Author: "Baralle D" - Searchworks@Jio Institute Digital Library Search Results

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1. Classification of variants of reduced penetrance in high-penetrance cancer susceptibility genes: Framework for genetics clinicians and clinical scientists by CanVIG-UK (Cancer Variant Interpretation Group-UK)

Author: Turnbull, C., Garrett, A., Loong, L., Choi, S., Torr, B., Allen, S., Durkie, M., Callaway, A., Drummond, J., Burghel, G.J., Robinson, R., Berry, I.R., Wallace, A.J., Eccles, D.M., Tischkowitz, M., Ellard, S., Hanson, H., Baple, E., Evans, D.G., Woodward, E., Lalloo, F., Samant, S., Lucassen, A., Znaczko, A., Shaw, A., Ansari, A., Kumar, A., Donaldson, A., Murray, A., Ross, A., Taylor-Beadling, A., Taylor, A., Innes, A., Brady, A., Kulkarni, A., Hogg, A.C., Bowden, A. Ramsay, Hadonou, A., Coad, B., McIldowie, B., Speight, B., DeSouza, B., Mullaney, B., McKenna, C., Brewer, C., Olimpio, C., Clabby, C., Crosby, C., Jenkins, C., Armstrong, C., Bowles, C., Brooks, C., Byrne, C., Maurer, C., Baralle, D., Chubb, D., Stobo, D., Moore, D., O'Sullivan, D., Donnelly, D., Randhawa, D., Halliday, D., Atkinson, E., Rauter, E., Johnston, E., Maher, E., Sofianopoulou, E., Petrides, E., McRonald, F., Pelz, F., Frayling, I., Corbett, G., Rea, G., Clouston, H., Powell, H., Williamson, H., Carley, H., Thomas, H.J.W., Tomlinson, I., Cook, J., Hoyle, J., Tellez, J., Whitworth, J., Williams, J., Murray, J., Campbell, J., Tolmie, J., Field, J., Mason, J., Burn, J., Bruty, J., Callaway, J., Grant, J., Del Rey Jimenez, J., Pagan, J., VanCampen, J., Barwell, J., Monahan, K., Tatton-Brown, K., Ong, K.R., Murphy, K., Andrews, K., Mokretar, K., Cadoo, K., Smith, K., Baker, K., Brown, K., Reay, K., McKay Bounford, K., Bradshaw, K., Russell, K., Stone, K., Snape, K., Crookes, L., Reed, L., Taggart, L., Yarram, L., Cobbold, L., Walker, L., Hawkes, L., Busby, L., Izatt, L., Kiely, L., Hughes, L., Side, L., Sarkies, L., Greenhalgh, K.-L., Shanmugasundaram, M., Duff, M., Bartlett, M., Watson, M., Owens, M., Bradford, M., Huxley, M., Slean, M., Ryten, M., Smith, M., Ahmed, M., Roberts, N., O'Brien, C., Middleton, O., Tarpey, P., Logan, P., Dean, P., May, P., Brace, P., Tredwell, R., Harrison, R., Hart, R., Kirk, R., Martin, R., Nyanhete, R., Wright, R., Davidson, R., Cleaver, R., Talukdar, S., Butler, S., Sampson, J., Ribeiro, S., Dell, S., Mackenzie, S., Hegarty, S., Albaba, S., McKee, S., Palmer-Smith, S., Heggarty, S., MacParland, S., Greville-Heygate, S., Daniels, S., Prapa, S., Abbs, S., Tennant, S., Hardy, S., MacMahon, S., McVeigh, T., Foo, T., Bedenham, T., Cranston, T., McDevitt, T., Clowes, V., Tripathi, V., McConnell, V., Woodwaer, N., Wallis, Y., Kemp, Z., Mullan, G., Pierson, L., Rainey, L., Joyce, C., Timbs, A., Reuther, A.-M., Frugtniet, B., Husher, C., Lawn, C., Corbett, C., Nocera-Jijon, D., Reay, D., Cross, E., Ryan, F., Lindsay, H., Oliver, J., Dring, J., Spiers, J., Harper, J., Ciucias, K., Connolly, L., Tsang, M., Brown, R., Shepherd, S., Begum, S., Tadiso, T., Linton-Willoughby, T., Heppell, H., Sahan, K., Worrillow, L., Allen, Z., Watt, C., Hegarty, M., Mitchell, R., Coles, R., Nickless, G., Cojocaru, E., Doal, I., Sava, F., McCarthy, C., Jeeneea, R., Goudie, D., McConachie, M., Botosneanu, S., Kavanaugh, G., Sherlaw, C., Tsoulaki, O., Forde, C., Petley, E., Jones, A.-B., Oprych, K., Pryde, S., Hyder, Z., Elkhateeb, N., Braham, R., Hanington, L., Huntley, C., Irving, R., Sadan, A., Ramos, M., Elliot, C., Wren, D., Lobo, D., McLean, J., May, D., Kearney, L., Campbell, T., Asakura, K., Alwadi, L., O’Shea, R., Gabriel, J., Chiecchio, L., Bowman, P., Sutton, L.A., Walsh, C., Cloke, V., Ucanok, D., Davies, J., Pleasance, B., Maguire, E., Whaite, A., Best, S., Westbury, S., Logan, A., Navarajasegaran, D., Bench, A., Wightman, P., Cartwright, A., Higgs, E., J.Bott, Whitehouse, H., Stevens, J., Martin, D., Dunlop, J., Thomas, S., Sau, C., Farndon, S., Coleman, N., Angelini, P., Massey, H., Rowlands, C., Garcia-Petit, C., Gillespie, K., Alder, A., Middleton, E., Cassidy, C., Orfali, N., Webb, A., Luharia, A., Walker, N., Charlton, J., Andreou, A., Peddie, J., Khan, M., Wilkinson, L., Bezuidenhout, H., Edis, M., Callard, A., Ostrowski, P., Moverley, P., Bean, K., Dunne, A., Moleirinho, A., Waller, S., Cox, K., Greensmith, L., Brittle, A., Gossan, N., Freestone, L., Shak, C., Langford, T., Clinch, Y., Livesey, H., Borland, S., Joshi, A., Wall, K., Whitworth, A., Wilsdon, A., Edgerley, K., Pugh, S., Chrysochoidi, N., Mutch, S., McMullan, C., Johnston, Y., Muraru, M., May, A., Begum, R., Smith, C., Patel, R., Bhatnagar, I., Brown, D., Willan, J., Taylor, S., Jones, K., Ramsden, C., Taiwo, O., Jaudzemaite, J., Sharmin, R., Young, L., C.O’Dubhshlaine, McSorley, L., Rodriguez, I. Abreu, Lillis, S., Alexopoulos, P., Mortensson, E., Kingham, L., Moore, R., Kosicka-Slawinska, M., Aslam, S., Wells, R., Carter, A., Warren, H., Rolf, E., Reed, H., Pearce, L., Lock, D., Ali, F., Kolozi, A., White, N., Wood, D., Hayden, C., Garrett, Alice, Allen, Sophie, Durkie, Miranda, Burghel, George J., Robinson, Rachel, Callaway, Alison, Field, Joanne, Frugtniet, Bethan, Palmer-Smith, Sheila, Grant, Jonathan, Pagan, Judith, McDevitt, Trudi, Rowlands, Charlie F., McVeigh, Terri, Hanson, Helen, and Turnbull, Clare
Published: 2024
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2. Clinical, splicing and functional analysis to classify BRCA2 exon 3 variants

Author: Thomassen, M., Mesman, R.L.S., Hansen, T.V.O., Menendez, M., Rossing, M., Esteban-Sanchez, A., Tudini, E., Torngren, T., Parsons, M.T., Pedersen, I.S., Teo, S.H., Kruse, T.A., Moller, P., Borg, A., Jensen, U.B., Christensen, L.L., Singer, C.F., Muhr, D., Santamarina, M., Brandao, R., Andresen, B.S., Feng, B.J., Canson, D., Richardson, M.E., Karam, R., Pesaran, T., LaDuca, H., Conner, B.R., Abualkheir, N., Hoang, L., Calleja, F.M.G.R., Andrews, L., James, P.A., Bunyan, D., Hamblett, A., Radice, P., Goldgar, D.E., Walker, L.C., Engel, C., Claes, K.B.M., Machackova, E., Baralle, D., Viel, A., Wappenschmidt, B., Lazaro, C., Vega, A., Vreeswijk, M.P.G., Hoya, M. de la, Spurdle, A.B., ENIGMA Consortium, RS: GROW - R4 - Reproductive and Perinatal Medicine, and Klinische Genetica
Subjects: splicing, AMP classification, quantitation, ACMG/AMP classification, dPCR, ACMG, Medicine and Health Sciences, Genetics, Biology and Life Sciences, BRCA2, Genetics (clinical), functional analysis
Abstract: Skipping of BRCA2 exon 3 (∆E3) is a naturally occurring splice event, complicating clinical classification of variants that may alter ∆E3 expression. This study used multiple evidence types to assess pathogenicity of 85 variants in/near BRCA2 exon 3. Bioinformatically predicted spliceogenic variants underwent mRNA splicing analysis using minigenes and/or patient samples. ∆E3 was measured using quantitative analysis. A mouse embryonic stem cell (mESC) based assay was used to determine the impact of 18 variants on mRNA splicing and protein function. For each variant, population frequency, bioinformatic predictions, clinical data and existing mRNA splicing and functional results were collated. Variant class was assigned using a gene-specific adaptation of ACMG/AMP guidelines, following a recently proposed points-based system. mRNA and mESC analysis combined identified six variants with transcript and/or functional profiles interpreted as loss of function. Cryptic splice site use for acceptor site variants generated a transcript encoding a shorter protein that retains activity. Overall, 69/85 (81%) variants were classified using the point-based approach. Our analysis shows the value of applying gene-specific ACMG/AMP guidelines using a points-based approach and highlights the consideration of cryptic splice site usage to appropriately assign PVS1 code strength. This article is protected by copyright. All rights reserved.
Published: 2022
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3. Biallelic PRMT7 pathogenic variants are associated with a recognizable syndromic neurodevelopmental disorder with short stature, obesity, and craniofacial and digital abnormalities.

Author: Cali, E., Suri, M., Scala, M., Ferla, M.P., Alavi, S., Faqeih, E.A., Bijlsma, E.K., Wigby, K.M., Baralle, D., Mehrjardi, M.Y.V., Schwab, J., Platzer, K., Steindl, K., Hashem, M., Jones, M., Niyazov, Dmitriy, Jacober, J., Littlejohn, R.O., Weis, D., Zadeh, N., Rodan, L., Goldenberg, A., Lecoquierre, F., Dutra-Clarke, M., Horvath, G., Young, D., Orenstein, N., Bawazeer, S., Vulto-van Silfhout, A.T., Herenger, Y., Dehghani, M., Seyedhassani, S.M., Bahreini, A., Nasab, M.E., Ercan-Sencicek, A.G., Firoozfar, Z., Movahedinia, M., Efthymiou, S., Striano, P., Karimiani, E.G., Salpietro, V., Taylor, J.C., Redman, M., Stegmann, A.P.A., Laner, A., Abdel-Salam, G., Li, M., Bengala, M., Müller, A.J., Digilio, M.C., Rauch, A., Gunel, M., Titheradge, H., Schweitzer, D.N., Kraus, A., Valenzuela, I., McLean, S.D., Phornphutkul, C., Salih, M., Begtrup, A., Schnur, R.E., Torti, E., Haack, T.B., Prada, C.E., Alkuraya, F.S., Houlden, H., Maroofian, R., Cali, E., Suri, M., Scala, M., Ferla, M.P., Alavi, S., Faqeih, E.A., Bijlsma, E.K., Wigby, K.M., Baralle, D., Mehrjardi, M.Y.V., Schwab, J., Platzer, K., Steindl, K., Hashem, M., Jones, M., Niyazov, Dmitriy, Jacober, J., Littlejohn, R.O., Weis, D., Zadeh, N., Rodan, L., Goldenberg, A., Lecoquierre, F., Dutra-Clarke, M., Horvath, G., Young, D., Orenstein, N., Bawazeer, S., Vulto-van Silfhout, A.T., Herenger, Y., Dehghani, M., Seyedhassani, S.M., Bahreini, A., Nasab, M.E., Ercan-Sencicek, A.G., Firoozfar, Z., Movahedinia, M., Efthymiou, S., Striano, P., Karimiani, E.G., Salpietro, V., Taylor, J.C., Redman, M., Stegmann, A.P.A., Laner, A., Abdel-Salam, G., Li, M., Bengala, M., Müller, A.J., Digilio, M.C., Rauch, A., Gunel, M., Titheradge, H., Schweitzer, D.N., Kraus, A., Valenzuela, I., McLean, S.D., Phornphutkul, C., Salih, M., Begtrup, A., Schnur, R.E., Torti, E., Haack, T.B., Prada, C.E., Alkuraya, F.S., Houlden, H., and Maroofian, R.
Abstract: 01 januari 2023, Item does not contain fulltext, PURPOSE: Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyzes the methylation of arginine residues on several protein substrates. Biallelic pathogenic PRMT7 variants have previously been associated with a syndromic neurodevelopmental disorder characterized by short stature, brachydactyly, intellectual developmental disability, and seizures. To our knowledge, no comprehensive study describes the detailed clinical characteristics of this syndrome. Thus, we aim to delineate the phenotypic spectrum of PRMT7-related disorder. METHODS: We assembled a cohort of 51 affected individuals from 39 different families, gathering clinical information from 36 newly described affected individuals and reviewing data of 15 individuals from the literature. RESULTS: The main clinical characteristics of the PRMT7-related syndrome are short stature, mild to severe developmental delay/intellectual disability, hypotonia, brachydactyly, and distinct facial morphology, including bifrontal narrowing, prominent supraorbital ridges, sparse eyebrows, short nose with full/broad nasal tip, thin upper lip, full and everted lower lip, and a prominent or squared-off jaw. Additional variable findings include seizures, obesity, nonspecific magnetic resonance imaging abnormalities, eye abnormalities (i.e., strabismus or nystagmus), and hearing loss. CONCLUSION: This study further delineates and expands the molecular, phenotypic spectrum and natural history of PRMT7-related syndrome characterized by a neurodevelopmental disorder with skeletal, growth, and endocrine abnormalities.
Published: 2023

