Monk, D, Moore, G, Antoniadi, T, Macdonald, F, Netchine, I, Lombardi, P, Soellner, L, Begemann, M, Prawitt, D, Maher, ER, Mannens, M, Riccio, A, Weksberg, R, Lapunzina, P, Gronskov, K, Mackay, DJG, and Eggermann, T

Abstract

Molecular genetic testing for the 11p15-associated imprinting disorders Silver-Russell and Beckwith-Wiedemann syndrome (SRS, BWS) is challenging because of the molecular heterogeneity and complexity of the affected imprinted regions. With the growing knowledge on the molecular basis of these disorders and the demand for molecular testing, it turned out that there is an urgent need for a standardized molecular diagnostic testing and reporting strategy. Based on the results from the first external pilot quality assessment schemes organized by the European Molecular Quality Network (EMQN) in 2014 and in context with activities of the European Network of Imprinting Disorders (EUCID.net) towards a consensus in diagnostics and management of SRS and BWS, best practice guidelines have now been developed. Members of institutions working in the field of SRS and BWS diagnostics were invited to comment, and in the light of their feedback amendments were made. The final document was ratified in the course of an EMQN best practice guideline meeting and is in accordance with the general SRS and BWS consensus guidelines, which are in preparation. These guidelines are based on the knowledge acquired from peer-reviewed and published data, as well as observations of the authors in their practice. However, these guidelines can only provide a snapshot of current knowledge at the time of manuscript submission and readers are advised to keep up with the literature.

Published
2016

22. Paternal uniparental disomy 11p15, hemihyperplasia and hepatoblastoma

Author

Celle, L., Russell, K.L., Zand, D.J., Meadows, A.T., Pressey, J., von Allmen, D., Weksberg, R., and Zackai, E.H.

Subjects
Human genetics -- Research, Genetic disorders -- Research, Beckwith-Wiedemann syndrome -- Genetic aspects, Nephroblastoma -- Genetic aspects, Biological sciences
Published
2001

23. Further delineation of cardiac abnormalities in Costello syndrome

Author

Lin, A., Grossfeld, P., Hamilton, R., Smoot, L., Gripp, K., Proud, V., Weksberg, R., Wheeler, P., Picker, J., Irons, M., Zackai, E., Scott, C. Jr., and Nicholson, L.

Subjects
Genetic disorders -- Research, Heart -- Abnormalities, Heart enlargement -- Genetic aspects, Arrhythmia -- Genetic aspects, Biological sciences
Published
2001

31. Phenotypic spectrum associated with PTCHD1 deletions and truncating mutations includes intellectual disability and autism spectrum disorder

Author

Chaudhry, A., Noor, A., Degagne, B., Baker, K., Bok, L. A., Brady, A. F., Chitayat, D., Chung, B. H., Cytrynbaum, C., Dyment, D., Filges, I., Helm, B., Hutchison, H. T., Jeng, L. J. B., Laumonnier, F., Marshall, C. R., Menzel, M., Parkash, S., Parker, M. J., Raymond, L. F., Rideout, A. L., Roberts, W., Rupps, R., Schanze, I., Schrander-Stumpel, C. T. R. M., Speevak, M. D., Stavropoulos, D. J., Stevens, S. J. C., Thomas, E. R. A., Toutain, A., Vergano, S., Weksberg, R., Scherer, S. W., Vincent, J. B., Carter, M. T., RS: GROW - Developmental Biology, RS: GROW - R4 - Reproductive and Perinatal Medicine, Afdeling Onderwijs FHML, and MUMC+: DA Pat Cytologie (9)

Subjects
X-linked, Adult, Male, Adolescent, Autism Spectrum Disorder, PTCHD1, Facies, Infant, Membrane Proteins, Exons, Young Adult, Phenotype, Child, Preschool, Intellectual Disability, Mutation, Humans, Female, Child, Sequence Deletion
Abstract

