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1. De novo variants in CNOT3 cause a variable neurodevelopmental disorder

Author: Martin, R., Splitt, M., Genevieve, D., Aten, E., Collins, A., de Bie, C. I., Faivre, L., Foulds, N., Giltay, J., Ibitoye, R., Joss, S., Kennedy, J., Kerr, B., Kivuva, E., Koopmans, M., Newbury-Ecob, R., Jean-Marçais, N., Peeters, E. A. J., Smithson, S., Tomkins, S., Tranmauthem, F., Piton, A., and van Haeringen, A.
Published: 2019
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2. Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition.

Author: Palmer, E.E., Pusch, M., Picollo, A., Forwood, C., Nguyen, M.H., Suckow, V., Gibbons, J., Hoff, A., Sigfrid, L., Megarbane, A., Nizon, M., Cogné, B., Beneteau, C., Alkuraya, F.S., Chedrawi, A., Hashem, M.O., Stamberger, H., Weckhuysen, S., Vanlander, A., Ceulemans, B., Rajagopalan, S., Nunn, K., Arpin, S., Raynaud, M., Motter, C.S., Ward-Melver, C., Janssens, K., Meuwissen, M., Beysen, D., Dikow, N., Grimmel, M., Haack, T.B., Clement, E., McTague, A., Hunt, D., Townshend, S., Ward, M., Richards, L.J., Simons, C., Costain, G., Dupuis, L., Mendoza-Londono, R., Dudding-Byth, T., Boyle, J., Saunders, C., Fleming, E., Chehadeh, S. El, Spitz, M.A., Piton, A., Gerard, B., bi Warde, M.T. A, Rea, G., McKenna, C., Douzgou, S., Banka, S., Akman, C., Bain, J.M., Sands, T.T., Wilson, G.N., Silvertooth, E.J., Miller, L., Lederer, D., Sachdev, R., Macintosh, R., Monestier, O., Karadurmus, D., Collins, F., Carter, M., Rohena, L., Willemsen, M.H., Ockeloen, C.W., Pfundt, R.P., Kroft, S.D., Field, M., Laranjeira, F.E.R., Fortuna, A.M., Soares, A.R., Michaud, V., Naudion, S., Golla, S., Weaver, D.D., Bird, L.M., Friedman, J., Clowes, V., Joss, S., Pölsler, L., Campeau, P.M., Blazo, M., Bijlsma, E.K., Rosenfeld, J.A., Beetz, C., Powis, Z., McWalter, K., Brandt, T., Torti, E., Mathot, M., Mohammad, S.S., Armstrong, R., Kalscheuer, V.M., Palmer, E.E., Pusch, M., Picollo, A., Forwood, C., Nguyen, M.H., Suckow, V., Gibbons, J., Hoff, A., Sigfrid, L., Megarbane, A., Nizon, M., Cogné, B., Beneteau, C., Alkuraya, F.S., Chedrawi, A., Hashem, M.O., Stamberger, H., Weckhuysen, S., Vanlander, A., Ceulemans, B., Rajagopalan, S., Nunn, K., Arpin, S., Raynaud, M., Motter, C.S., Ward-Melver, C., Janssens, K., Meuwissen, M., Beysen, D., Dikow, N., Grimmel, M., Haack, T.B., Clement, E., McTague, A., Hunt, D., Townshend, S., Ward, M., Richards, L.J., Simons, C., Costain, G., Dupuis, L., Mendoza-Londono, R., Dudding-Byth, T., Boyle, J., Saunders, C., Fleming, E., Chehadeh, S. El, Spitz, M.A., Piton, A., Gerard, B., bi Warde, M.T. A, Rea, G., McKenna, C., Douzgou, S., Banka, S., Akman, C., Bain, J.M., Sands, T.T., Wilson, G.N., Silvertooth, E.J., Miller, L., Lederer, D., Sachdev, R., Macintosh, R., Monestier, O., Karadurmus, D., Collins, F., Carter, M., Rohena, L., Willemsen, M.H., Ockeloen, C.W., Pfundt, R.P., Kroft, S.D., Field, M., Laranjeira, F.E.R., Fortuna, A.M., Soares, A.R., Michaud, V., Naudion, S., Golla, S., Weaver, D.D., Bird, L.M., Friedman, J., Clowes, V., Joss, S., Pölsler, L., Campeau, P.M., Blazo, M., Bijlsma, E.K., Rosenfeld, J.A., Beetz, C., Powis, Z., McWalter, K., Brandt, T., Torti, E., Mathot, M., Mohammad, S.S., Armstrong, R., and Kalscheuer, V.M.
Abstract: 01 februari 2023, Item does not contain fulltext, Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.
Published: 2023