4. PhenoScore quantifies phenotypic variation for rare genetic diseases by combining facial analysis with other clinical features using a machine-learning framework

Author: Dingemans, A.J.M., Hinne, M., Truijen, K.M.G., Goltstein, C.M.J., Reeuwijk, J. van, Leeuw, N. de, Schuurs-Hoeijmakers, J.H.M., Pfundt, R.P., Diets, I.J., Hoed, J. den, Boer, E. de, Spek, J. van der, Bon, B.W.M. van, Ockeloen, C.W., Vulto-van Silfhout, A.T., Kleefstra, T., Koolen, D.A., Campeau, P.M., Palmer, E.E., Esch, H. van, Lyon, G.J., Alkuraya, F.S., Rauch, A., Marom, R., Baralle, D., Sluijs, P.J. van der, Santen, G.W.E., Kooy, R.F., Gerven, M.A.J. van, Vissers, L.E.L.M., Vries, L.B.A. de, Dingemans, A.J.M., Hinne, M., Truijen, K.M.G., Goltstein, C.M.J., Reeuwijk, J. van, Leeuw, N. de, Schuurs-Hoeijmakers, J.H.M., Pfundt, R.P., Diets, I.J., Hoed, J. den, Boer, E. de, Spek, J. van der, Bon, B.W.M. van, Ockeloen, C.W., Vulto-van Silfhout, A.T., Kleefstra, T., Koolen, D.A., Campeau, P.M., Palmer, E.E., Esch, H. van, Lyon, G.J., Alkuraya, F.S., Rauch, A., Marom, R., Baralle, D., Sluijs, P.J. van der, Santen, G.W.E., Kooy, R.F., Gerven, M.A.J. van, Vissers, L.E.L.M., and Vries, L.B.A. de
Abstract: 07 augustus 2023, Item does not contain fulltext, Several molecular and phenotypic algorithms exist that establish genotype–phenotype correlations, including facial recognition tools. However, no unified framework that investigates both facial data and other phenotypic data directly from individuals exists. We developed PhenoScore: an open-source, artificial intelligence-based phenomics framework, combining facial recognition technology with Human Phenotype Ontology data analysis to quantify phenotypic similarity. Here we show PhenoScore’s ability to recognize distinct phenotypic entities by establishing recognizable phenotypes for 37 of 40 investigated syndromes against clinical features observed in individuals with other neurodevelopmental disorders and show it is an improvement on existing approaches. PhenoScore provides predictions for individuals with variants of unknown significance and enables sophisticated genotype–phenotype studies by testing hypotheses on possible phenotypic (sub)groups. PhenoScore confirmed previously known phenotypic subgroups caused by variants in the same gene for SATB1, SETBP1 and DEAF1 and provides objective clinical evidence for two distinct ADNP-related phenotypes, already established functionally.
Published: 2023

5. Recurrent de novo missense variants across multiple histone H4 genes underlie a neurodevelopmental syndrome

Author: Tessadori, F., Duran, K., Knapp, K., Fellner, M., Smithson, S., Meireles, A. Beleza, Elting, M.W., Waisfisz, Q., O'Donnell-Luria, A., Nowak, C., Douglas, J., Ronan, A., Brunet, T., Kotzaeridou, U., Svihovec, S., Saenz, M.S., Thiffault, I., Viso, F. Del, Devine, P., Rego, S., Tenney, J., Haeringen, A. van, Ruivenkamp, C.A.L., Koene, S., Robertson, S.P., Deshpande, C., Pfundt, R.P., Verbeek, N., Kamp, J.M. van de, Weiss, J., Ruiz, A., Gabau, E., Banne, E., Pepler, A., Bottani, A., Laurent, S., Guipponi, M., Bijlsma, E., Bruel, A.L., Sorlin, A., Willis, M., Powis, Z., Smol, T., Vincent-Delorme, C., Baralle, D., Colin, E., Revencu, N., Calpena, E., Wilkie, A.O.M., Chopra, M., Cormier-Daire, V., Keren, B., Afenjar, A., Niceta, M., Terracciano, A., Specchio, N., Tartaglia, M., Rio, M. del, Barcia, G., Rondeau, S., Colson, C., Bakkers, J., Mace, P.D., Bicknell, L.S., Haaften, G. van, Tessadori, F., Duran, K., Knapp, K., Fellner, M., Smithson, S., Meireles, A. Beleza, Elting, M.W., Waisfisz, Q., O'Donnell-Luria, A., Nowak, C., Douglas, J., Ronan, A., Brunet, T., Kotzaeridou, U., Svihovec, S., Saenz, M.S., Thiffault, I., Viso, F. Del, Devine, P., Rego, S., Tenney, J., Haeringen, A. van, Ruivenkamp, C.A.L., Koene, S., Robertson, S.P., Deshpande, C., Pfundt, R.P., Verbeek, N., Kamp, J.M. van de, Weiss, J., Ruiz, A., Gabau, E., Banne, E., Pepler, A., Bottani, A., Laurent, S., Guipponi, M., Bijlsma, E., Bruel, A.L., Sorlin, A., Willis, M., Powis, Z., Smol, T., Vincent-Delorme, C., Baralle, D., Colin, E., Revencu, N., Calpena, E., Wilkie, A.O.M., Chopra, M., Cormier-Daire, V., Keren, B., Afenjar, A., Niceta, M., Terracciano, A., Specchio, N., Tartaglia, M., Rio, M. del, Barcia, G., Rondeau, S., Colson, C., Bakkers, J., Mace, P.D., Bicknell, L.S., and Haaften, G. van
Abstract: Contains fulltext : 252023.pdf (Publisher’s version ) (Open Access), Chromatin is essentially an array of nucleosomes, each of which consists of the DNA double-stranded fiber wrapped around a histone octamer. This organization supports cellular processes such as DNA replication, DNA transcription, and DNA repair in all eukaryotes. Human histone H4 is encoded by fourteen canonical histone H4 genes, all differing at the nucleotide level but encoding an invariant protein. Here, we present a cohort of 29 subjects with de novo missense variants in six H4 genes (H4C3, H4C4, H4C5, H4C6, H4C9, and H4C11) identified by whole-exome sequencing and matchmaking. All individuals present with neurodevelopmental features of intellectual disability and motor and/or gross developmental delay, while non-neurological features are more variable. Ten amino acids are affected, six recurrently, and are all located within the H4 core or C-terminal tail. These variants cluster to specific regions of the core H4 globular domain, where protein-protein interactions occur with either other histone subunits or histone chaperones. Functional consequences of the identified variants were evaluated in zebrafish embryos, which displayed abnormal general development, defective head organs, and reduced body axis length, providing compelling evidence for the causality of the reported disorder(s). While multiple developmental syndromes have been linked to chromatin-associated factors, missense-bearing histone variants (e.g., H3 oncohistones) are only recently emerging as a major cause of pathogenicity. Our findings establish a broader involvement of H4 variants in developmental syndromes.
Published: 2022

6. Quantifying prediction of pathogenicity for within-codon concordance (PM5) using 7541 functional classifications of BRCA1 and MSH2 missense variants

Author: Loong, Lucy, primary, Cubuk, Cankut, additional, Choi, Subin, additional, Allen, Sophie, additional, Torr, Beth, additional, Garrett, Alice, additional, Loveday, Chey, additional, Durkie, Miranda, additional, Callaway, Alison, additional, Burghel, George J., additional, Drummond, James, additional, Robinson, Rachel, additional, Berry, Ian R., additional, Wallace, Andrew, additional, Eccles, Diana M., additional, Tischkowitz, Marc, additional, Ellard, Sian, additional, Ware, James S., additional, Hanson, Helen, additional, Turnbull, Clare, additional, Samant, S., additional, Lucassen, A., additional, Znaczko, A., additional, Shaw, A., additional, Ansari, A., additional, Kumar, A., additional, Donaldson, A., additional, Murray, A., additional, Ross, A., additional, Taylor-Beadling, A., additional, Taylor, A., additional, Innes, A., additional, Brady, A., additional, Kulkarni, A., additional, Hogg, A.-C., additional, Bowden, A. Ramsay, additional, Hadonou, A., additional, Coad, B., additional, McIldowie, B., additional, Speight, B., additional, DeSouza, B., additional, Mullaney, B., additional, McKenna, C., additional, Brewer, C., additional, Olimpio, C., additional, Clabby, C., additional, Crosby, C., additional, Jenkins, C., additional, Armstrong, C., additional, Bowles, C., additional, Brooks, C., additional, Byrne, C., additional, Maurer, C., additional, Baralle, D., additional, Chubb, D., additional, Stobo, D., additional, Moore, D., additional, O'Sullivan, D., additional, Donnelly, D., additional, Randhawa, D., additional, Halliday, D., additional, Atkinson, E., additional, Baple, E., additional, Rauter, E., additional, Johnston, E., additional, Woodward, E., additional, Maher, E., additional, Sofianopoulou, E., additional, Petrides, E., additional, Lalloo, F., additional, McRonald, F., additional, Pelz, F., additional, Frayling, I., additional, Evans, G., additional, Corbett, G., additional, Rea, G., additional, Clouston, H., additional, Powell, H., additional, Williamson, H., additional, Carley, H., additional, Thomas, H.J.W., additional, Tomlinson, I., additional, Cook, J., additional, Hoyle, J., additional, Tellez, J., additional, Whitworth, J., additional, Williams, J., additional, Murray, J., additional, Campbell, J., additional, Tolmie, J., additional, Field, J., additional, Mason, J., additional, Burn, J., additional, Bruty, J., additional, Callaway, J., additional, Grant, J., additional, Del Rey Jimenez, J., additional, Pagan, J., additional, VanCampen, J., additional, Barwell, J., additional, Monahan, K., additional, Tatton-Brown, K., additional, Ong, K.-R., additional, Murphy, K., additional, Andrews, K., additional, Mokretar, K., additional, Cadoo, K., additional, Smith, K., additional, Baker, K., additional, Brown, K., additional, Reay, K., additional, McKay Bounford, K., additional, Bradshaw, K., additional, Russell, K., additional, Stone, K., additional, Snape, K., additional, Crookes, L., additional, Reed, L., additional, Taggart, L., additional, Yarram, L., additional, Cobbold, L., additional, Walker, L., additional, Hawkes, L., additional, Busby, L., additional, Izatt, L., additional, Kiely, L., additional, Hughes, L., additional, Side, L., additional, Sarkies, L., additional, Greenhalgh, K.-L., additional, Shanmugasundaram, M., additional, Duff, M., additional, Bartlett, M., additional, Watson, M., additional, Owens, M., additional, Bradford, M., additional, Huxley, M., additional, Slean, M., additional, Ryten, M., additional, Smith, M., additional, Ahmed, M., additional, Roberts, N., additional, O'Brien, C., additional, Middleton, O., additional, Tarpey, P., additional, Logan, P., additional, Dean, P., additional, May, P., additional, Brace, P., additional, Tredwell, R., additional, Harrison, R., additional, Hart, R., additional, Kirk, R., additional, Martin, R., additional, Nyanhete, R., additional, Wright, R., additional, Davidson, R., additional, Cleaver, R., additional, Talukdar, S., additional, Butler, S., additional, Sampson, J., additional, Ribeiro, S., additional, Dell, S., additional, Mackenzie, S., additional, Hegarty, S., additional, Albaba, S., additional, McKee, S., additional, Palmer-Smith, S., additional, Heggarty, S., additional, MacParland, S., additional, Greville-Heygate, S., additional, Daniels, S., additional, Prapa, S., additional, Abbs, S., additional, Tennant, S., additional, Hardy, S., additional, MacMahon, S., additional, McVeigh, T., additional, Foo, T., additional, Bedenham, T., additional, Cranston, T., additional, McDevitt, T., additional, Clowes, V., additional, Tripathi, V., additional, McConnell, V., additional, Woodwaer, N., additional, Wallis, Y., additional, Kemp, Z., additional, Mullan, G., additional, Pierson, L., additional, Rainey, L., additional, Joyce, C., additional, Timbs, A., additional, Reuther, A.-M., additional, Frugtniet, B., additional, Husher, C., additional, Lawn, C., additional, Corbett, C., additional, Nocera-Jijon, D., additional, Reay, D., additional, Cross, E., additional, Ryan, F., additional, Lindsay, H., additional, Oliver, J., additional, Dring, J., additional, Spiers, J., additional, Harper, J., additional, Ciucias, K., additional, Connolly, L., additional, Tsang, M., additional, Brown, R., additional, Shepherd, S., additional, Begum, S., additional, Tadiso, T., additional, Linton-Willoughby, T., additional, Heppell, H., additional, Sahan, K., additional, Worrillow, L., additional, Allen, Z., additional, Barlett, M., additional, Watt, C., additional, and Hegarty, M., additional
Published: 2022
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7. Large-scale discovery of novel genetic causes of developmental disorders