Studies of genomic copy number variants (CNVs) have identified genes associated with autism spectrum disorder (ASD) and intellectual disability (ID) such as NRXN1, SHANK2, SHANK3 and PTCHD1. Deletions have been reported in PTCHD1 however there has been little information available regarding the clinical presentation of these individuals. Herein we present 23 individuals with PTCHD1 deletions or truncating mutations with detailed phenotypic descriptions. The results suggest that individuals with disruption of the PTCHD1 coding region may have subtle dysmorphic features including a long face, prominent forehead, puffy eyelids and a thin upper lip. They do not have a consistent pattern of associated congenital anomalies or growth abnormalities. They have mild to moderate global developmental delay, variable degrees of ID, and many have prominent behavioral issues. Over 40% of subjects have ASD or ASD-like behaviors. The only consistent neurological findings in our cohort are orofacial hypotonia and mild motor incoordination. Our findings suggest that hemizygous PTCHD1 loss of function causes an X-linked neurodevelopmental disorder with a strong propensity to autistic behaviors. Detailed neuropsychological studies are required to better define the cognitive and behavioral phenotype.

Published
2014

32. NSD1 mutations generate a genome-wide DNA methylation signature

Author

Choufani, S., primary, Cytrynbaum, C., additional, Chung, B. H. Y., additional, Turinsky, A. L., additional, Grafodatskaya, D., additional, Chen, Y. A., additional, Cohen, A. S. A., additional, Dupuis, L., additional, Butcher, D. T., additional, Siu, M. T., additional, Luk, H. M., additional, Lo, I. F. M., additional, Lam, S. T. S., additional, Caluseriu, O., additional, Stavropoulos, D. J., additional, Reardon, W., additional, Mendoza-Londono, R., additional, Brudno, M., additional, Gibson, W. T., additional, Chitayat, D., additional, and Weksberg, R., additional

Published
2015
Full Text
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33. Functional impact of global rare copy number variation in autism spectrum disorders

Author

Pinto, D. Pagnamenta, A.T. Klei, L. Anney, R. Merico, D. Regan, R. Conroy, J. Magalhaes, T.R. Correia, C. Abrahams, B.S. Almeida, J. Bacchelli, E. Bader, G.D. Bailey, A.J. Baird, G. Battaglia, A. Berney, T. Bolshakova, N. Bölte, S. Bolton, P.F. Bourgeron, T. Brennan, S. Brian, J. Bryson, S.E. Carson, A.R. Casallo, G. Casey, J. Chung, B.H.Y. Cochrane, L. Corsello, C. Crawford, E.L. Crossett, A. Cytrynbaum, C. Dawson, G. De Jonge, M. Delorme, R. Drmic, I. Duketis, E. Duque, F. Estes, A. Farrar, P. Fernandez, B.A. Folstein, S.E. Fombonne, E. Freitag, C.M. Gilbert, J. Gillberg, C. Glessner, J.T. Goldberg, J. Green, A. Green, J. Guter, S.J. Hakonarson, H. Heron, E.A. Hill, M. Holt, R. Howe, J.L. Hughes, G. Hus, V. Igliozzi, R. Kim, C. Klauck, S.M. Kolevzon, A. Korvatska, O. Kustanovich, V. Lajonchere, C.M. Lamb, J.A. Laskawiec, M. Leboyer, M. Le Couteur, A. Leventhal, B.L. Lionel, A.C. Liu, X.-Q. Lord, C. Lotspeich, L. Lund, S.C. Maestrini, E. Mahoney, W. Mantoulan, C. Marshall, C.R. McConachie, H. McDougle, C.J. McGrath, J. McMahon, W.M. Merikangas, A. Migita, O. Minshew, N.J. Mirza, G.K. Munson, J. Nelson, S.F. Noakes, C. Noor, A. Nygren, G. Oliveira, G. Papanikolaou, K. Parr, J.R. Parrini, B. Paton, T. Pickles, A. Pilorge, M. Piven, J. Ponting, C.P. Posey, D.J. Poustka, A. Poustka, F. Prasad, A. Ragoussis, J. Renshaw, K. Rickaby, J. Roberts, W. Roeder, K. Roge, B. Rutter, M.L. Bierut, L.J. Rice, J.P. Salt, J. Sansom, K. Sato, D. Segurado, R. Sequeira, A.F. Senman, L. Shah, N. Sheffield, V.C. Soorya, L. Sousa, I. Stein, O. Sykes, N. Stoppioni, V. Strawbridge, C. Tancredi, R. Tansey, K. Thiruvahindrapduram, B. Thompson, A.P. Thomson, S. Tryfon, A. Tsiantis, J. Van Engeland, H. Vincent, J.B. Volkmar, F. Wallace, S. Wang, K. Wang, Z. Wassink, T.H. Webber, C. Weksberg, R. Wing, K. Wittemeyer, K. Wood, S. Wu, J. Yaspan, B.L. Zurawiecki, D. Zwaigenbaum, L. Buxbaum, J.D. Cantor, R.M. Cook, E.H. Coon, H. Cuccaro, M.L. Devlin, B. Ennis, S. Gallagher, L. Geschwind, D.H. Gill, M. Haines, J.L. Hallmayer, J. Miller, J. Monaco, A.P. Nurnberger Jr, J.I. Paterson, A.D. Pericak-Vance, M.A. Schellenberg, G.D. Szatmari, P. Vicente, A.M. Vieland, V.J. Wijsman, E.M. Scherer, S.W. Sutcliffe, J.S. Betancur, C.