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

Author: Rots, D., Jakub, T.E., Keung, C., Jackson, A., Banka, S., Pfundt, R.P., Vries, B.B.A. de, Jaarsveld, R.H. van, Hopman, S.M.J., Binsbergen, E. van, Valenzuela, I., Hempel, M., Bierhals, T., Kortüm, F., Lecoquierre, F., Goldenberg, A., Hertz, J.M., Andersen, C.B., Kibæk, M., Prijoles, E.J., Stevenson, R.E., Everman, D.B., Patterson, W.G., Meng, L., Gijavanekar, C., Dios, K. De, Lakhani, S., Levy, T., Wagner, M., Wieczorek, D., Benke, P.J., Lopez Garcia, M.S., Perrier, R., Sousa, S.B., Almeida, P.M., Simões, M.J., Isidor, B., Deb, W., Schmanski, A.A., Abdul-Rahman, O., Philippe, C., Bruel, A.L., Faivre, L., Vitobello, A., Thauvin, C., Smits, J.J., Garavelli, L., Caraffi, S.G., Peluso, F., Davis-Keppen, L., Platt, D., Royer, E., Leeuwen, L van, Sinnema, M., Stegmann, A.P.A., Stumpel, C.T., Tiller, G.E., Bosch, D.G.M., Potgieter, S.T., Joss, S., Splitt, M., Holden, S., Prapa, M., Foulds, N., Douzgou, S., Puura, K., Waltes, R., Chiocchetti, A.G., Freitag, C.M., Satterstrom, F.K., Rubeis, S. de, Buxbaum, J., Gelb, B.D., Branko, A., Kushima, I., Howe, J., Scherer, S.W., Arado, A., Baldo, C., Patat, O., Bénédicte, D., Lopergolo, D., Santorelli, F.M., Haack, T.B., Dufke, A., Bertrand, M., Falb, R.J., Rieß, A., Krieg, P., Spranger, S., Bedeschi, M.F., Iascone, M., Josephi-Taylor, S., Roscioli, T., Buckley, M.F., Liebelt, J., Dagli, A.I., Aten, E., Hurst, A.C.E., Hicks, A., Suri, M., Aliu, E., Naik, S., Sidlow, R., Coursimault, J., Nicolas, G., Küpper, H., Petit, F., Ibrahim, V., Top, D., Cara, F. Di, Louie, R.J., Stolerman, E., Brunner, H.G., Vissers, L.E.L.M., Kramer, J.M., Kleefstra, T., Rots, D., Jakub, T.E., Keung, C., Jackson, A., Banka, S., Pfundt, R.P., Vries, B.B.A. de, Jaarsveld, R.H. van, Hopman, S.M.J., Binsbergen, E. van, Valenzuela, I., Hempel, M., Bierhals, T., Kortüm, F., Lecoquierre, F., Goldenberg, A., Hertz, J.M., Andersen, C.B., Kibæk, M., Prijoles, E.J., Stevenson, R.E., Everman, D.B., Patterson, W.G., Meng, L., Gijavanekar, C., Dios, K. De, Lakhani, S., Levy, T., Wagner, M., Wieczorek, D., Benke, P.J., Lopez Garcia, M.S., Perrier, R., Sousa, S.B., Almeida, P.M., Simões, M.J., Isidor, B., Deb, W., Schmanski, A.A., Abdul-Rahman, O., Philippe, C., Bruel, A.L., Faivre, L., Vitobello, A., Thauvin, C., Smits, J.J., Garavelli, L., Caraffi, S.G., Peluso, F., Davis-Keppen, L., Platt, D., Royer, E., Leeuwen, L van, Sinnema, M., Stegmann, A.P.A., Stumpel, C.T., Tiller, G.E., Bosch, D.G.M., Potgieter, S.T., Joss, S., Splitt, M., Holden, S., Prapa, M., Foulds, N., Douzgou, S., Puura, K., Waltes, R., Chiocchetti, A.G., Freitag, C.M., Satterstrom, F.K., Rubeis, S. de, Buxbaum, J., Gelb, B.D., Branko, A., Kushima, I., Howe, J., Scherer, S.W., Arado, A., Baldo, C., Patat, O., Bénédicte, D., Lopergolo, D., Santorelli, F.M., Haack, T.B., Dufke, A., Bertrand, M., Falb, R.J., Rieß, A., Krieg, P., Spranger, S., Bedeschi, M.F., Iascone, M., Josephi-Taylor, S., Roscioli, T., Buckley, M.F., Liebelt, J., Dagli, A.I., Aten, E., Hurst, A.C.E., Hicks, A., Suri, M., Aliu, E., Naik, S., Sidlow, R., Coursimault, J., Nicolas, G., Küpper, H., Petit, F., Ibrahim, V., Top, D., Cara, F. Di, Louie, R.J., Stolerman, E., Brunner, H.G., Vissers, L.E.L.M., Kramer, J.M., and Kleefstra, T.
Abstract: Item does not contain fulltext, De novo variants are a leading cause of neurodevelopmental disorders (NDDs), but because every monogenic NDD is different and usually extremely rare, it remains a major challenge to understand the complete phenotype and genotype spectrum of any morbid gene. According to OMIM, heterozygous variants in KDM6B cause "neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities." Here, by examining the molecular and clinical spectrum of 85 reported individuals with mostly de novo (likely) pathogenic KDM6B variants, we demonstrate that this description is inaccurate and potentially misleading. Cognitive deficits are seen consistently in all individuals, but the overall phenotype is highly variable. Notably, coarse facies and distal skeletal anomalies, as defined by OMIM, are rare in this expanded cohort while other features are unexpectedly common (e.g., hypotonia, psychosis, etc.). Using 3D protein structure analysis and an innovative dual Drosophila gain-of-function assay, we demonstrated a disruptive effect of 11 missense/in-frame indels located in or near the enzymatic JmJC or Zn-containing domain of KDM6B. Consistent with the role of KDM6B in human cognition, we demonstrated a role for the Drosophila KDM6B ortholog in memory and behavior. Taken together, we accurately define the broad clinical spectrum of the KDM6B-related NDD, introduce an innovative functional testing paradigm for the assessment of KDM6B variants, and demonstrate a conserved role for KDM6B in cognition and behavior. Our study demonstrates the critical importance of international collaboration, sharing of clinical data, and rigorous functional analysis of genetic variants to ensure correct disease diagnosis for rare disorders.
Published: 2023