Author: Fitzgerald, T. W., Gerety, S. S., Jones, W. D., van Kogelenberg, M., King, D. A., McRae, J., Morley, K. I., Parthiban, V., Al-Turki, S., Ambridge, K., Barrett, D. M., Bayzetinova, T., Clayton, S., Coomber, E. L., Gribble, S., Jones, P., Krishnappa, N., Mason, L. E., Middleton, A., Miller, R., Prigmore, E., Rajan, D., Sifrim, A., Tivey, A. R., Ahmed, M., Akawi, N., Andrews, R., Anjum, U., Archer, H., Armstrong, R., Balasubramanian, M., Banerjee, R., Baralle, D., Batstone, P., Baty, D., Bennett, C., Berg, J., Bernhard, B., Bevan, A. P., Blair, E., Blyth, M., Bohanna, D., Bourdon, L., Bourn, D., Brady, A., Bragin, E., Brewer, C., Brueton, L., Brunstrom, K., Bumpstead, S. J., Bunyan, D. J., Burn, J., Burton, J., Canham, N., Castle, B., Chandler, K., Clasper, S., Clayton-Smith, J., Cole, T., Collins, A., Collinson, M. N., Connell, F., Cooper, N., Cox, H., Cresswell, L., Cross, G., Crow, Y., DʼAlessandro, M., Dabir, T., Davidson, R., Davies, S., Dean, J., Deshpande, C., Devlin, G., Dixit, A., Dominiczak, A., Donnelly, C., Donnelly, D., Douglas, A., Duncan, A., Eason, J., Edkins, S., Ellard, S., Ellis, P., Elmslie, F., Evans, K., Everest, S., Fendick, T., Fisher, R., Flinter, F., Foulds, N., Fryer, A., Fu, B., Gardiner, C., Gaunt, L., Ghali, N., Gibbons, R., Pereira, Gomes S. L., Goodship, J., Goudie, D., Gray, E., Greene, P., Greenhalgh, L., Harrison, L., Hawkins, R., Hellens, S., Henderson, A., Hobson, E., Holden, S., Holder, S., Hollingsworth, G., Homfray, T., Humphreys, M., Hurst, J., Ingram, S., Irving, M., Jarvis, J., Jenkins, L., Johnson, D., Jones, D., Jones, E., Josifova, D., Joss, S., Kaemba, B., Kazembe, S., Kerr, B., Kini, U., Kinning, E., Kirby, G., Kirk, C., Kivuva, E., Kraus, A., Kumar, D., Lachlan, K., Lam, W., Lampe, A., Langman, C., Lees, M., Lim, D., Lowther, G., Lynch, S. A., Magee, A., Maher, E., Mansour, S., Marks, K., Martin, K., Maye, U., McCann, E., McConnell, V., McEntagart, M., McGowan, R., McKay, K., McKee, S., McMullan, D. J., McNerlan, S., Mehta, S., Metcalfe, K., Miles, E., Mohammed, S., Montgomery, T., Moore, D., Morgan, S., Morris, A., Morton, J., Mugalaasi, H., Murday, V., Nevitt, L., Newbury-Ecob, R., Norman, A., OʼShea, R., Ogilvie, C., Park, S., Parker, M. J., Patel, C., Paterson, J., Payne, S., Phipps, J., Pilz, D. T., Porteous, D., Pratt, N., Prescott, K., Price, S., Pridham, A., Procter, A., Purnell, H., Ragge, N., Rankin, J., Raymond, L., Rice, D., Robert, L., Roberts, E., Roberts, G., Roberts, J., Roberts, P., Ross, A., Rosser, E., Saggar, A., Samant, S., Sandford, R., Sarkar, A., Schweiger, S., Scott, C., Scott, R., Selby, A., Seller, A., Sequeira, C., Shannon, N., Sharif, S., Shaw-Smith, C., Shearing, E., Shears, D., Simonic, I., Simpkin, D., Singzon, R., Skitt, Z., Smith, A., Smith, B., Smith, K., Smithson, S., Sneddon, L., Splitt, M., Squires, M., Stewart, F., Stewart, H., Suri, M., Sutton, V., Swaminathan, G. J., Sweeney, E., Tatton-Brown, K., Taylor, C., Taylor, R., Tein, M., Temple, I. K., Thomson, J., Tolmie, J., Torokwa, A., Treacy, B., Turner, C., Turnpenny, P., Tysoe, C., Vandersteen, A., Vasudevan, P., Vogt, J., Wakeling, E., Walker, D., Waters, J., Weber, A., Wellesley, D., Whiteford, M., Widaa, S., Wilcox, S., Williams, D., Williams, N., Woods, G., Wragg, C., Wright, M., Yang, F., Yau, M., Carter, N. P., Parker, M., Firth, H. V., FitzPatrick, D. R., Wright, C. F., Barrett, J. C., and Hurles, M. E.
Published: 2015
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8. Pathogenic variants causing ABL1 malformation syndrome cluster in a myristoyl-binding pocket and increase tyrosine kinase activity

Author: Blakes, AJM, Gaul, E, Lam, W, Shannon, N, Knapp, KM, Bicknell, LS, Jackson, MR, Wade, EM, Robertson, S, White, SM, Heller, R, Chase, A, Baralle, D, Douglas, AGL, Blakes, AJM, Gaul, E, Lam, W, Shannon, N, Knapp, KM, Bicknell, LS, Jackson, MR, Wade, EM, Robertson, S, White, SM, Heller, R, Chase, A, Baralle, D, and Douglas, AGL
Abstract: ABL1 is a proto-oncogene encoding a nonreceptor tyrosine kinase, best known in the somatic BCR-ABL fusion gene associated with chronic myeloid leukaemia. Recently, germline missense variants in ABL1 have been found to cause an autosomal dominant developmental syndrome with congenital heart disease, skeletal malformations and characteristic facies. Here, we describe a series of six new unrelated individuals with heterozygous missense variants in ABL1 (including four novel variants) identified via whole exome sequencing. All the affected individuals in this series recapitulate the phenotype of the ABL1 developmental syndrome and additionally we affirm that hearing impairment is a common feature of the condition. Four of the variants cluster in the myristoyl-binding pocket of ABL1, a region critical for auto-inhibitory regulation of the kinase domain. Bio-informatic analysis of transcript-wide conservation and germline/somatic variation reveals that this pocket region is subject to high missense constraint and evolutionary conservation. Functional work to investigate ABL1 kinase activity in vitro by transient transfection of HEK293T cells with variant ABL1 plasmid constructs revealed increased phosphorylation of ABL1-specific substrates compared to wild-type. The increased tyrosine kinase activity was suppressed by imatinib treatment. This case series of six new patients with germline heterozygous ABL1 missense variants further delineates the phenotypic spectrum of this condition and recognises microcephaly as a common finding. Our analysis supports an ABL1 gain-of-function mechanism due to loss of auto-inhibition, and demonstrates the potential for pharmacological inhibition using imatinib.
Published: 2021

9. An intronic mutation in MLH1 associated with familial colon and breast cancer

Author: Bianchi, F., Raponi, M., Piva, F., Viel, A., Bearzi, I., Galizia, E., Bracci, R., Belvederesi, L., Loretelli, C., Brugiati, C., Corradini, F., Baralle, D., and Cellerino, R.
Published: 2011
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10. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes

Author: Mefford, H., Sharp, A., Baker, C., Itsara, A., Jiang, Z., Huang, S., de Ravel, T., Norga, K., Mercer, C., Collins, A., Baralle, D., Crolia, J., Maloney, V., Devriendt, K., Bongers, E., de Leeuw, N., Reardon, W., Gimelli, S., Bena, F., Mehta, S., Park, S., Simonic, I., Clayton-Smoth, J., Gaunt, L., Male, A., Hennekam, R., Nik-Zainal, S., Woods, C., Firth, H., Parkin, G., Fichera, M., Reitano, S., Schwerzmann, M., Conrad, B., Broomer, A., Casuga, I., Li, K., and Lo Guidice, M.
Subjects: Human chromosomes -- Research, Human genome -- Research, Human genome -- Health aspects, Phenotype -- Research
Abstract: A study was conducted to determine the effects of duplications or deletions in the human genome that could be a cause or predispose an individual to disease. Results revealed that recurrent molecular lesions when noticed should be further investigated on the basis of genotype rather than phenotype.
Published: 2008

11. An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c.2970-2972 delAAT): Evidence of a clinically significant NF1 genotype-Phenotype correlation

Author: Upadhyaya, M., Huson, S.M., Davies, M., Thomas, N., Chuzhanova, N., Giovannini, S., Evans, D.G., Howard, E., Kerr, B., Griffiths, S., Consoli, C., Side, L., Adams, D., Pierpont, M., Hachen, R., Barnicoat, A., Li, H., Wallace, P., Biervliet, J.P. Van, Stevenson, D., Viskochil, D., Baralle, D., Haan, E., Riccardi, V., Turnpenny, P., Lazaro, C., and Messiaen, L.
Subjects: Neurofibroma -- Research, Neurofibromatosis -- Research, Chromosome deletion -- Research, Biological sciences
Abstract: A Study provides molecular evidence implicating the role of a specific 3-bp inframe deletion of the neurofibromatosis type 1 (NF1) gene in the determination of a clinical phenotype such as development of cutaneous, subcutaneous and superficial plexiform neurofibromas. Molecular analysis led to the identification of the same 3-bp inframe deletion (c.2970-2972 delAAT) in exon 17 of the NF1 gene in all affected subjects.
Published: 2007

12. Opposite Modulation of RAC1 by Mutations in TRIO Is Associated with Distinct, Domain-Specific Neurodevelopmental Disorders

Author: Barbosa, Sonia, Greville-Heygate, S., Bonnet, Maxime, Godwin, Annie, Fagotto-Kaufmann, Christine, Kajava, A.V., Dingemans, A.J.M., Vries, B.B.A. de, Schmidt, S., Baralle, D., Barbosa, Sonia, Greville-Heygate, S., Bonnet, Maxime, Godwin, Annie, Fagotto-Kaufmann, Christine, Kajava, A.V., Dingemans, A.J.M., Vries, B.B.A. de, Schmidt, S., and Baralle, D.
Abstract: Contains fulltext : 217385.pdf (Publisher’s version ) (Open Access)
Published: 2020

13. Systematic screening of FBN1 gene unclassified missense variants for splice abnormalities

Author: Robinson, DO, Lin, F, Lyon, M, Raponi, M, Cross, E, White, HE, Cox, H, Clayton-Smith, J, and Baralle, D
Published: 2012
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14. Alternative splicing: good and bad effects of translationally silent substitutions

Author: Raponi, M. and Baralle, D.
Published: 2010
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15. Functional Splicing Assay Shows a Pathogenic Intronic Mutation in Neurofibromatosis Type 1 (NF1) Due to Intronic Sequence Exonization

Author: Raponi, M., Upadhyaya, M., and Baralle, D.
Published: 2006
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16. Splicing in action: assessing disease causing sequence changes

Author: Baralle, D and Baralle, M
Published: 2005

17. Re: Pitfalls of automated comparative sequence analysis as a single platform for routine clinical testing for NF1 (Messiaen and Wimmer)

Author: Whittaker, J L, Mattocks, C, Baralle, D, Tarpey, P, ffrench-Constant, C, and Bobrow, M
Published: 2005

18. Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging.