Subjects
mental disorders
Abstract

The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours 1. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability2. Although ASDs are known to be highly heritable ( ∼90%)3, the underlying genetic determinants are still largely unknown.Hereweanalysed the genome-wide characteristics of rare (

Published
2010

34. Clinical utility gene card for: Beckwith-Wiedemann Syndrome.

Author

Prawitt D., Netchine I., Riccio A., Weksberg R., Temple I.K., Eggermann T., Algar E., Lapunzina P., MacKay D., Maher E.R., Mannens M., Prawitt D., Netchine I., Riccio A., Weksberg R., Temple I.K., Eggermann T., Algar E., Lapunzina P., MacKay D., Maher E.R., and Mannens M.

Published
2014

35. Postmaturity in a genetic subtype of schizophrenia

Author

Chow, E. W. C., Husted, J., Weksberg, R., and Bassett, A. S.

Subjects
Adult, Male, Brain Diseases, Chromosomes, Human, Pair 22, Infant, Newborn, Article, Infant, Postmature, Risk Factors, Case-Control Studies, Schizophrenia, Birth Weight, Humans, Female, Chromosome Deletion
Abstract

To determine whether postmaturity (gestation41 weeks), small for gestational age (SGA), and other pregnancy and birth complications that may elevate risk for neurodevelopmental disorders, are associated with elevated risk for schizophrenia in 22q11 Deletion Syndrome (22qDS), a genetic subtype of schizophrenia.Antepartum and intrapartum features were examined in 20 adults with 22qDS-schizophrenia and three comparison groups: newborn encephalopathy (n = 164) and healthy newborn controls (n = 400) from Badawi et al.'s (Br Med J 1998, 317: 1549) study, and 16 non-psychotic 22qDS adults (22qDS-NP).Postmaturity (OR 13.0, 95% CI 3.95, 42.77; P0.001) and SGA (OR 3.59, 95% CI 1.23, 10.5; P = 0.03) were more prevalent in 22qDS-SZ than controls. Postmaturity was non-significantly more prevalent in 22qDS-SZ than in newborn encephalopathy (P = 0.06) or 22qDS-NP (P = 0.2). SGA showed similar rates in the two 22qDS groups and newborn encephalopathy, but was more prevalent in 22qDS-NP than controls (P = 0.05).The results suggest that postmaturity may be associated with expression of schizophrenia in a 22qDS subtype of schizophrenia. SGA may be a non-specific marker of neurodevelopmental disturbance.