4. Situated, yet silent: data relations in smart street furniture

Author: Gangneux, J., Joss, S., Humphry, J., Hanchard, M., Maalsen, S., Merrington, P., and Wessels, B.
Abstract: This article provides new evidence of the ways that smart cities materialize within specific sites and contexts through smart street furniture (SSF). Drawing on empirical data generated through mixed-method field research, the article examines the situated data relations that emerge in the context of the adoption of InLinkUK smart kiosks in Glasgow and Strawberry Energy smart benches in London. The concept of “silences” is proposed to analyze insufficiently articulated data relations resulting from gaps or absences in the use, design, and governance of this new type of urban furniture. The argument made is that data silences lead to failures to account for decisions and the deferral of responsibilities regarding the data aspects of these objects. It is suggested that an approach that focuses on “listening” to and “speaking” about data relations can enable dialogical forms of accountability, and realize the potential of SSF for citizens in local contexts.
Published: 2022

5. Expanding the genotype and phenotype spectrum of SYT1-associated neurodevelopmental disorder

Author: Melland, H, Bumbak, F, Kolesnik-Taylor, A, Ng-Cordell, E, John, A, Constantinou, P, Joss, S, Larsen, M, Fagerberg, C, Laulund, LW, Thies, J, Emslie, F, Willemsen, M, Kleefstra, T, Pfundt, R, Barrick, R, Chang, R, Loong, L, Alfadhel, M, van der Smagt, J, Nizon, M, Kurian, MA, Scott, DJ, Ziarek, JJ, Gordon, SL, Baker, K, Melland, H, Bumbak, F, Kolesnik-Taylor, A, Ng-Cordell, E, John, A, Constantinou, P, Joss, S, Larsen, M, Fagerberg, C, Laulund, LW, Thies, J, Emslie, F, Willemsen, M, Kleefstra, T, Pfundt, R, Barrick, R, Chang, R, Loong, L, Alfadhel, M, van der Smagt, J, Nizon, M, Kurian, MA, Scott, DJ, Ziarek, JJ, Gordon, SL, and Baker, K
Abstract: PURPOSE: Synaptotagmin-1 (SYT1) is a critical mediator of neurotransmitter release in the central nervous system. Previously reported missense SYT1 variants in the C2B domain are associated with severe intellectual disability, movement disorders, behavioral disturbances, and electroencephalogram abnormalities. In this study, we expand the genotypes and phenotypes and identify discriminating features of this disorder. METHODS: We describe 22 individuals with 15 de novo missense SYT1 variants. The evidence for pathogenicity is discussed, including the American College of Medical Genetics and Genomics/Association for Molecular Pathology criteria, known structure-function relationships, and molecular dynamics simulations. Quantitative behavioral data for 14 cases were compared with other monogenic neurodevelopmental disorders. RESULTS: Four variants were located in the C2A domain with the remainder in the C2B domain. We classified 6 variants as pathogenic, 4 as likely pathogenic, and 5 as variants of uncertain significance. Prevalent clinical phenotypes included delayed developmental milestones, abnormal eye physiology, movement disorders, and sleep disturbances. Discriminating behavioral characteristics were severity of motor and communication impairment, presence of motor stereotypies, and mood instability. CONCLUSION: Neurodevelopmental disorder-associated SYT1 variants extend beyond previously reported regions, and the phenotypic spectrum encompasses a broader range of severities than initially reported. This study guides the diagnosis and molecular understanding of this rare neurodevelopmental disorder and highlights a key role for SYT1 function in emotional regulation, motor control, and emergent cognitive function.
Published: 2022

6. Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants

Author: Kayumi, S, Perez-Jurado, LA, Palomares, M, Rangu, S, Sheppard, SE, Chung, WK, Kruer, MC, Kharbanda, M, Amor, DJ, McGillivray, G, Cohen, JS, Garcia-Minaur, S, van Eyk, CL, Harper, K, Jolly, LA, Webber, DL, Barnett, CP, Santos-Simarro, F, Pacio-Miguez, M, del Pozo, A, Bakhtiari, S, Deardorff, M, Dubbs, HA, Izumi, K, Grand, K, Gray, C, Mark, PR, Bhoj, EJ, Li, D, Ortiz-Gonzalez, XR, Keena, B, Zackai, EH, Goldberg, EM, de Nanclares, GP, Pereda, A, Llano-Rivas, I, Arroyo, I, Fernandez-Cuesta, MA, Thauvin-Robinet, C, Faivre, L, Garde, A, Mazel, B, Bruel, A-L, Tress, ML, Brilstra, E, Fine, AS, Crompton, KE, Stegmann, APA, Sinnema, M, Stevens, SCJ, Nicolai, J, Lesca, G, Lion-Francois, L, Haye, D, Chatron, N, Piton, A, Nizon, M, Cogne, B, Srivastava, S, Bassetti, J, Muss, C, Gripp, KW, Procopio, RA, Millan, F, Morrow, MM, Assaf, M, Moreno-De-Luca, A, Joss, S, Hamilton, MJ, Bertoli, M, Foulds, N, McKee, S, MacLennan, AH, Gecz, J, Corbett, MA, Kayumi, S, Perez-Jurado, LA, Palomares, M, Rangu, S, Sheppard, SE, Chung, WK, Kruer, MC, Kharbanda, M, Amor, DJ, McGillivray, G, Cohen, JS, Garcia-Minaur, S, van Eyk, CL, Harper, K, Jolly, LA, Webber, DL, Barnett, CP, Santos-Simarro, F, Pacio-Miguez, M, del Pozo, A, Bakhtiari, S, Deardorff, M, Dubbs, HA, Izumi, K, Grand, K, Gray, C, Mark, PR, Bhoj, EJ, Li, D, Ortiz-Gonzalez, XR, Keena, B, Zackai, EH, Goldberg, EM, de Nanclares, GP, Pereda, A, Llano-Rivas, I, Arroyo, I, Fernandez-Cuesta, MA, Thauvin-Robinet, C, Faivre, L, Garde, A, Mazel, B, Bruel, A-L, Tress, ML, Brilstra, E, Fine, AS, Crompton, KE, Stegmann, APA, Sinnema, M, Stevens, SCJ, Nicolai, J, Lesca, G, Lion-Francois, L, Haye, D, Chatron, N, Piton, A, Nizon, M, Cogne, B, Srivastava, S, Bassetti, J, Muss, C, Gripp, KW, Procopio, RA, Millan, F, Morrow, MM, Assaf, M, Moreno-De-Luca, A, Joss, S, Hamilton, MJ, Bertoli, M, Foulds, N, McKee, S, MacLennan, AH, Gecz, J, and Corbett, MA
Abstract: PURPOSE: Germline loss-of-function variants in CTNNB1 cause neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; OMIM 615075) and are the most frequent, recurrent monogenic cause of cerebral palsy (CP). We investigated the range of clinical phenotypes owing to disruptions of CTNNB1 to determine the association between NEDSDV and CP. METHODS: Genetic information from 404 individuals with collectively 392 pathogenic CTNNB1 variants were ascertained for the study. From these, detailed phenotypes for 52 previously unpublished individuals were collected and combined with 68 previously published individuals with comparable clinical information. The functional effects of selected CTNNB1 missense variants were assessed using TOPFlash assay. RESULTS: The phenotypes associated with pathogenic CTNNB1 variants were similar. A diagnosis of CP was not significantly associated with any set of traits that defined a specific phenotypic subgroup, indicating that CP is not additional to NEDSDV. Two CTNNB1 missense variants were dominant negative regulators of WNT signaling, highlighting the utility of the TOPFlash assay to functionally assess variants. CONCLUSION: NEDSDV is a clinically homogeneous disorder irrespective of initial clinical diagnoses, including CP, or entry points for genetic testing.
Published: 2022

7. The design and public imaginaries of smart street furniture

Author: Humphry, J., Maalsen, S., Gangneux, J., Chesher, C., Hanchard, M., Joss, S., Merrington, P., Wessels, B., and Flynn, S.
Published: 2022

8. X-linked congenital ptosis and associated intellectual disability, short stature, microcephaly, cleft palate, digital and genital abnormalities define novel Xq25q26 duplication syndrome

Author: Møller, R. S., Jensen, L. R., Maas, S. M., Filmus, J., Capurro, M., Hansen, C., Marcelis, C. L. M., Ravn, K., Andrieux, J., Mathieu, M., Kirchhoff, M., Rødningen, O. K., de Leeuw, N., Yntema, H. G., Froyen, G., Vandewalle, J., Ballon, K., Klopocki, E., Joss, S., Tolmie, J., Knegt, A. C., Lund, A. M., Hjalgrim, H., Kuss, A. W., Tommerup, N., Ullmann, R., de Brouwer, A. P. M., Strømme, P., Kjaergaard, S., Tümer, Z., and Kleefstra, T.
Published: 2014
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9. 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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10. Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction

Author: Hoed, J. den, Boer, E. de, Voisin, N., Dingemans, A.J.M., Guex, N., Wiel, L.J.M. van de, Nellaker, C., Amudhavalli, S.M., Banka, S., Bena, F.S., Ben-Zeev, B., Bonagura, V.R., Bruel, A.L., Brunet, T., Brunner, H.G., Chew, H.B., Chrast, J., Cimbalistienė, L., Coon, H., Délot, E.C., Démurger, F., Denommé-Pichon, A.S., Depienne, C., Donnai, D., Dyment, D.A., Elpeleg, O., Faivre, L., Gilissen, C.F., Granger, L., Haber, B., Hachiya, Y., Abedi, Y.H., Hanebeck, J., Hehir-Kwa, J.Y., Horist, B., Itai, T., Jackson, A., Jewell, R., Jones, K.L., Joss, S., Kashii, H., Kato, M., Kattentidt-Mouravieva, A.A., Kok, F., Kotzaeridou, U., Krishnamurthy, V., Kučinskas, V., Kuechler, A., Lavillaureix, A., Liu, P, Manwaring, L., Matsumoto, N., Mazel, B., McWalter, K., Meiner, V., Mikati, M.A., Miyatake, S., Mizuguchi, T., Moey, L.H., Mohammed, S, Mor-Shaked, H., Mountford, H., Newbury-Ecob, R., Odent, S., Orec, L., Osmond, M., Palculict, T.B., Parker, M., Petersen, A.K., Pfundt, R.P., Preikšaitienė, E., Radtke, K., Ranza, E., Rosenfeld, J.A., Santiago-Sim, T., Schwager, C., Sinnema, M., Snijders Blok, L., Spillmann, R.C., Stegmann, A.P.A., Thiffault, I., Tran, L., Vaknin-Dembinsky, A., Vedovato-Dos-Santos, J.H., Schrier Vergano, S.A., Vilain, E., Vitobello, A., Wagner, M., Waheeb, A., Willing, M., Zuccarelli, B., Kini, U., Newbury, D.F., Kleefstra, T., Reymond, A., Fisher, S.E., Vissers, L.E.L.M., Hoed, J. den, Boer, E. de, Voisin, N., Dingemans, A.J.M., Guex, N., Wiel, L.J.M. van de, Nellaker, C., Amudhavalli, S.M., Banka, S., Bena, F.S., Ben-Zeev, B., Bonagura, V.R., Bruel, A.L., Brunet, T., Brunner, H.G., Chew, H.B., Chrast, J., Cimbalistienė, L., Coon, H., Délot, E.C., Démurger, F., Denommé-Pichon, A.S., Depienne, C., Donnai, D., Dyment, D.A., Elpeleg, O., Faivre, L., Gilissen, C.F., Granger, L., Haber, B., Hachiya, Y., Abedi, Y.H., Hanebeck, J., Hehir-Kwa, J.Y., Horist, B., Itai, T., Jackson, A., Jewell, R., Jones, K.L., Joss, S., Kashii, H., Kato, M., Kattentidt-Mouravieva, A.A., Kok, F., Kotzaeridou, U., Krishnamurthy, V., Kučinskas, V., Kuechler, A., Lavillaureix, A., Liu, P, Manwaring, L., Matsumoto, N., Mazel, B., McWalter, K., Meiner, V., Mikati, M.A., Miyatake, S., Mizuguchi, T., Moey, L.H., Mohammed, S, Mor-Shaked, H., Mountford, H., Newbury-Ecob, R., Odent, S., Orec, L., Osmond, M., Palculict, T.B., Parker, M., Petersen, A.K., Pfundt, R.P., Preikšaitienė, E., Radtke, K., Ranza, E., Rosenfeld, J.A., Santiago-Sim, T., Schwager, C., Sinnema, M., Snijders Blok, L., Spillmann, R.C., Stegmann, A.P.A., Thiffault, I., Tran, L., Vaknin-Dembinsky, A., Vedovato-Dos-Santos, J.H., Schrier Vergano, S.A., Vilain, E., Vitobello, A., Wagner, M., Waheeb, A., Willing, M., Zuccarelli, B., Kini, U., Newbury, D.F., Kleefstra, T., Reymond, A., Fisher, S.E., and Vissers, L.E.L.M.
Abstract: Contains fulltext : 231687.pdf (Publisher’s version ) (Closed access), Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.
Published: 2021

11. KAT6A Syndrome

Author: Kennedy, J., Goudie, D., Blair, E., Chandler, K., Joss, S., McKay, V., Green, A., Armstrong, R., Lees, M., Kamien, B., Hopper, B., Tan, T.Y., Yap, P., Stark, Z., Okamoto, N., Miyake, N., Matsumoto, N., Macnamara, E., Murphy, J.L., McCormick, E., Hakonarson, H., Falk, M.J., Li, D., Blackburn, P., Klee, E., Babovic-Vuksanovic, D., Schelley, S., Hudgins, L., Kant, S., Isidor, B., Cogne, B., Bradbury, K., Williams, M., Patel, C., Heussler, H., Duff-Farrier, C., Lakeman, P., Scurr, I., Kini, U., Elting, M., Reijnders, M., Schuurs-Hoeijmakers, J., Wafik, M., Blomhoff, A., Ruivenkamp, C.A.L., Nibbeling, E., Dingemans, A.J.M., Douine, E.D., Nelson, S.F., Hempel, M., Bierhals, T., Lessel, D., Johannsen, J., Arboleda, V.A., Newbury-Ecob, R., and DDD Study
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Published: 2020

12. An intellectual disability syndrome with single-nucleotide variants in O-GlcNAc transferase

Author: Pravata, V.M., Omelková, M., Stavridis, M.P., Desbiens, C.M., Stephen, H.M., Lefeber, D.J., Gecz, J., Gundogdu, M., Õunap, K., Joss, S., Schwartz, C.E., Wells, L., Aalten, D.M.F. van, Pravata, V.M., Omelková, M., Stavridis, M.P., Desbiens, C.M., Stephen, H.M., Lefeber, D.J., Gecz, J., Gundogdu, M., Õunap, K., Joss, S., Schwartz, C.E., Wells, L., and Aalten, D.M.F. van
Abstract: Contains fulltext : 220584.pdf (Publisher’s version ) (Open Access), Intellectual disability (ID) is a neurodevelopmental condition that affects ~1% of the world population. In total 5-10% of ID cases are due to variants in genes located on the X chromosome. Recently, variants in OGT have been shown to co-segregate with X-linked intellectual disability (XLID) in multiple families. OGT encodes O-GlcNAc transferase (OGT), an essential enzyme that catalyses O-linked glycosylation with β-N-acetylglucosamine (O-GlcNAc) on serine/threonine residues of thousands of nuclear and cytosolic proteins. In this review, we compile the work from the last few years that clearly delineates a new syndromic form of ID, which we propose to classify as a novel Congenital Disorder of Glycosylation (OGT-CDG). We discuss potential hypotheses for the underpinning molecular mechanism(s) that provide impetus for future research studies geared towards informed interventions.
Published: 2020

13. MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis

Author: Mak, C.C., Doherty, D., Lin, A.E., Vegas, N., Cho, M.T., Viot, G., Dimartino, C., Weisfeld-Adams, J.D., Lessel, D., Joss, S., Li, C., Gonzaga-Jauregui, C., Zarate, Y.A., Ehmke, N., Horn, D., Troyer, C., Kant, S.G., Lee, Y., Ishak, G.E., Leung, G., Pritchard, A. Barone, Yang, S., Bend, E.G., Filippini, F., Roadhouse, C., Lebrun, N., Mehaffey, M.G., Martin, P.M., Apple, B., Millan, F., Puk, O., Hoffer, M.J.V., Henderson, L.B., McGowan, R., Wentzensen, I.M., Pei, S., Zahir, F.R., Yu, M., Gibson, W.T., Seman, A., Steeves, M., Murrell, J.R., Luettgen, S., Francisco, E., Strom, T.M., Amlie-Wolf, L., Kaindl, A.M., Wilson, W.G., Halbach, S., Basel-Salmon, L., Lev-El, N., Denecke, J., Vissers, L.E.L.M., Radtke, K., Chelly, J., Zackai, E., Friedman, J.M., Bamshad, M.J., Nickerson, D.A., Reid, R.R., Devriendt, K., Chae, J.H., Stolerman, E., McDougall, C., Powis, Z., Bienvenu, T., Tan, T.Y., Orenstein, N., Dobyns, W.B., Shieh, J.T., Choi, M., Waggoner, D., Gripp, K.W., Parker, M.J., Stoler, J., Lyonnet, S., Cormier-Daire, V., Viskochil, D., Hoffman, T.L., Amiel, J., Chung, B.H., Gordon, C.T., Mak, C.C., Doherty, D., Lin, A.E., Vegas, N., Cho, M.T., Viot, G., Dimartino, C., Weisfeld-Adams, J.D., Lessel, D., Joss, S., Li, C., Gonzaga-Jauregui, C., Zarate, Y.A., Ehmke, N., Horn, D., Troyer, C., Kant, S.G., Lee, Y., Ishak, G.E., Leung, G., Pritchard, A. Barone, Yang, S., Bend, E.G., Filippini, F., Roadhouse, C., Lebrun, N., Mehaffey, M.G., Martin, P.M., Apple, B., Millan, F., Puk, O., Hoffer, M.J.V., Henderson, L.B., McGowan, R., Wentzensen, I.M., Pei, S., Zahir, F.R., Yu, M., Gibson, W.T., Seman, A., Steeves, M., Murrell, J.R., Luettgen, S., Francisco, E., Strom, T.M., Amlie-Wolf, L., Kaindl, A.M., Wilson, W.G., Halbach, S., Basel-Salmon, L., Lev-El, N., Denecke, J., Vissers, L.E.L.M., Radtke, K., Chelly, J., Zackai, E., Friedman, J.M., Bamshad, M.J., Nickerson, D.A., Reid, R.R., Devriendt, K., Chae, J.H., Stolerman, E., McDougall, C., Powis, Z., Bienvenu, T., Tan, T.Y., Orenstein, N., Dobyns, W.B., Shieh, J.T., Choi, M., Waggoner, D., Gripp, K.W., Parker, M.J., Stoler, J., Lyonnet, S., Cormier-Daire, V., Viskochil, D., Hoffman, T.L., Amiel, J., Chung, B.H., and Gordon, C.T.
Abstract: Contains fulltext : 218289.pdf (Publisher’s version ) (Closed access), MN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions encompassing MN1 have been reported in individuals with variable neurodevelopmental anomalies and non-specific facial features. We identified a cluster of de novo truncating mutations in MN1 in a cohort of 23 individuals with strikingly similar dysmorphic facial features, especially midface hypoplasia, and intellectual disability with severe expressive language delay. Imaging revealed an atypical form of rhombencephalosynapsis, a distinctive brain malformation characterized by partial or complete loss of the cerebellar vermis with fusion of the cerebellar hemispheres, in 8/10 individuals. Rhombencephalosynapsis has no previously known definitive genetic or environmental causes. Other frequent features included perisylvian polymicrogyria, abnormal posterior clinoid processes and persistent trigeminal artery. MN1 is encoded by only two exons. All mutations, including the recurrent variant p.Arg1295* observed in 8/21 probands, fall in the terminal exon or the extreme 3' region of exon 1, and are therefore predicted to result in escape from nonsense-mediated mRNA decay. This was confirmed in fibroblasts from three individuals. We propose that the condition described here, MN1 C-terminal truncation (MCTT) syndrome, is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein. Our data show that MN1 plays a critical role in human craniofacial and brain development, and opens the door to understanding the biological mechanisms underlying rhombencephalosynapsis.
Published: 2020