Author: Mill J., Yachelevich N., Tatton-Brown K., Crosby A.H., Hunter M.F., Baple E.L., Jeffries A.R., Maroofian R., Salter C.G., Chioza B.A., Cross H.E., Patton M.A., Dempster E., Karen Temple I., Mackay D.J.G., Rezwan F.I., Aksglaede L., Baralle D., Dabir T., Kamath A., Kumar A., Newbury-Ecob R., Selicorni A., Springer A., Van Maldergem L., Varghese V., Mill J., Yachelevich N., Tatton-Brown K., Crosby A.H., Hunter M.F., Baple E.L., Jeffries A.R., Maroofian R., Salter C.G., Chioza B.A., Cross H.E., Patton M.A., Dempster E., Karen Temple I., Mackay D.J.G., Rezwan F.I., Aksglaede L., Baralle D., Dabir T., Kamath A., Kumar A., Newbury-Ecob R., Selicorni A., Springer A., Van Maldergem L., and Varghese V.
Abstract: Germline mutations in fundamental epigenetic regulatory molecules including DNA methyltransferase 3 alpha (DNMT3A) are commonly associated with growth disorders, whereas somatic mutations are often associated with malignancy. We profiled genome-wide DNA methylation patterns in DNMT3A c.2312G > A; p.(Arg771Gln) carriers in a large Amish sibship with Tatton-Brown-Rahman syndrome (TBRS), their mosaic father, and 15 TBRS patients with distinct pathogenic de novo DNMT3A variants. This defined widespread DNA hypomethylation at specific genomic sites enriched at locations annotated as genes involved in morphogenesis, development, differentiation, and malignancy predisposition pathways. TBRS patients also displayed highly accelerated DNA methylation aging. These findings were most marked in a carrier of the AML-associated driver mutation p.Arg882Cys. Our studies additionally defined phenotype-related accelerated and decelerated epigenetic aging in two histone methyltransferase disorders: NSD1 Sotos syndrome overgrowth disorder and KMT2D Kabuki syndrome growth impairment. Together, our findings provide fundamental new insights into aberrant epigenetic mechanisms, the role of epigenetic machinery maintenance, and determinants of biological aging in these growth disorders.Copyright © 2019 Jeffries et al. This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
Published: 2019

19. Automated comparative sequence analysis identifies mutations in 89% of NF1 patients and confirms a mutation cluster in exons 11–17 distinct from the GAP related domain

Author: Mattocks, C, Baralle, D, Tarpey, P, ffrench-Constant, C, Bobrow, M, and Whittaker, J
Published: 2004

20. Identification of a mutation that perturbs NF1 agene splicing using genomic DNA samples and a minigene assay

Author: Baralle, M, Baralle, D, De Conti, L, Mattocks, C, Whittaker, J, Knezevich, A, ffrench-Constant, C, and Baralle, F E
Published: 2003

21. Myoclonic movement disorder associated with microdeletion of chromosome 22q11

Author: Baralle, D, Trump, D, ffrench-Constant, C, and Dick, D J
Published: 2002

22. Quantifying prediction of pathogenicity for within-codon concordance (PM5) using 7541 functional classifications of BRCA1and MSH2missense variants

Author: Loong, Lucy, Cubuk, Cankut, Choi, Subin, Allen, Sophie, Torr, Beth, Garrett, Alice, Loveday, Chey, Durkie, Miranda, Callaway, Alison, Burghel, George J., Drummond, James, Robinson, Rachel, Berry, Ian R., Wallace, Andrew, Eccles, Diana M., Tischkowitz, Marc, Ellard, Sian, Ware, James S., Hanson, Helen, Turnbull, Clare, Samant, S., Lucassen, A., Znaczko, A., Shaw, A., Ansari, A., Kumar, A., Donaldson, A., Murray, A., Ross, A., Taylor-Beadling, A., Taylor, A., Innes, A., Brady, A., Kulkarni, A., Hogg, A.-C., Bowden, A. Ramsay, Hadonou, A., Coad, B., McIldowie, B., Speight, B., DeSouza, B., Mullaney, B., McKenna, C., Brewer, C., Olimpio, C., Clabby, C., Crosby, C., Jenkins, C., Armstrong, C., Bowles, C., Brooks, C., Byrne, C., Maurer, C., Baralle, D., Chubb, D., Stobo, D., Moore, D., O'Sullivan, D., Donnelly, D., Randhawa, D., Halliday, D., Atkinson, E., Baple, E., Rauter, E., Johnston, E., Woodward, E., Maher, E., Sofianopoulou, E., Petrides, E., Lalloo, F., McRonald, F., Pelz, F., Frayling, I., Evans, G., Corbett, G., Rea, G., Clouston, H., Powell, H., Williamson, H., Carley, H., Thomas, H.J.W., Tomlinson, I., Cook, J., Hoyle, J., Tellez, J., Whitworth, J., Williams, J., Murray, J., Campbell, J., Tolmie, J., Field, J., Mason, J., Burn, J., Bruty, J., Callaway, J., Grant, J., Del Rey Jimenez, J., Pagan, J., VanCampen, J., Barwell, J., Monahan, K., Tatton-Brown, K., Ong, K.-R., Murphy, K., Andrews, K., Mokretar, K., Cadoo, K., Smith, K., Baker, K., Brown, K., Reay, K., McKay Bounford, K., Bradshaw, K., Russell, K., Stone, K., Snape, K., Crookes, L., Reed, L., Taggart, L., Yarram, L., Cobbold, L., Walker, L., Walker, L., Hawkes, L., Busby, L., Izatt, L., Kiely, L., Hughes, L., Side, L., Sarkies, L., Greenhalgh, K.-L., Shanmugasundaram, M., Duff, M., Bartlett, M., Watson, M., Owens, M., Bradford, M., Huxley, M., Slean, M., Ryten, M., Smith, M., Ahmed, M., Roberts, N., O'Brien, C., Middleton, O., Tarpey, P., Logan, P., Dean, P., May, P., Brace, P., Tredwell, R., Harrison, R., Hart, R., Kirk, R., Martin, R., Nyanhete, R., Wright, R., Martin, R., Davidson, R., Cleaver, R., Talukdar, S., Butler, S., Sampson, J., Ribeiro, S., Dell, S., Mackenzie, S., Hegarty, S., Albaba, S., McKee, S., Palmer-Smith, S., Heggarty, S., MacParland, S., Greville-Heygate, S., Daniels, S., Prapa, S., Abbs, S., Tennant, S., Hardy, S., MacMahon, S., McVeigh, T., Foo, T., Bedenham, T., Cranston, T., McDevitt, T., Clowes, V., Tripathi, V., McConnell, V., Woodwaer, N., Wallis, Y., Kemp, Z., Mullan, G., Pierson, L., Rainey, L., Joyce, C., Timbs, A., Reuther, A.-M., Frugtniet, B., DeSouza, B., Husher, C., Lawn, C., Corbett, C., Nocera-Jijon, D., Reay, D., Cross, E., Ryan, F., Lindsay, H., Oliver, J., Dring, J., Spiers, J., Harper, J., Ciucias, K., Connolly, L., Tsang, M., Brown, R., Shepherd, S., Begum, S., Daniels, S., Tadiso, T., Linton-Willoughby, T., Heppell, H., Sahan, K., Worrillow, L., Allen, Z., Barlett, M., Watt, C., and Hegarty, M.
Abstract: Conditions and thresholds applied for evidence weighting of within-codon concordance (PM5) for pathogenicity vary widely between laboratories and expert groups. Because of the sparseness of available clinical classifications, there is little evidence for variation in practice.
Published: 2022
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23. Benign familial infantile convulsions: report of a UK family and confirmation of genetic heterogeneity

Author: BARALLE, D, DEARLOVE, A M, BEACH, R, FFRENCH-CONSTANT, C, and REID, E
Published: 2000

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

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

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

Author: Reijnders, M.R.F., Miller, K.A., Alvi, M., Goos, J.A.C., Lees, M.M., Burca, A. de, Henderson, A., Kraus, A., Mikat, B., Vries, B.B.A. de, Isidor, B., Kerr, B., Marcelis, C.L.M., Schluth-Bolard, C., Deshpande, C., Ruivenkamp, C.A.L., Wieczorek, D., Baralle, D., Blair, E.M., Engels, H., Ludecke, H.J., Eason, J., Santen, G.W.E., Clayton-Smith, J., Chandler, K., Tatton-Brown, K., Payne, K., Helbig, K., Radtke, K., Nugent, K.M., Cremer, K., Strom, T.M., Bird, L.M., Sinnema, M., Bitner-Glindzicz, M., Dooren, M.F. van, Alders, M., Koopmans, M., Brick, L., Kozenko, M., Harline, M.L., Klaassens, M., Steinraths, M., Cooper, N.S., Edery, P., Yap, P., Terhal, P.A., Spek, P.J. van der, Lakeman, P., Taylor, R.L., Littlejohn, R.O., Pfundt, R.P., Mercimek-Andrews, S., Stegmann, A.P.A., Kant, S.G., McLean, S., Joss, S., Swagemakers, S.M.A., Douzgou, S., Wall, S.A., Kury, S., Calpena, E., Koelling, N., McGowan, S.J., Twigg, S.R.F., Mathijssen, I.M.J., Nellaker, C., Brunner, H.G., Wilkie, A.O.M., Plastic and Reconstructive Surgery and Hand Surgery, Clinical Genetics, and Pathology
Subjects: Tousled-like, Facial Averaging, Haploinsufficiency, Intellectual Disability, Kinase, Adult, Male, Adolescent, kinase, viruses, Inheritance Patterns, Medizin, Translocation, Genetic, Cell Line, Young Adult, Loss of Function Mutation, Report, Humans, RNA, Messenger, Child, Genetic Association Studies, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Base Sequence, Facies, Infant, haploinsufficiency, Neurodevelopmental Disorders, intellectual disability, Child, Preschool, Female, Protein Kinases, facial averaging, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract: Human adenovirus (HAdV) E1B-55K is a multifunctional regulator of productive viral replication and oncogenic transformation in nonpermissive mammalian cells. These functions depend on E1B-55K's posttranslational modification with the SUMO protein and its binding to HAdV E4orf6. Both early viral proteins recruit specific host factors to form an E3 ubiquitin ligase complex that targets antiviral host substrates for proteasomal degradation. Recently, we reported that the PML-NB associated factor Daxx represses efficient HAdV productive infection and is proteasomally degraded via a SUMO-E1B-55K-dependent, E4orf6-independent pathway, the details of which remained to be established. RNF4, a cellular SUMO-targeted ubiquitin ligase (STUbL), induces ubiquitinylation of specific SUMOy lated proteins and plays an essential role during DNA repair. Here, we show that E1B-55K recruits RNF4 to the insoluble nuclear matrix fraction of the infected cell to support RNF4/Daxx association, promoting Daxx PTM and thus inhibiting this antiviral factor. Removing RNF4 from infected cells using RNA interference resulted in blocking the proper establishment of viral replication centers and significantly diminished viral gene expression. These results provide a model for how HAdV antagonize the antiviral host responses by exploiting the functional capacity of cellular STUbLs. Thus, RNF4 and its STUbL function represent a positive factor during lytic infection and a novel candidate for future therapeutic antiviral intervention strategies.IMPORTANCE Daxx is a PML-NB-associated transcription factor that was recently shown to repress efficient HAdV productive infection. To counteract this antiviral measurement during infection, Daxx is degraded via a novel pathway including viral E1B-55K and host proteasomes. This virus-mediated degradation is independent of the classical HAdV E3 ubiquitin ligase complex, which is essential during viral infection to target other host antiviral substrates. To maintain a productive viral life cycle, HAdV E1B-55K early viral protein inhibits the chromatin-remodeling factor Daxx in a SUMO-dependent manner. In addition, viral E1B-55K protein recruits the STUbL RNF4 and sequesters it into the insoluble fraction of the infected cell. E1B-55K promotes complex formation between RNF4-and E1B-55K-targeted Daxx protein, supporting Daxx posttranslational modification prior to functional inhibition. Hence, RNF4 represents a novel host factor that is beneficial for HAdV gene expression by supporting Daxx counteraction. In this regard, RNF4 and other STUbL proteins might represent novel targets for therapeutic intervention.
Published: 2018