Published
2003

36. Diversity parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome

Author

Zampino, Giuseppe, Pantaleoni, F., Carta, C., Cobellis, G., Vasta, Isabella, Neri, C., Pogna, E. A., De Feo, Emma, Delogu, Angelica Bibiana, Sarkozy, A., Atzeri, F., Selicorni, Angelo, Rauen, K. A., Cytrynbaum, C. S., Weksberg, R., Dallapiccola, Bruno, Ballabio, A., Gelb, B. D., Neri, Giovanni, Tartaglia, Marco, Zampino, Giuseppe (ORCID:0000-0003-3865-3253), Delogu, Angelica Bibiana (ORCID:0000-0002-2283-3180), Zampino, Giuseppe, Pantaleoni, F., Carta, C., Cobellis, G., Vasta, Isabella, Neri, C., Pogna, E. A., De Feo, Emma, Delogu, Angelica Bibiana, Sarkozy, A., Atzeri, F., Selicorni, Angelo, Rauen, K. A., Cytrynbaum, C. S., Weksberg, R., Dallapiccola, Bruno, Ballabio, A., Gelb, B. D., Neri, Giovanni, Tartaglia, Marco, Zampino, Giuseppe (ORCID:0000-0003-3865-3253), and Delogu, Angelica Bibiana (ORCID:0000-0002-2283-3180)

Published
2007

37. BIOLOGY

Author

Kim, J. H., primary, Song, H. B., additional, Kim, D. H., additional, Park, K. D., additional, Kim, J. H., additional, Lee, B. J., additional, Khatua, S., additional, Kalkan, E., additional, Brown, R., additional, Pearlman, M., additional, Vats, T., additional, Abela, L., additional, Fiaschetti, G., additional, Shalaby, T., additional, Grunder, E., additional, Ma, M., additional, Grahlert, J., additional, Baumgartner, M., additional, Siler, U., additional, Nonoguchi, N., additional, Ohgaki, H., additional, Grotzer, M., additional, Adachi, J.-i., additional, Suzuki, T., additional, Fukuoka, K., additional, Yanagisawa, T., additional, Mishima, K., additional, Koga, T., additional, Matsutani, M., additional, Nishikawa, R., additional, Sardi, I., additional, Giunti, L., additional, Bresci, C., additional, Cardellicchio, S., additional, Da Ros, M., additional, Buccoliero, A. M., additional, Farina, S., additional, Arico, M., additional, Genitori, L., additional, Massimino, M., additional, Filippi, L., additional, Erdreich-Epstein, A., additional, Zhou, H., additional, Ren, X., additional, Schur, M., additional, Davidson, T. B., additional, Ji, L., additional, Sposto, R., additional, Asgharzadeh, S., additional, Tong, Y., additional, White, E., additional, Murugesan, M., additional, Nimmervoll, B., additional, Wang, M., additional, Marino, D., additional, Ellison, D., additional, Finkelstein, D., additional, Pounds, S., additional, Malkin, D., additional, Gilbertson, R., additional, Eden, C., additional, Ju, B., additional, Phoenix, T., additional, Poppleton, H., additional, Lessman, C., additional, Taylor, M., additional, la Marca, G., additional, Malvagia, S., additional, Fratoni, V., additional, Giovannini, M. G., additional, Giangaspero, F., additional, Badiali, M., additional, Gleize, V., additional, Paris, S., additional, Moi, L., additional, Elhouadani, S., additional, Arcella, A., additional, Morace, R., additional, Antonelli, M., additional, Buttarelli, F., additional, Mokhtari, K., additional, Sanson, M., additional, Smith, S., additional, Ward, J., additional, Wilson, M., additional, Rahman, C., additional, Rose, F., additional, Peet, A., additional, Macarthur, D., additional, Grundy, R., additional, Rahman, R., additional, Venkatraman, S., additional, Birks, D., additional, Balakrishnan, I., additional, Alimova, I., additional, Harris, P., additional, Patel, P., additional, Foreman, N., additional, Vibhakar, R., additional, Wu, H., additional, Zhou, Q., additional, Wang, D., additional, Wang, G., additional, Dang, D., additional, Pencreach, E., additional, Nguyen, A., additional, Guerin, E., additional, Lasthaus, C., additional, Guenot, D., additional, Entz-Werle, N., additional, Unland, R., additional, Schlosser, S., additional, Farwick, N., additional, Plagemann, T., additional, Richter, G., additional, Juergens, H., additional, Fruehwald, M., additional, Chien, C.-L., additional, Lee, Y.-H., additional, Lin, C.-I., additional, Hsieh, J.-Y., additional, Lin, S.-C., additional, Wong, T.-T., additional, Ho, D. M.-T., additional, Wang, H.-W., additional, Lagah, S., additional, Tan, I.-L., additional, Malcolm, S., additional, Majani, Y., additional, van Vuurden, D. G., additional, Aronica, E., additional, Wedekind, L. E., additional, Hulleman, E., additional, Biesmans, D., additional, Bugiani, M., additional, Vandertop, W. P., additional, Kaspers, G. J. L., additional, Wurdinger, T., additional, Noske, D. P., additional, Van der Stoop, P. M., additional, Shukla, S., additional, Kuipers, G. K., additional, Slotman, B. J., additional, Cloos, J., additional, Sun, T., additional, Warrington, N., additional, Luo, J., additional, Ganzhorn, S., additional, Tabori, U., additional, Druley, T., additional, Gutmann, D., additional, Rubin, J., additional, Castelo-Branco, P., additional, Choufani, S., additional, Mack, S., additional, Galagher, D., additional, Zhang, C., additional, Lipman, T., additional, Zhukova, N., additional, Martin, D., additional, Merino, D., additional, Wasserman, J., additional, Samuel, C., additional, Alon, N., additional, Hitzler, J., additional, Wang, J. C. Y., additional, Keller, G., additional, Dirks, P. B., additional, Pfister, S., additional, Taylor, M. D., additional, Weksberg, R., additional, Leblond, P., additional, Meignan, S., additional, Dewitte, A., additional, Le Tinier, F., additional, Wattez, N., additional, Lartigau, E., additional, Lansiaux, A., additional, Hanson, R., additional, Gordon, I., additional, Zhao, S., additional, Camphausen, K., additional, Warren, K., additional, Warrington, N. M., additional, Gutmann, D. H., additional, Rubin, J. B., additional, Jaillet, M., additional, Kovacs, Z., additional, Martin-Fiori, E., additional, Bernasconi, M., additional, Werner, B., additional, Dyberg, C., additional, Baryawno, N., additional, Milosevic, J., additional, Wickstrom, M., additional, Northcott, P. A., additional, Kool, M., additional, Kogner, P., additional, Johnsen, J. I., additional, Reynolds, G., additional, Davies, N., additional, Arvanitis, T., additional, Zoghbi, A., additional, Meisterernst, M., additional, Fruehwald, M. C., additional, Kerl, K., additional, Orr, B., additional, Haffner, M., additional, Nelson, W., additional, Yegnasubramanian, S., additional, Eberhart, C., additional, Fotovati, A., additional, Abu-Ali, S., additional, Wang, P.-S., additional, Deleyrolle, L., additional, Lee, C., additional, Triscott, J., additional, Chen, J., additional, Franciosi, S., additional, Nakamura, Y., additional, Sugita, Y., additional, Uchiumi, T., additional, Kuwano, M., additional, Leavitt, B., additional, Singh, S., additional, Jury, A., additional, Jones, C., additional, Wakimoto, H., additional, Reynolds, B., additional, Pallen, C., additional, Dunn, S., additional, Fletcher, S., additional, Levine, J., additional, Li, M., additional, Kagawa, N., additional, Hirayama, R., additional, Chiba, Y., additional, Kijima, N., additional, Arita, H., additional, Kinoshita, M., additional, Hashimoto, N., additional, Izumoto, S., additional, Maruno, M., additional, and Yoshimine, T., additional