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

Author: Reijnders, M.R.F., Janowski, R., Alvi, M., Self, J.E., Essen, T.J. van, Vreeburg, M., Rouhl, R.P.W., Stevens, S.J.C., Stegmann, A.P.A., Schieving, J.H., Pfundt, R.P., Dijk, K van, Smeets, E., Stumpel, C., Bok, L.A, Cobben, J.M., Engelen, M., Mansour, S., Whiteford, M., Chandler, K.E., Douzgou, S., Cooper, N.S., Tan, Ene-Choo, Foo, R., Lai, A.H., Rankin, J., Green, A., Lonnqvist, T., Isohanni, P., Williams, S., Ruhoy, I., Carvalho, K.S., Dowling, J.J., Lev, D.L., Sterbova, K., Lassuthova, P., Neupauerova, J., Waugh, J.L., Keros, S., Clayton-Smith, J., Smithson, S.F., Brunner, H.G., Hoeckel, C. van, Anderson, M., Clowes, V.E., Siu, V.M., Study, T. Ddd, Selber, P., Leventer, R.J., Nellaker, C., Niessing, D., Hunt, D., Baralle, D., Reijnders, M.R.F., Janowski, R., Alvi, M., Self, J.E., Essen, T.J. van, Vreeburg, M., Rouhl, R.P.W., Stevens, S.J.C., Stegmann, A.P.A., Schieving, J.H., Pfundt, R.P., Dijk, K van, Smeets, E., Stumpel, C., Bok, L.A, Cobben, J.M., Engelen, M., Mansour, S., Whiteford, M., Chandler, K.E., Douzgou, S., Cooper, N.S., Tan, Ene-Choo, Foo, R., Lai, A.H., Rankin, J., Green, A., Lonnqvist, T., Isohanni, P., Williams, S., Ruhoy, I., Carvalho, K.S., Dowling, J.J., Lev, D.L., Sterbova, K., Lassuthova, P., Neupauerova, J., Waugh, J.L., Keros, S., Clayton-Smith, J., Smithson, S.F., Brunner, H.G., Hoeckel, C. van, Anderson, M., Clowes, V.E., Siu, V.M., Study, T. Ddd, Selber, P., Leventer, R.J., Nellaker, C., Niessing, D., Hunt, D., and Baralle, D.
Abstract: Contains fulltext : 190731.pdf (publisher's version ) (Open Access), BACKGROUND: De novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia. OBJECTIVES: To delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations. METHODS: Diagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of Drosophila-derived Pur-alpha homologues. Finally, we explored genotype-phenotype correlations by analysis of both recurrent mutations as well as mutation classes. RESULTS: We report mutations in PURA (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes. CONCLUSION: We delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and
Published: 2018

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

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

28. Expanding the neurodevelopmental phenotype of PURA syndrome

Author: Lee, BH, Reijnders, MRF, Abubakare, O, Tuttle, E, Lape, B, Minks, KQ, Stodgell, C, Bennetto, L, Kwon, J, Fong, C-T, Gripp, KW, Marsh, ED, Smith, WE, Huq, AM, Coury, SA, Tan, W-H, Solis, O, Mehta, RI, Leventer, RJ, Baralle, D, Hunt, D, Paciorkowski, AR, Lee, BH, Reijnders, MRF, Abubakare, O, Tuttle, E, Lape, B, Minks, KQ, Stodgell, C, Bennetto, L, Kwon, J, Fong, C-T, Gripp, KW, Marsh, ED, Smith, WE, Huq, AM, Coury, SA, Tan, W-H, Solis, O, Mehta, RI, Leventer, RJ, Baralle, D, Hunt, D, and Paciorkowski, AR
Abstract: PURA syndrome is a recently described developmental encephalopathy presenting with neonatal hypotonia, feeding difficulties, global developmental delay, severe intellectual disability, and frequent apnea and epilepsy. We describe 18 new individuals with heterozygous sequence variations in PURA. A neuromotor disorder starting with neonatal hyptonia, but ultimately allowing delayed progression to walking, was present in nearly all individuals. Congenital apnea was present in 56% during infancy, but all cases in this cohort resolved during the first year of life. Feeding difficulties were frequently reported, with gastrostomy tube placement required in 28%. Epilepsy was present in 50% of the subjects, including infantile spasms and Lennox-Gastaut syndrome. Skeletal complications were found in 39%. Disorders of gastrointestinal motility and nystagmus were also recurrent features. Autism was diagnosed in one individual, potentially expanding the neurodevelopmental phenotype associated with this syndrome. However, we did not find additional PURA sequence variations in a cohort of 120 subjects with autism. We also present the first neuropathologic studies of PURA syndrome, and describe chronic inflammatory changes around the arterioles within the deep white matter. We did not find significant correlations between mutational class and severity, nor between location of the sequence variation in PUR repeat domains. Further studies are required in larger cohorts of subjects with PURA syndrome to clarify these genotype-phenotype associations.
Published: 2018

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

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

30. Early development of infants with neurofibromatosis type 1: A case series

Author: Kolesnik, A, Jones, E, Garg, S, Green, J, Charman, T, Johnson, M, Baron-Cohen, S, Begum-Ali, J, Bolton, P, Cheung, C, Dafner, L, Davies, K, Elsabbagh, M, Fernandes, J, Fish, L, Gammer, I, Greensmith, M, Gliga, T, Kalwarowsky, S, Liew, M, Pasco, G, Pickles, A, Ribeiro, H, Salomone, E, Taylor, C, Tucker, L, Wass, S, Burkitt-Wright, E, Evans, D, Vassallo, G, Eelloo, J, West, S, Howard, E, Hupton, E, Huson, S, Lewis, L, Tricker, K, Dobbie, A, Drimer, R, Sharif, S, Baralle, D, Redman, C, Symth, C, Lam, W, Bradbury, A, Harrower, N, Quarrell, O, Bethell, H, Jones, R, Musson, S, Prem, C, Splitt, M, Horridge, K, Steiger, C, Jim, C, Kolesnik, Anna May, Jones, Emily Jane Harrison, Garg, Shruti, Green, Jonathan, Charman, Tony, Johnson, Mark Henry, Baron-Cohen, Simon, Begum-Ali, Jannath, Bolton, Patrick, Cheung, Celeste, Dafner, Leila, Davies, Kim, Elsabbagh, Mayada, Fernandes, Janice, Fish, Laurel, Gammer, Isobel, Greensmith, Marian, Gliga, Teodora, Kalwarowsky, Sarah, Liew, Michelle, Pasco, Greg, Pickles, Andrew, Ribeiro, Helena, Salomone, Erica, Taylor, Chloe, Tucker, Leslie, Wass, Sam, Burkitt-Wright, Emma, Evans, D. Gareth, Vassallo, Grace, Eelloo, Judith, West, Siobhan, Howard, Elizabeth, Hupton, Eileen, Huson, Sue, Lewis, Lauren, Tricker, Karen, Dobbie, Angus, Drimer, Ruth, Sharif, Saghira Malik, Baralle, Diane, Redman, Carolyn, Sharif, Saba, Symth, Carolyn, Lam, Wayne, Bradbury, Alyson, Harrower, Neil, Quarrell, Oliver, Bethell, Helen, Jones, Rachel, Musson, Susan, Prem, Catherine, Splitt, Miranda, Horridge, Karen, Steiger, Christine, Jim, Carly, Kolesnik, A, Jones, E, Garg, S, Green, J, Charman, T, Johnson, M, Baron-Cohen, S, Begum-Ali, J, Bolton, P, Cheung, C, Dafner, L, Davies, K, Elsabbagh, M, Fernandes, J, Fish, L, Gammer, I, Greensmith, M, Gliga, T, Kalwarowsky, S, Liew, M, Pasco, G, Pickles, A, Ribeiro, H, Salomone, E, Taylor, C, Tucker, L, Wass, S, Burkitt-Wright, E, Evans, D, Vassallo, G, Eelloo, J, West, S, Howard, E, Hupton, E, Huson, S, Lewis, L, Tricker, K, Dobbie, A, Drimer, R, Sharif, S, Baralle, D, Redman, C, Symth, C, Lam, W, Bradbury, A, Harrower, N, Quarrell, O, Bethell, H, Jones, R, Musson, S, Prem, C, Splitt, M, Horridge, K, Steiger, C, Jim, C, Kolesnik, Anna May, Jones, Emily Jane Harrison, Garg, Shruti, Green, Jonathan, Charman, Tony, Johnson, Mark Henry, Baron-Cohen, Simon, Begum-Ali, Jannath, Bolton, Patrick, Cheung, Celeste, Dafner, Leila, Davies, Kim, Elsabbagh, Mayada, Fernandes, Janice, Fish, Laurel, Gammer, Isobel, Greensmith, Marian, Gliga, Teodora, Kalwarowsky, Sarah, Liew, Michelle, Pasco, Greg, Pickles, Andrew, Ribeiro, Helena, Salomone, Erica, Taylor, Chloe, Tucker, Leslie, Wass, Sam, Burkitt-Wright, Emma, Evans, D. Gareth, Vassallo, Grace, Eelloo, Judith, West, Siobhan, Howard, Elizabeth, Hupton, Eileen, Huson, Sue, Lewis, Lauren, Tricker, Karen, Dobbie, Angus, Drimer, Ruth, Sharif, Saghira Malik, Baralle, Diane, Redman, Carolyn, Sharif, Saba, Symth, Carolyn, Lam, Wayne, Bradbury, Alyson, Harrower, Neil, Quarrell, Oliver, Bethell, Helen, Jones, Rachel, Musson, Susan, Prem, Catherine, Splitt, Miranda, Horridge, Karen, Steiger, Christine, and Jim, Carly
Abstract: Background: Prospective studies of infants at familial risk for autism spectrum disorder (ASD) have yielded insights into the earliest signs of the disorder but represent heterogeneous samples of unclear aetiology. Complementing this approach by studying cohorts of infants with monogenic syndromes associated with high rates of ASD offers the opportunity to elucidate the factors that lead to ASD. Methods: We present the first report from a prospective study of ten 10-month-old infants with neurofibromatosis type 1 (NF1), a monogenic disorder with high prevalence of ASD or ASD symptomatology. We compared data from infants with NF1 to a large cohort of infants at familial risk for ASD, separated by outcome at age 3 of ASD (n = 34), atypical development (n = 44), or typical development (n = 89), and low-risk controls (n = 75). Domains assessed at 10 months by parent report and examiner observation include cognitive and adaptive function, sensory processing, social engagement, and temperament. Results: Infants with NF1 showed striking impairments in motor functioning relative to low-risk infants; this pattern was seen in infants with later ASD from the familial cohort (HR-ASD). Both infants with NF1 and the HR-ASD group showed communication delays relative to low-risk infants. Conclusions: Ten-month-old infants with NF1 show a range of developmental difficulties that were particularly striking in motor and communication domains. As with HR-ASD infants, social skills at this age were not notably impaired. This is some of the first information on early neurodevelopment in NF1. Strong inferences are limited by the sample size, but the findings suggest implications for early comparative developmental science and highlight motor functioning as an important domain to inform the development of relevant animal models. The findings have clinical implications in indicating an important focus for early surveillance and remediation in this early diagnosed genetic disorder.
Published: 2017

31. Identification of a mutation that perturbs NF1 gene splicing using genomic DNA samples and a minigene assay. (Letter to JMG)

Author: Baralle, M., Baralle, D., Conti, L. De, Mattocks, C., Whittaker, J., Knezevich, A., Ffrench-Constant, C., and Baralle, F.E.
Subjects: Gene mutations -- Physiological aspects -- Research -- Genetic aspects, Neurofibromatosis -- Genetic aspects -- Research, Health, Physiological aspects, Research, Genetic aspects
Abstract: Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic disease. In recent studies on the neurofibromatosis type 1 (NF1) gene neurofibromin, splicing abnormalities were seen in 30-50% of cases [...]
Published: 2003

32. Human NDE1 splicing and mammalian brain development

Author: Mosca, S., primary, Raponi, M., additional, Meneghello, A., additional, Buratti, E., additional, Woods, C. G., additional, and Baralle, D., additional
Published: 2017
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33. Classification of variants of reduced penetrance in high-penetrance cancer susceptibility genes: Framework for genetics clinicians and clinical scientists by CanVIG-UK (Cancer Variant Interpretation Group-UK)