Published
2012
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38. Hemizygous deletions on chromosome 1p21.3 involving the DPYD gene in individuals with autism spectrum disorder

Author

Carter, MT, primary, Nikkel, SM, additional, Fernandez, BA, additional, Marshall, CR, additional, Noor, A, additional, Lionel, AC, additional, Prasad, A, additional, Pinto, D, additional, Joseph-George, AM, additional, Noakes, C, additional, Fairbrother-Davies, C, additional, Roberts, W, additional, Vincent, J, additional, Weksberg, R, additional, and Scherer, SW, additional

Published
2010
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40. Phenotypic spectrum associated with de novo and inherited deletions and duplications at 16p11.2 in individuals ascertained for diagnosis of autism spectrum disorder

Author

Fernandez, B. A., primary, Roberts, W., additional, Chung, B., additional, Weksberg, R., additional, Meyn, S., additional, Szatmari, P., additional, Joseph-George, A. M., additional, MacKay, S., additional, Whitten, K., additional, Noble, B., additional, Vardy, C., additional, Crosbie, V., additional, Luscombe, S., additional, Tucker, E., additional, Turner, L., additional, Marshall, C. R., additional, and Scherer, S. W., additional

Published
2009
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44. A mutation in the pro alpha 2(I) gene (COL1A2) for type I procollagen in Ehlers-Danlos syndrome type VII: evidence suggesting that skipping of exon 6 in RNA splicing may be a common cause of the phenotype

Author

Vasan, N S, Kuivaniemi, H, Vogel, B E, Minor, R R, Wootton, J A, Tromp, G, Weksberg, R, and Prockop, D J

Subjects
Electrophoresis, Base Sequence, RNA Splicing, Molecular Sequence Data, DNA, Exons, Polymerase Chain Reaction, Introns, Mutation, Humans, Ehlers-Danlos Syndrome, Female, RNA, Messenger, Child, Alleles, Procollagen, Research Article
Abstract

Fibroblasts from a proband with Ehlers-Danlos syndrome type VII synthesized approximately equal amounts of normal and shortened pro alpha 2(I) chains of type I procollagen. Nuclease S1 probe protection experiments with mRNA demonstrated that the pro alpha 2(I) chains were shortened because of a deletion of most or all of the 54 nucleotides in exon 6, the exon that contains codons for the cleavage site for procollagen N-proteinase. Sequencing of genomic clones revealed a single-base mutation that converted the first nucleotide of intron 6 from G to A. Therefore, the mutation was a change, in the -GT-consensus splice site, that produced efficient exon skipping. Allele-specific oligonucleotide hybridizations demonstrated that the proband's mother, father, and brother did not have the mutation. Therefore, the mutation was a sporadic one. Analysis of potential 5' splice sites in the 5' end of intron 6 indicated that none had favorable values by the two commonly employed techniques for evaluating such sites. The proband is the fourth reported proband with Ehlers-Danlos syndrome VII with a single-base mutation that causes skipping of exon 6 in the splicing of RNA from either the COL1A1 gene or COL1A2 gene. No other mutations in the two type I procollagen genes have been found in the syndrome. Therefore, such mutations may be a common cause of the phenotype. The primers developed should be useful in screening for the same or similar mutations causing the disease.

Published
1991

46. Parental Imprinting of Human Chromosome Region 11p15.3-pter Involved in the Beckwith-Wiedemann Syndrome and Various Human Neoplasia

Author

Mannens, M., primary, Hoovers, J.M.N., additional, Redeker, E., additional, Verjaal, M., additional, Feinberg, A.P., additional, Little, P., additional, Boavida, M., additional, Coad, N., additional, Steenman, M., additional, Bliek, J., additional, Niikawa, N., additional, Tonoki, H., additional, Nakamura, Y., additional, de Boer, E.G., additional, Slater, R.M., additional, John, R., additional, Cowell, J.K., additional, Junien, C., additional, Henry, I., additional, Tommerup, N., additional, Weksberg, R,, additional, Pueschel, S.M., additional, Leschot, N.J., additional, and Westerveld, A., additional

Published
1994
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49. Bridging markers defining the map position of X linked hypophosphataemic rickets.