Author: Garrett, Alice, Allen, Sophie, Durkie, Miranda, Burghel, George J., Robinson, Rachel, Callaway, Alison, Field, Joanne, Frugtniet, Bethan, Palmer-Smith, Sheila, Grant, Jonathan, Pagan, Judith, McDevitt, Trudi, Rowlands, Charlie F., McVeigh, Terri, Hanson, Helen, Turnbull, Clare, Turnbull, C., Garrett, A., Loong, L., Choi, S., Torr, B., Allen, S., Durkie, M., Callaway, A., Drummond, J., Burghel, G.J., Robinson, R., Berry, I.R., Wallace, A.J., Eccles, D.M., Tischkowitz, M., Ellard, S., Hanson, H., Baple, E., Evans, D.G., Woodward, E., Lalloo, F., Samant, S., Lucassen, A., Znaczko, A., Shaw, A., Ansari, A., Kumar, A., Donaldson, A., Murray, A., Ross, A., Taylor-Beadling, A., Taylor, A., Innes, A., Brady, A., Kulkarni, A., Hogg, A.C., Bowden, A. Ramsay, Hadonou, A., Coad, B., McIldowie, B., Speight, B., DeSouza, B., Mullaney, B., McKenna, C., Brewer, C., Olimpio, C., Clabby, C., Crosby, C., Jenkins, C., Armstrong, C., Bowles, C., Brooks, C., Byrne, C., Maurer, C., Baralle, D., Chubb, D., Stobo, D., Moore, D., O'Sullivan, D., Donnelly, D., Randhawa, D., Halliday, D., Atkinson, E., Rauter, E., Johnston, E., Maher, E., Sofianopoulou, E., Petrides, E., McRonald, F., Pelz, F., Frayling, I., Corbett, G., Rea, G., Clouston, H., Powell, H., Williamson, H., Carley, H., Thomas, H.J.W., Tomlinson, I., Cook, J., Hoyle, J., Tellez, J., Whitworth, J., Williams, J., Murray, J., Campbell, J., Tolmie, J., Field, J., Mason, J., Burn, J., Bruty, J., Callaway, J., Grant, J., Del Rey Jimenez, J., Pagan, J., VanCampen, J., Barwell, J., Monahan, K., Tatton-Brown, K., Ong, K.R., Murphy, K., Andrews, K., Mokretar, K., Cadoo, K., Smith, K., Baker, K., Brown, K., Reay, K., McKay Bounford, K., Bradshaw, K., Russell, K., Stone, K., Snape, K., Crookes, L., Reed, L., Taggart, L., Yarram, L., Cobbold, L., Walker, L., Walker, L., Hawkes, L., Busby, L., Izatt, L., Kiely, L., Hughes, L., Side, L., Sarkies, L., Greenhalgh, K.-L., Shanmugasundaram, M., Duff, M., Bartlett, M., Watson, M., Owens, M., Bradford, M., Huxley, M., Slean, M., Ryten, M., Smith, M., Ahmed, M., Roberts, N., O'Brien, C., Middleton, O., Tarpey, P., Logan, P., Dean, P., May, P., Brace, P., Tredwell, R., Harrison, R., Hart, R., Kirk, R., Martin, R., Nyanhete, R., Wright, R., Martin, R., Davidson, R., Cleaver, R., Talukdar, S., Butler, S., Sampson, J., Ribeiro, S., Dell, S., Mackenzie, S., Hegarty, S., Albaba, S., McKee, S., Palmer-Smith, S., Heggarty, S., MacParland, S., Greville-Heygate, S., Daniels, S., Prapa, S., Abbs, S., Tennant, S., Hardy, S., MacMahon, S., McVeigh, T., Foo, T., Bedenham, T., Cranston, T., McDevitt, T., Clowes, V., Tripathi, V., McConnell, V., Woodwaer, N., Wallis, Y., Kemp, Z., Mullan, G., Pierson, L., Rainey, L., Joyce, C., Timbs, A., Reuther, A.-M., Frugtniet, B., DeSouza, B., Husher, C., Lawn, C., Corbett, C., Nocera-Jijon, D., Reay, D., Cross, E., Ryan, F., Lindsay, H., Oliver, J., Dring, J., Spiers, J., Harper, J., Ciucias, K., Connolly, L., Tsang, M., Brown, R., Shepherd, S., Begum, S., Daniels, S., Tadiso, T., Linton-Willoughby, T., Heppell, H., Sahan, K., Worrillow, L., Allen, Z., Watt, C., Hegarty, M., Mitchell, R., Coles, R., Nickless, G., Cojocaru, E., Doal, I., Sava, F., McCarthy, C., Jeeneea, R., Goudie, D., McConachie, M., Botosneanu, S., Kavanaugh, G., Russell, K., Sherlaw, C., Tsoulaki, O., Forde, C., Petley, E., Jones, A.-B., Oprych, K., Pryde, S., Hyder, Z., Elkhateeb, N., Braham, R., Hanington, L., Huntley, C., Irving, R., Sadan, A., Ramos, M., Elliot, C., Wren, D., Lobo, D., McLean, J., May, D., Kearney, L., Campbell, T., Asakura, K., Alwadi, L., O’Shea, R., Gabriel, J., Chiecchio, L., Bowman, P., Sutton, L.A., Walsh, C., Cloke, V., Ucanok, D., Davies, J., Pleasance, B., Maguire, E., Whaite, A., Best, S., Westbury, S., Logan, A., Navarajasegaran, D., Bench, A., Wightman, P., Cartwright, A., Higgs, E., J.Bott, Whitehouse, H., Stevens, J., Martin, D., Dunlop, J., Thomas, S., Sau, C., Farndon, S., Coleman, N., Angelini, P., Duff, M., Massey, H., Rowlands, C., Garcia-Petit, C., Gillespie, K., Alder, A., Middleton, E., Cassidy, C., Orfali, N., Webb, A., Luharia, A., Walker, N., Charlton, J., Andreou, A., Peddie, J., Khan, M., Wilkinson, L., Bezuidenhout, H., Edis, M., Callard, A., Ostrowski, P., Moverley, P., Bean, K., Dunne, A., Moleirinho, A., Waller, S., Cox, K., Greensmith, L., Brittle, A., Gossan, N., Freestone, L., Shak, C., Langford, T., Clinch, Y., Livesey, H., Borland, S., Joshi, A., Wall, K., Whitworth, A., Wilsdon, A., Edgerley, K., Pugh, S., Chrysochoidi, N., Mutch, S., McMullan, C., Johnston, Y., Muraru, M., May, A., Begum, R., Smith, C., Patel, R., Bhatnagar, I., Taylor, A., Brown, D., Willan, J., Taylor, S., Jones, K., Cox, K., Ramsden, C., Taiwo, O., Jaudzemaite, J., Sharmin, R., Young, L., C.O’Dubhshlaine, McSorley, L., Rodriguez, I. Abreu, Lillis, S., Alexopoulos, P., Mortensson, E., Kingham, L., Moore, R., Kosicka-Slawinska, M., Aslam, S., Wells, R., Carter, A., Warren, H., Rolf, E., Reed, H., Pearce, L., Lock, D., Ali, F., Kolozi, A., White, N., Wood, D., and Hayden, C.
Abstract: Current practice is to report and manage likely pathogenic/pathogenic variants in a given cancer susceptibility gene as though having equivalent penetrance, despite increasing evidence of intervariant variability in risk associations. Using existing variant interpretation approaches, largely based on full-penetrance models, variants in which reduced penetrance is suspected may be classified inconsistently and/or as variants of uncertain significance. We aimed to develop a national consensus approach for such variants within the Cancer Variant Interpretation Group UK (CanVIG-UK) multidisciplinary network.
Published: 2024
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34. Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling

Author: Snijders Blok, C., Madsen, E., Juusola, J., Gilissen, C.F., Baralle, D., Reijnders, M.R.F., Venselaar, H., Helsmoortel, C., Cho, M.T., Hoischen, A., Vissers, L.E., Koemans, T.S., Wissink, W.M., Eichler, E.E., Romano, C, Esch, H. Van, Stumpel, C., Vreeburg, M., Smeets, E., Oberndorff, K., Bon, B.W. van, Shaw, M., Gecz, J., Haan, E., Bienek, M., Jensen, C., Loeys, B.L., Dijck, A. Van, Innes, A.M., Racher, H., Vermeer, S., Donato, N. Di, Rump, A., Tatton-Brown, K., Parker, M.J., Henderson, A., Lynch, S.A., Fryer, A., Ross, A., Vasudevan, P., Kini, U., Newbury-Ecob, R., Chandler, K., Male, A., Dijkstra, S, Schieving, J., Giltay, J., Gassen, K.L. van, Schuurs-Hoeijmakers, J., Tan, P.L., Pediaditakis, I., Haas, S.A., Retterer, K., Reed, P., Monaghan, K.G., Haverfield, E., Natowicz, M., Myers, A., Kruer, M.C., Stein, Q., Strauss, K.A., Brigatti, K.W., Keating, K., Burton, B.K., Kim, K.H., Charrow, J., Norman, J., Foster-Barber, A., Kline, A.D., Kimball, A., Zackai, E., Harr, M., Fox, J., McLaughlin, J., Lindstrom, K., Haude, K.M., Roozendaal, K. van, Brunner, H.G., Chung, W.K., Kooy, R.F., Pfundt, R., Kalscheuer, V., Mehta, S.G., Katsanis, N., Kleefstra, T., Snijders Blok, C., Madsen, E., Juusola, J., Gilissen, C.F., Baralle, D., Reijnders, M.R.F., Venselaar, H., Helsmoortel, C., Cho, M.T., Hoischen, A., Vissers, L.E., Koemans, T.S., Wissink, W.M., Eichler, E.E., Romano, C, Esch, H. Van, Stumpel, C., Vreeburg, M., Smeets, E., Oberndorff, K., Bon, B.W. van, Shaw, M., Gecz, J., Haan, E., Bienek, M., Jensen, C., Loeys, B.L., Dijck, A. Van, Innes, A.M., Racher, H., Vermeer, S., Donato, N. Di, Rump, A., Tatton-Brown, K., Parker, M.J., Henderson, A., Lynch, S.A., Fryer, A., Ross, A., Vasudevan, P., Kini, U., Newbury-Ecob, R., Chandler, K., Male, A., Dijkstra, S, Schieving, J., Giltay, J., Gassen, K.L. van, Schuurs-Hoeijmakers, J., Tan, P.L., Pediaditakis, I., Haas, S.A., Retterer, K., Reed, P., Monaghan, K.G., Haverfield, E., Natowicz, M., Myers, A., Kruer, M.C., Stein, Q., Strauss, K.A., Brigatti, K.W., Keating, K., Burton, B.K., Kim, K.H., Charrow, J., Norman, J., Foster-Barber, A., Kline, A.D., Kimball, A., Zackai, E., Harr, M., Fox, J., McLaughlin, J., Lindstrom, K., Haude, K.M., Roozendaal, K. van, Brunner, H.G., Chung, W.K., Kooy, R.F., Pfundt, R., Kalscheuer, V., Mehta, S.G., Katsanis, N., and Kleefstra, T.
Abstract: Contains fulltext : 153453.pdf (publisher's version ) (Closed access), Intellectual disability (ID) affects approximately 1%-3% of humans with a gender bias toward males. Previous studies have identified mutations in more than 100 genes on the X chromosome in males with ID, but there is less evidence for de novo mutations on the X chromosome causing ID in females. In this study we present 35 unique deleterious de novo mutations in DDX3X identified by whole exome sequencing in 38 females with ID and various other features including hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. Based on our findings, mutations in DDX3X are one of the more common causes of ID, accounting for 1%-3% of unexplained ID in females. Although no de novo DDX3X mutations were identified in males, we present three families with segregating missense mutations in DDX3X, suggestive of an X-linked recessive inheritance pattern. In these families, all males with the DDX3X variant had ID, whereas carrier females were unaffected. To explore the pathogenic mechanisms accounting for the differences in disease transmission and phenotype between affected females and affected males with DDX3X missense variants, we used canonical Wnt defects in zebrafish as a surrogate measure of DDX3X function in vivo. We demonstrate a consistent loss-of-function effect of all tested de novo mutations on the Wnt pathway, and we further show a differential effect by gender. The differential activity possibly reflects a dose-dependent effect of DDX3X expression in the context of functional mosaic females versus one-copy males, which reflects the complex biological nature of DDX3X mutations.
Published: 2015