Author

Thakker, R V, Read, A P, Davies, K E, Whyte, M P, Weksberg, R, Glorieux, F, Davies, M, Mountford, R C, Harris, R, and King, A

Abstract

Hypophosphataemic rickets is commonly an X linked dominant hereditary disorder associated with a renal tubular defect in phosphate transport and bone deformities. The gene causing this disorder has been mapped to Xp22.31----p21.3 by using cloned human X chromosome sequences identifying restriction fragment length polymorphisms (RFLPs) in linkage studies of affected families. The hypophosphataemic rickets gene locus (HPDR) was previously mapped distal to the X linked polymorphic locus DXS41 (99.6) but its position in relation to the distal loci DXS43 (D2) and DXS85 (782) was not established. In order to obtain a precise mapping of the disease locus in relation to these genetic loci, additional affected families informative for these X linked markers have been investigated. The combined results from the two studies have established linkage with the loci DXS41 (99.6) and DXS43 (D2); peak lod score for DXS41 (99.6) = 7.35, theta = 0.09, and peak lod score for DXS43 (D2) = 4.77, theta = 0.16. Multilocus linkage analysis mapped the hypophosphataemic rickets gene distal to the DXS41 (99.6) locus and proximal to the DXS43 (D2) locus, thereby revealing two bridging genetic markers for the disease. [ABSTRACT FROM PUBLISHER]

Published
1987
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50. Gastrointestinal cancers and neurofibromatosis type 1 features in children with a germline homozygous MLH1 mutation

Author

Gallinger, S., Aronson, M., Shayan, K., Ratcliffe, E.M., Gerstle, J.T., Parkin, P.C., Rothenmund, H., Croitoru, M., Baumann, E., Durie, P.R., Weksberg, R., Pollett, A., Riddell, R.H., Ngan, B.Y., Cutz, E., Lagarde, A.E., and Chan, H.S.L.

Abstract

Heterozygous germline DNA mismatch repair gene mutations are typically associated with hereditary nonpolyposis colorectal cancer. The molecular hallmark of this syndrome is high-frequency microsatellite instability in the tumors. Rare childhood cases with homozygous or compound heterozygous DNA mismatch repair gene mutations have a described predisposition to leukemia, lymphoma, and brain tumors but not to gastrointestinal cancer. We have now characterized a family in which 2 children with a homozygous germline DNA mismatch repair gene mutation developed early-onset gastrointestinal cancers. The 11-year-old proband had cafe-au-lait macules and developed metastatic duodenal adenocarcinoma that arose in a tubulovillous adenoma. His 9-year-old sister with cafe-au-lait macules and axillary freckling presented with malignant colon polyps. A 6-year-old sister with cafe-au-lait macules, hairy nevi, and a plexiform neurofibroma of the tongue has no malignancies to date. The family history did not fulfill the Amsterdam criteria for hereditary nonpolyposis colorectal cancer, but 2 relatives in their 60s had gastric cancer and colorectal cancer, whereas the parents, who are first cousins, remain cancer free. The proband's metastatic duodenal cancer and his sister's malignant colon polyps had high-frequency microsatellite instability but had detectable MLH1, MSH2, and MSH6 proteins by immunohistochemistry. Because some germline DNA mismatch repair gene deficiencies are associated with apparently intact immunohistochemical DNA mismatch repair gene expression in tumors, we proceeded to DNA sequencing, which showed that all 3 children had a germline homozygous MLH1 missense mutation (exon 18, codon 687, CGG->TGG), whereas both parents were heterozygous for this mutation.

Published
2004
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