35. Large-scale discovery of novel genetic causes of developmental disorders

Author: Fitzgerald, TW, Gerety, SS, Jones, WD, van Kogelenberg, M, King, DA, McRae, J, Morley, KI, Parthiban, V, Al-Turki, S, Ambridge, K, Barrett, DM, Bayzetinova, T, Clayton, S, Coomber, EL, Gribble, S, Jones, P, Krishnappa, N, Mason, LE, Middleton, A, Miller, R, Prigmore, E, Rajan, D, Sifrim, A, Tivey, AR, Ahmed, M, Akawi, N, Andrews, R, Anjum, U, Archer, H, Armstrong, R, Balasubramanian, M, Banerjee, R, Baralle, D, Batstone, P, Baty, D, Bennett, C, Berg, J, Bernhard, B, Bevan, AP, Blair, E, Blyth, M, Bohanna, D, Bourdon, L, Bourn, D, Brady, A, Bragin, E, Brewer, C, Brueton, L, Brunstrom, K, Bumpstead, SJ, Bunyan, DJ, Burn, J, Burton, J, Canham, N, Castle, B, Chandler, K, Clasper, S, Clayton-Smith, J, Cole, T, Collins, A, Collinson, MN, Connell, F, Cooper, N, Cox, H, Cresswell, L, Cross, G, Crow, Y, D'Alessandro, M, Dabir, T, Davidson, R, Davies, S, Dean, J, Deshpande, C, Devlin, G, Dixit, A, Dominiczak, A, Donnelly, C, Donnelly, D, Douglas, A, Duncan, A, Eason, J, Edkins, S, Ellard, S, Ellis, P, Elmslie, F, Evans, K, Everest, S, Fendick, T, Fisher, R, Flinter, F, Foulds, N, Fryer, A, Fu, B, Gardiner, C, Gaunt, L, Ghali, N, Gibbons, R, Pereira, SLG, Goodship, J, Goudie, D, Gray, E, Greene, P, Greenhalgh, L, Harrison, L, Hawkins, R, Hellens, S, Henderson, A, Hobson, E, Holden, S, Holder, S, Hollingsworth, G, Homfray, T, Humphreys, M, Hurst, J, Ingram, S, Irving, M, Jarvis, J, Jenkins, L, Johnson, D, Jones, D, Jones, E, Josifova, D, Joss, S, Kaemba, B, Kazembe, S, Kerr, B, Kini, U, Kinning, E, Kirby, G, Kirk, C, Kivuva, E, Kraus, A, Kumar, D, Lachlan, K, Lam, W, Lampe, A, Langman, C, Lees, M, Lim, D, Lowther, G, Lynch, SA, Magee, A, Maher, E, Mansour, S, Marks, K, Martin, K, Maye, U, McCann, E, McConnell, V, McEntagart, M, McGowan, R, McKay, K, McKee, S, McMullan, DJ, McNerlan, S, Mehta, S, Metcalfe, K, Miles, E, Mohammed, S, Montgomery, T, Moore, D, Morgan, S, Morris, A, Morton, J, Mugalaasi, H, Murday, V, Nevitt, L, Newbury-Ecob, R, Norman, A, O'Shea, R, Ogilvie, C, Park, S, Parker, MJ, Patel, C, Paterson, J, Payne, S, Phipps, J, Pilz, DT, Porteous, D, Pratt, N, Prescott, K, Price, S, Pridham, A, Procter, A, Purnell, H, Ragge, N, Rankin, J, Raymond, L, Rice, D, Robert, L, Roberts, E, Roberts, G, Roberts, J, Roberts, P, Ross, A, Rosser, E, Saggar, A, Samant, S, Sandford, R, Sarkar, A, Schweier, S, Scott, C, Scott, R, Selby, A, Seller, A, Sequeira, C, Shannon, N, Shanrif, S, Shaw-Smith, C, Shearing, E, Shears, D, Simonic, I, Simpkin, D, Singzon, R, Skitt, Z, Smith, A, Smith, B, Smith, K, Smithson, S, Sneddon, L, Splitt, M, Squires, M, Stewart, F, Stewart, H, Suri, M, Sutton, V, Swaminathan, GJ, Sweeney, E, Tatton-Brown, K, Taylor, C, Taylor, R, Tein, M, Temple, IK, Thomson, J, Tolmie, J, Torokwa, A, Treacy, B, Turner, C, Turnpenny, P, Tysoe, C, Vandersteen, A, Vasudevan, P, Vogt, J, Wakeling, E, Walker, D, Waters, J, Weber, A, Wellesley, D, Whiteford, M, Widaa, S, Wilcox, S, Williams, D, Williams, N, Woods, G, Wragg, C, Wright, M, Yang, F, Yau, M, Carter, NP, Parker, M, Firth, HV, FitzPatrick, DR, Wright, CF, Barrett, JC, Hurles, ME, Fitzgerald, TW, Gerety, SS, Jones, WD, van Kogelenberg, M, King, DA, McRae, J, Morley, KI, Parthiban, V, Al-Turki, S, Ambridge, K, Barrett, DM, Bayzetinova, T, Clayton, S, Coomber, EL, Gribble, S, Jones, P, Krishnappa, N, Mason, LE, Middleton, A, Miller, R, Prigmore, E, Rajan, D, Sifrim, A, Tivey, AR, Ahmed, M, Akawi, N, Andrews, R, Anjum, U, Archer, H, Armstrong, R, Balasubramanian, M, Banerjee, R, Baralle, D, Batstone, P, Baty, D, Bennett, C, Berg, J, Bernhard, B, Bevan, AP, Blair, E, Blyth, M, Bohanna, D, Bourdon, L, Bourn, D, Brady, A, Bragin, E, Brewer, C, Brueton, L, Brunstrom, K, Bumpstead, SJ, Bunyan, DJ, Burn, J, Burton, J, Canham, N, Castle, B, Chandler, K, Clasper, S, Clayton-Smith, J, Cole, T, Collins, A, Collinson, MN, Connell, F, Cooper, N, Cox, H, Cresswell, L, Cross, G, Crow, Y, D'Alessandro, M, Dabir, T, Davidson, R, Davies, S, Dean, J, Deshpande, C, Devlin, G, Dixit, A, Dominiczak, A, Donnelly, C, Donnelly, D, Douglas, A, Duncan, A, Eason, J, Edkins, S, Ellard, S, Ellis, P, Elmslie, F, Evans, K, Everest, S, Fendick, T, Fisher, R, Flinter, F, Foulds, N, Fryer, A, Fu, B, Gardiner, C, Gaunt, L, Ghali, N, Gibbons, R, Pereira, SLG, Goodship, J, Goudie, D, Gray, E, Greene, P, Greenhalgh, L, Harrison, L, Hawkins, R, Hellens, S, Henderson, A, Hobson, E, Holden, S, Holder, S, Hollingsworth, G, Homfray, T, Humphreys, M, Hurst, J, Ingram, S, Irving, M, Jarvis, J, Jenkins, L, Johnson, D, Jones, D, Jones, E, Josifova, D, Joss, S, Kaemba, B, Kazembe, S, Kerr, B, Kini, U, Kinning, E, Kirby, G, Kirk, C, Kivuva, E, Kraus, A, Kumar, D, Lachlan, K, Lam, W, Lampe, A, Langman, C, Lees, M, Lim, D, Lowther, G, Lynch, SA, Magee, A, Maher, E, Mansour, S, Marks, K, Martin, K, Maye, U, McCann, E, McConnell, V, McEntagart, M, McGowan, R, McKay, K, McKee, S, McMullan, DJ, McNerlan, S, Mehta, S, Metcalfe, K, Miles, E, Mohammed, S, Montgomery, T, Moore, D, Morgan, S, Morris, A, Morton, J, Mugalaasi, H, Murday, V, Nevitt, L, Newbury-Ecob, R, Norman, A, O'Shea, R, Ogilvie, C, Park, S, Parker, MJ, Patel, C, Paterson, J, Payne, S, Phipps, J, Pilz, DT, Porteous, D, Pratt, N, Prescott, K, Price, S, Pridham, A, Procter, A, Purnell, H, Ragge, N, Rankin, J, Raymond, L, Rice, D, Robert, L, Roberts, E, Roberts, G, Roberts, J, Roberts, P, Ross, A, Rosser, E, Saggar, A, Samant, S, Sandford, R, Sarkar, A, Schweier, S, Scott, C, Scott, R, Selby, A, Seller, A, Sequeira, C, Shannon, N, Shanrif, S, Shaw-Smith, C, Shearing, E, Shears, D, Simonic, I, Simpkin, D, Singzon, R, Skitt, Z, Smith, A, Smith, B, Smith, K, Smithson, S, Sneddon, L, Splitt, M, Squires, M, Stewart, F, Stewart, H, Suri, M, Sutton, V, Swaminathan, GJ, Sweeney, E, Tatton-Brown, K, Taylor, C, Taylor, R, Tein, M, Temple, IK, Thomson, J, Tolmie, J, Torokwa, A, Treacy, B, Turner, C, Turnpenny, P, Tysoe, C, Vandersteen, A, Vasudevan, P, Vogt, J, Wakeling, E, Walker, D, Waters, J, Weber, A, Wellesley, D, Whiteford, M, Widaa, S, Wilcox, S, Williams, D, Williams, N, Woods, G, Wragg, C, Wright, M, Yang, F, Yau, M, Carter, NP, Parker, M, Firth, HV, FitzPatrick, DR, Wright, CF, Barrett, JC, and Hurles, ME
Abstract: Despite three decades of successful, predominantly phenotype-driven discovery of the genetic causes of monogenic disorders, up to half of children with severe developmental disorders of probable genetic origin remain without a genetic diagnosis. Particularly challenging are those disorders rare enough to have eluded recognition as a discrete clinical entity, those with highly variable clinical manifestations, and those that are difficult to distinguish from other, very similar, disorders. Here we demonstrate the power of using an unbiased genotype-driven approach to identify subsets of patients with similar disorders. By studying 1,133 children with severe, undiagnosed developmental disorders, and their parents, using a combination of exome sequencing and array-based detection of chromosomal rearrangements, we discovered 12 novel genes associated with developmental disorders. These newly implicated genes increase by 10% (from 28% to 31%) the proportion of children that could be diagnosed. Clustering of missense mutations in six of these newly implicated genes suggests that normal development is being perturbed by an activating or dominant-negative mechanism. Our findings demonstrate the value of adopting a comprehensive strategy, both genome-wide and nationwide, to elucidate the underlying causes of rare genetic disorders.
Published: 2015

36. hnRNP H binding at the 5' splice site correlates with the pathological effect of two intronic mutations in the NF-1 and TSHbeta genes

Author: BURATTI E, BARALLE M, DE CONTI L, BARALLE D, AYALA YM, BARALLE FE, ROMANO, MAURIZIO, Buratti, E, Baralle, M, DE CONTI, L, Baralle, D, Romano, Maurizio, Ayala, Ym, and Baralle, Fe
Subjects: Binding Sites Exons Genetic Predisposition to Disease Hela Cells Heterogeneous-Nuclear Ribonucleoprotein Group F-H/*metabolism Heterogeneous-Nuclear Ribonucleoproteins/metabolism Human Introns Model, beta Subunit/*genetics/metabolism, Genetic Neurofibromin 1/*genetics/metabolism *Point Mutation *RNA Splice Sites *RNA Splicing RNA, Binding Sites Exons Genetic Predisposition to Disease Hela Cells Heterogeneous-Nuclear Ribonucleoprotein Group F-H/*metabolism Heterogeneous-Nuclear Ribonucleoproteins/metabolism Human Introns Models, Messenger/chemistry/metabolism Ribonucleoprotein, U1 Small Nuclear/metabolism Support, Non-U.S. Gov't Thyrotropin
Abstract: We have recently reported a disease-causing substitution (+5G > C) at the donor site of NF-1 exon 3 that produces its skipping. We have now studied in detail the splicing mechanism involved in analyzing RNA-protein complexes at several 5' splice sites. Characteristic protein patterns were observed by pulldown and band-shift/super-shift analysis. Here, we show that hnRNP H binds specifically to the wild-type GGGgu donor sequence of the NF-1 exon 3. Depletion analyses shows that this protein restricts the accessibility of U1 small nuclear ribonucleoprotein (U1snRNA) to the donor site. In this context, the +5G > C mutation abolishes both U1snRNP base pairing and the 5' splice site (5'ss) function. However, exon recognition in the mutant can be rescued by disrupting the binding of hnRNP H, demonstrating that this protein enhances the effects of the +5G > C substitution. Significantly, a similar situation was found for a second disease-causing +5G > A substitution in the 5'ss of TSHbeta exon 2, which harbors a GGgu donor sequence. Thus, the reason why similar nucleotide substitutions can be either neutral or very disruptive of splicing function can be explained by the presence of specific binding signatures depending on local contexts.
Published: 2004

37. ENIGMA - Evidence-based Network for the Interpretation of Germline Mutant Alleles: An international initiative to evaluate risk and clinical significance associated with sequence variation in BRCA1 and BRCA2 genes

Author: Spurdle, Ab, Healey, S, Devereau, A, Hogervorst, Fb, Monteiro, An, Nathanson, Kl, Radice, P, Stoppa Lyonnet, D, Tavtigian, S, Wappenschmidt, B, Couch, Fj, Goldgar, De, ENIGMA: Goldgar, D, Couch, F, Fackenthal, Jd, Thomassen, M, Teo, Sh, Hansen, Tv, Borg, Å, Eeles, R, Toland, A, Rogan, P, Guidugli, L, Brody, Lc, Brown, M, Kwong, A, Lei po CW, Nevanlinna, H, Garber, J, Foretova, L, Singer, Cf, Blok, Mj, Osorio, A, Kote Jarai, Z, Baralle, D, Vega, A, Blanco, A, Santamariña, M, Fachal, L, Nederlof, P, Peock, S, Pasini, Barbara, Tommasi, S, Lafferty, A, Ansari, A, Konstantopoulou, I, Pal, T, Simard, J, Bonetti, A, Varesco, L, Peissel, B, Evans, Dg, Foulkes, W, Szabo, C, van Asperen, C, Jonkers, J, Walker, L, Mitchell, G, Gutiérrez Enríquez, S, Diez, O, Millot, G, Fostira, F, Selkirk, C, Antoniou, A, Monteiro, A, Carvalho, M, Rubinstein, Ws, de la Hoya, M, Domchek, S, Caputo, S, Houdayer, C, Blanco, I, Lázaro, C, Whiley, P, Becker, A, Aretini, P, Eccles, D, Caldes, T, Viel, A, Izatt, L, Hogervorst, F, Nathanson, K, Pedersen, Is, Vreeswijk, M, Neuhausen, S, Yannoukakos, K, Tucker, K, Southey, M, Leary, J, Caligo, Ma, Gomez Garcia, E, Brandao, R, Lidereau, R, Montagna, M, Pertesi, M, Cornell, M, Rouleau, E, Sharan, S, Rahman, N, Lalloo, F, Weitzel, J, Campbell, J, Cummings, Machakova, E, Olopade, F, Godwin, A, Ozcelik, H, Seminara, D., Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), Genetica & Celbiologie, and RS: GROW - School for Oncology and Reproduction
Subjects: Evidence-based practice, unclassified variant, RNA Splicing, Genes, BRCA2, Genes, BRCA1, consortium, Breast Neoplasms, Biology, Article, Germline mutation, breast cancer, Risk Factors, Genetic variation, Genetics, medicine, Humans, Clinical significance, Genetic Predisposition to Disease, BRCA1/BRCA2, Genetic Testing, Allele, unclassified variants, Gene, Genetics (clinical), Alleles, Germ-Line Mutation, Genetic testing, Ovarian Neoplasms, medicine.diagnostic_test, Mechanism (biology), Genetic Variation, BRCA1, BRCA2, ovarian cancer, Germ Cells, Organization and Administration, Data Interpretation, Statistical, international collaboration, Practice Guidelines as Topic, Female, Algorithms
Abstract: As genetic testing for predisposition to human diseases has become an increasingly common practice in medicine, the need for clear interpretation of the test results is apparent. However, for many disease genes, including the breast cancer susceptibility genes BRCA1 and BRCA2, a significant fraction of tests results in the detection of a genetic variant for which disease association is not known. The finding of an "unclassified" variant (UV)/variant of uncertain significance (VUS) complicates genetic test reporting and counseling. As these variants are individually rare, a large collaboration of researchers and clinicians will facilitate studies to assess their association with cancer predisposition. It was with this in mind that the ENIGMA consortium (www.enigmaconsortium.org) was initiated in 2009. The membership is both international and interdisciplinary, and currently includes more than 100 research scientists and clinicians from 19 countries. Within ENIGMA, there are presently six working groups focused on the following topics: analysis, clinical, database, functional, tumor histopathology, and mRNA splicing. ENIGMA provides a mechanism to pool resources, exchange methods and data, and coordinately develop and apply algorithms for classification of variants in BRCA1 and BRCA2. It is envisaged that the research and clinical application of models developed by ENIGMA will be relevant to the interpretation of sequence variants in other disease genes. Hum Mutat 00:1-6, 2011. © 2011 Wiley Periodicals, Inc.
Published: 2011
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38. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes.

Author: Mefford, H.C., Sharp, A.J., Baker, C., Itsara, A., Jiang, Z., Buysse, K., Huang, S., Maloney, V.K., Crolla, J.A., Baralle, D., Collins, A., Mercer, C., Norga, K., Ravel, T. de, Devriendt, K., Bongers, E.M.H.F., Leeuw, N. de, Reardon, W., Gimelli, S., Bena, F., Hennekam, R.C.M., Male, A., Gaunt, L., Clayton-Smith, J., Simonic, I., Park, S.M., Mehta, S.G., Nik-Zainal, S., Woods, C.G., Firth, H.V., Parkin, G., Fichera, M., Reitano, S., Giudice, M. Lo, Li, K.E., Casuga, I., Broomer, A., Conrad, B., Schwerzmann, M., Raber, L., Gallati, S., Striano, P., Coppola, A., Tolmie, J.L., Tobias, E.S., Lilley, C., Armengol, L., Spysschaert, Y., Verloo, P., Coene, A. De, Goossens, L., Mortier, G., Speleman, F., Binsbergen, E. van, Nelen, M.R., Hochstenbach, R., Poot, M., Gallagher, L., Gill, M., McClellan, J., King, M.C., Regan, R., Skinner, C., Stevenson, R.E., Antonarakis, S.E., Chen, C., Estivill, X., Menten, B., Gimelli, G., Gribble, S.M., Schwartz, S., Sutcliffe, J.S., Walsh, T., Knight, S.J., Sebat, J., Romano, C, Schwartz, C.E., Veltman, J.A., Vries, L.B.A. de, Vermeesch, J.R., Barber, J.C., Willatt, L., Tassabehji, M., Eichler, E.E., Mefford, H.C., Sharp, A.J., Baker, C., Itsara, A., Jiang, Z., Buysse, K., Huang, S., Maloney, V.K., Crolla, J.A., Baralle, D., Collins, A., Mercer, C., Norga, K., Ravel, T. de, Devriendt, K., Bongers, E.M.H.F., Leeuw, N. de, Reardon, W., Gimelli, S., Bena, F., Hennekam, R.C.M., Male, A., Gaunt, L., Clayton-Smith, J., Simonic, I., Park, S.M., Mehta, S.G., Nik-Zainal, S., Woods, C.G., Firth, H.V., Parkin, G., Fichera, M., Reitano, S., Giudice, M. Lo, Li, K.E., Casuga, I., Broomer, A., Conrad, B., Schwerzmann, M., Raber, L., Gallati, S., Striano, P., Coppola, A., Tolmie, J.L., Tobias, E.S., Lilley, C., Armengol, L., Spysschaert, Y., Verloo, P., Coene, A. De, Goossens, L., Mortier, G., Speleman, F., Binsbergen, E. van, Nelen, M.R., Hochstenbach, R., Poot, M., Gallagher, L., Gill, M., McClellan, J., King, M.C., Regan, R., Skinner, C., Stevenson, R.E., Antonarakis, S.E., Chen, C., Estivill, X., Menten, B., Gimelli, G., Gribble, S.M., Schwartz, S., Sutcliffe, J.S., Walsh, T., Knight, S.J., Sebat, J., Romano, C, Schwartz, C.E., Veltman, J.A., Vries, L.B.A. de, Vermeesch, J.R., Barber, J.C., Willatt, L., Tassabehji, M., and Eichler, E.E.
Abstract: Contains fulltext : 71235.pdf (publisher's version ) (Open Access), BACKGROUND: Duplications and deletions in the human genome can cause disease or predispose persons to disease. Advances in technologies to detect these changes allow for the routine identification of submicroscopic imbalances in large numbers of patients. METHODS: We tested for the presence of microdeletions and microduplications at a specific region of chromosome 1q21.1 in two groups of patients with unexplained mental retardation, autism, or congenital anomalies and in unaffected persons. RESULTS: We identified 25 persons with a recurrent 1.35-Mb deletion within 1q21.1 from screening 5218 patients. The microdeletions had arisen de novo in eight patients, were inherited from a mildly affected parent in three patients, were inherited from an apparently unaffected parent in six patients, and were of unknown inheritance in eight patients. The deletion was absent in a series of 4737 control persons (P=1.1x10(-7)). We found considerable variability in the level of phenotypic expression of the microdeletion; phenotypes included mild-to-moderate mental retardation, microcephaly, cardiac abnormalities, and cataracts. The reciprocal duplication was enriched in nine children with mental retardation or autism spectrum disorder and other variable features (P=0.02). We identified three deletions and three duplications of the 1q21.1 region in an independent sample of 788 patients with mental retardation and congenital anomalies. CONCLUSIONS: We have identified recurrent molecular lesions that elude syndromic classification and whose disease manifestations must be considered in a broader context of development as opposed to being assigned to a specific disease. Clinical diagnosis in patients with these lesions may be most readily achieved on the basis of genotype rather than phenotype.
Published: 2008

39. Systematic screening of FBN1 gene unclassified missense variants for splice abnormalities

Author: Robinson, DO, primary, Lin, F, additional, Lyon, M, additional, Raponi, M, additional, Cross, E, additional, White, HE, additional, Cox, H, additional, Clayton-Smith, J, additional, and Baralle, D, additional
Published: 2011
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40. Novel Tandem Duplication in Exon 1 of the SNURF/SNRPN Gene in a Child with Transient Excessive Eating Behaviour and Weight Gain

Author: Naik, S., primary, Thomas, N.S., additional, Davies, J.H., additional, Lever, M., additional, Raponi, M., additional, Baralle, D., additional, Temple, I.K., additional, and Caliebe, A., additional
Published: 2011
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41. An intronic mutation in MLH1 associated with familial colon and breast cancer

Author: Bianchi, F., primary, Raponi, M., additional, Piva, F., additional, Viel, A., additional, Bearzi, I., additional, Galizia, E., additional, Bracci, R., additional, Belvederesi, L., additional, Loretelli, C., additional, Brugiati, C., additional, Corradini, F., additional, Baralle, D., additional, and Cellerino, R., additional
Published: 2010
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42. Expanding the tuberous sclerosis phenotype: mild disease caused by a TSC1 splicing mutation

Author: Blyth, M., primary, Raponi, M., additional, Treacy, R., additional, Raymond, F L., additional, Yates, J. R W, additional, and Baralle, D., additional
Published: 2010
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43. A prospective study of neurofibromatosis type 1 cancer incidence in the UK

Author: Walker, L, primary, Thompson, D, additional, Easton, D, additional, Ponder, B, additional, Ponder, M, additional, Frayling, I, additional, and Baralle, D, additional
Published: 2006
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44. Erratum: Corrigendum: A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size

Author: Bond, J, primary, Roberts, E, additional, Springel, K, additional, Lizarraga, S, additional, Scott, S, additional, Higgins, J, additional, Hampshire, D J, additional, Morrison, E E, additional, Leal, G F, additional, Silva, E O, additional, Costa, S M R, additional, Baralle, D, additional, Raponi, M, additional, Karbani, G, additional, Rashid, Y, additional, Jafri, H, additional, Bennett, C, additional, Corry, P, additional, Walsh, C A, additional, and Woods, C G, additional
Published: 2005
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45. L�ri-Weill syndrome associated with a pseudodicentric X;Y translocation chromosome and skewed X-inactivation: Implications for genetic counselling

Author: Baralle, D., primary, Willatt, L.R., additional, and Shears, D.J., additional
Published: 2000
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46. Linkage Analysis of Idiopathic Generalised Epilepsy in Families of Probands with Juvenile Myoclonic Epilepsy and Marker Loci in the Region of EPM 1 on Chromosome 21 q: Unverricht-Lundborg Disease and JME are not Allelic Variants

Author: Rees, M., primary, Curtis, D., additional, Parker, K., additional, Sundqvist, A., additional, Baralle, D., additional, Bespalova, I., additional, Burmeister, M., additional, Chung, E., additional, Gardiner, R., additional, and Whitehouse, W., additional
Published: 1994
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47. Novel Tandem Duplication in Exon 1 of the SNURF/SNRPN Gene in a Child with Transient Excessive Eating Behaviour and Weight Gain.

Author: Naik, S., Thomas, N.S., Davies, J.H., Lever, M., Raponi, M., Baralle, D., Temple, I.K., and Caliebe, A.
Published: 2012
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48. Linkage analysis of idiopathic generalized epilepsy (IGE) and marker loci on chromosome 6p in families of patients with juvenile myoclonic epilepsy: No evidence for an epilepsy locus in the HLA region

Author: Whitehouse, W. P., Rees, M., David Curtis, Sundqvist, A., Parker, K., Chung, E., Baralle, D., and Gardiner, R. M.
Subjects: Adult, Genetic Markers, Male, Polymorphism, Genetic, Adolescent, Genetic Linkage, Chromosome Mapping, Epilepsies, Myoclonic, Genes, Recessive, Pedigree, Major Histocompatibility Complex, Humans, Chromosomes, Human, Pair 6, Epilepsy, Generalized, Female, Lod Score, Child, Research Article, Genes, Dominant
Abstract: Evidence for a locus (EJM1) in the HLA region of chromosome 6p predisposing to idiopathic generalized epilepsy (IGE) in the families of patients with juvenile myoclonic epilepsy (JME) has been obtained in two previous studies of separately ascertained groups of kindreds. Linkage analysis has been undertaken in a third set of 25 families including a patient with JME and at least one first-degree relative with IGE. Family members were typed for eight polymorphic loci on chromosome 6p: F13A, D6S89, D6S109, D6S105, D6S10, C4B, DQA1/A2, and TCTE1. Pairwise and multipoint linkage analysis was carried out assuming autosomal dominant and autosomal recessive inheritance and age-dependent high or low penetrance. No significant evidence in favor of linkage was obtained at any locus. Multipoint linkage analysis generated significant exclusion data (lod score < -2.0) at HLA and for a region 10-30 cM telomeric to HLA, the extent of which varied with the level of penetrance assumed. These observations indicate that genetic heterogeneity exists within this epilepsy phenotype.

49. BRCA1 exon 11 a model of long exon splicing regulation

Author: Raponi M, Ld, Smith, Silipo M, Stuani C, Emanuele Buratti, and Baralle D

50. Propellant tank for telecommunication platforms

Author: BARALLE, D., primary and FOURNIER, J., additional
Published: 1989
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