14. Urban Governance for a Sustainable Future

Author: Davidson, K, Nagendra, H, van der Heijden, J, Kundu, D, Joss, S, Santos, AADS, Abrahams, C, Zhang, X, Davidson, K, Nagendra, H, van der Heijden, J, Kundu, D, Joss, S, Santos, AADS, Abrahams, C, and Zhang, X
Abstract: Cities have the potential to lead the way to a cleaner, greener, more inclusive future, but this cannot be achieved without effective leadership and governance. Here, we ask experts to reflect upon the governance challenges on the way to a sustainable urban world.
Published: 2020

15. Delineation of dominant and recessive forms of LZTR1‐associated Noonan syndrome

Author: Pagnamenta, A, Kaisaki, P, Bennett, F, Burkitt-Wright, E, Martin, H, Ferla, M, Taylor, J, Gompertz, L, Lahiri, N, Tatton-Brown, K, Newbury-Ecob, R, Henderson, A, Joss, S, Weber, A, Carmichael, J, Turnpenny, P, McKee, S, Forzano, F, Ashraf, T, Bradbury, K, Shears, D, Kini, U, De Burca, A, Study, The DDD, Blair, E, and Stewart, H
Subjects: Male, Heterozygote, Adolescent, Infant, Genes, Recessive, Original Articles, Pedigree, Cohort Studies, Gene Ontology, Phenotype, Child, Preschool, Mutation, RAS‐MAPK signalling, Humans, Noonan syndrome, Female, Original Article, Exome, LZTR1, Child, Alleles, developmental disorder, Transcription Factors, Genes, Dominant
Abstract: Noonan syndrome (NS) is characterised by distinctive facial features, heart defects, variable degrees of intellectual disability and other phenotypic manifestations. Although the mode of inheritance is typically dominant, recent studies indicate LZTR1 may be associated with both dominant and recessive forms. Seeking to describe the phenotypic characteristics of LZTR1‐associated NS, we searched for likely pathogenic variants using two approaches. First, scrutiny of exomes from 9624 patients recruited by the Deciphering Developmental Disorders (DDDs) study uncovered six dominantly‐acting mutations (p.R97L; p.Y136C; p.Y136H, p.N145I, p.S244C; p.G248R) of which five arose de novo, and three patients with compound‐heterozygous variants (p.R210*/p.V579M; p.R210*/p.D531N; c.1149+1G>T/p.R688C). One patient also had biallelic loss‐of‐function mutations in NEB, consistent with a composite phenotype. After removing this complex case, analysis of human phenotype ontology terms indicated significant phenotypic similarities (P = 0.0005), supporting a causal role for LZTR1. Second, targeted sequencing of eight unsolved NS‐like cases identified biallelic LZTR1 variants in three further subjects (p.W469*/p.Y749C, p.W437*/c.‐38T>A and p.A461D/p.I462T). Our study strengthens the association of LZTR1 with NS, with de novo mutations clustering around the KT1‐4 domains. Although LZTR1 variants explain ~0.1% of cases across the DDD cohort, the gene is a relatively common cause of unsolved NS cases where recessive inheritance is suspected.
Published: 2019

16. A nonsense mutation in the first transmembrane domain of connexin 43 underlies autosomal recessive oculodentodigital syndrome

Author: Richardson, R J, Joss, S, Tomkin, S, Ahmed, M, Sheridan, E, and Dixon, M J
Published: 2006

17. Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability

Author: Cogne, B., Ehresmann, S., Beauregard-Lacroix, E., Rousseau, J., Besnard, T., Garcia, T., Petrovski, S., Avni, S., McWalter, K., Blackburn, P.R., Sanders, S.J., Uguen, K., Harris, J., Cohen, J.S., Blyth, M., Lehman, A., Berg, J ., Li, M.H., Kini, U., Joss, S., Lippe, C., Gordon, C.T., Humberson, J.B., Robak, L., Scott, D.A., Sutton, V.R., Skraban, C.M., Johnston, J.J., Poduri, A., Nordenskjold, M., Shashi, V., Gerkes, E.H., Bongers, E.M.H.F., Gilissen, C.F., Zarate, Y.A., Kvarnung, M., Lally, K.P., Kulch, P.A., Daniels, B., Hernandez-Garcia, A., Stong, N., McGaughran, J., Retterer, K., Tveten, K., Sullivan, J., Geisheker, M.R., Stray-Pedersen, A., Tarpinian, J.M., Klee, E.W., Sapp, J.C., Zyskind, J., Holla, O.L., Bedoukian, E., Filippini, F., Guimier, A., Picard, A., Busk, O.L., Punetha, J., Pfundt, R.P., Lindstrand, A., Nordgren, A., Kalb, F., Desai, M., Ebanks, A.H., Jhangiani, S.N., Dewan, T., Akdemir, Z.H. Coban, Telegrafi, A., Zackai, E.H., Begtrup, A., Song, X., Toutain, A., Wentzensen, I.M., Odent, S., Bonneau, D., Latypova, X., Deb, W., Redon, S., Bilan, F., Legendre, M., Troyer, C., Whitlock, K., Caluseriu, O., Murphree, M.I., Pichurin, P.N., Agre, K., Gavrilova, R., Rinne, T.K., Park, M., Shain, C., Heinzen, E.L., Xiao, R., Amiel, J., Lyonnet, S., Isidor, B., Biesecker, L.G., Lowenstein, D., Posey, J.E., Denomme-Pichon, A.S., Ferec, C., et al., Cogne, B., Ehresmann, S., Beauregard-Lacroix, E., Rousseau, J., Besnard, T., Garcia, T., Petrovski, S., Avni, S., McWalter, K., Blackburn, P.R., Sanders, S.J., Uguen, K., Harris, J., Cohen, J.S., Blyth, M., Lehman, A., Berg, J ., Li, M.H., Kini, U., Joss, S., Lippe, C., Gordon, C.T., Humberson, J.B., Robak, L., Scott, D.A., Sutton, V.R., Skraban, C.M., Johnston, J.J., Poduri, A., Nordenskjold, M., Shashi, V., Gerkes, E.H., Bongers, E.M.H.F., Gilissen, C.F., Zarate, Y.A., Kvarnung, M., Lally, K.P., Kulch, P.A., Daniels, B., Hernandez-Garcia, A., Stong, N., McGaughran, J., Retterer, K., Tveten, K., Sullivan, J., Geisheker, M.R., Stray-Pedersen, A., Tarpinian, J.M., Klee, E.W., Sapp, J.C., Zyskind, J., Holla, O.L., Bedoukian, E., Filippini, F., Guimier, A., Picard, A., Busk, O.L., Punetha, J., Pfundt, R.P., Lindstrand, A., Nordgren, A., Kalb, F., Desai, M., Ebanks, A.H., Jhangiani, S.N., Dewan, T., Akdemir, Z.H. Coban, Telegrafi, A., Zackai, E.H., Begtrup, A., Song, X., Toutain, A., Wentzensen, I.M., Odent, S., Bonneau, D., Latypova, X., Deb, W., Redon, S., Bilan, F., Legendre, M., Troyer, C., Whitlock, K., Caluseriu, O., Murphree, M.I., Pichurin, P.N., Agre, K., Gavrilova, R., Rinne, T.K., Park, M., Shain, C., Heinzen, E.L., Xiao, R., Amiel, J., Lyonnet, S., Isidor, B., Biesecker, L.G., Lowenstein, D., Posey, J.E., Denomme-Pichon, A.S., and Ferec, C., et al.
Abstract: Contains fulltext : 202928.pdf (publisher's version ) (Open Access), Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.
Published: 2019

18. The phenotype of Sotos syndrome in adulthood: A review of 44 individuals

Author: Foster, A, Zachariou, A, Loveday, C, Ashraf, T, Blair, E, Clayton-Smith, J, Dorkins, H, Fryer, A, Gener, B, Goudie, D, Henderson, A, Irving, M, Joss, S, Keeley, V, Lahiri, N, Lynch, SA, Mansour, S, McCann, E, Morton, J, Motton, N, Murray, A, Riches, K, Shears, D, Stark, Z, Thompson, E, Vogt, J, Wright, M, Cole, T, Tatton-Brown, K, Foster, A, Zachariou, A, Loveday, C, Ashraf, T, Blair, E, Clayton-Smith, J, Dorkins, H, Fryer, A, Gener, B, Goudie, D, Henderson, A, Irving, M, Joss, S, Keeley, V, Lahiri, N, Lynch, SA, Mansour, S, McCann, E, Morton, J, Motton, N, Murray, A, Riches, K, Shears, D, Stark, Z, Thompson, E, Vogt, J, Wright, M, Cole, T, and Tatton-Brown, K
Abstract: Sotos syndrome is an overgrowth-intellectual disability (OGID) syndrome caused by NSD1 pathogenic variants and characterized by a distinctive facial appearance, an intellectual disability, tall stature and/or macrocephaly. Other associated clinical features include scoliosis, seizures, renal anomalies, and cardiac anomalies. However, many of the published Sotos syndrome clinical descriptions are based on studies of children; the phenotype in adults with Sotos syndrome is not yet well described. Given that it is now 17 years since disruption of NSD1 was shown to cause Sotos syndrome, many of the children first reported are now adults. It is therefore timely to investigate the phenotype of 44 adults with Sotos syndrome and NSD1 pathogenic variants. We have shown that adults with Sotos syndrome display a wide spectrum of intellectual ability with functioning ranging from fully independent to fully dependent. Reproductive rates are low. In our cohort, median height in adult women is +1.9 SD and men +0.5 SD. There is a distinctive facial appearance in adults with a tall, square, prominent chin. Reassuringly, adults with Sotos syndrome are generally healthy with few new medical issues; however, lymphedema, poor dentition, hearing loss, contractures and tremor have developed in a small number of individuals.
Published: 2019

19. De novo variants in CNOT3 cause a variable neurodevelopmental disorder

Author: Sectie Morfologie/CMC, Genetica Klinische Genetica, Child Health, Martin, R., Splitt, M., Genevieve, D., Aten, E., Collins, A., de Bie, C. I., Faivre, L., Foulds, N., Giltay, J., Ibitoye, R., Joss, S., Kennedy, J., Kerr, B., Kivuva, E., Koopmans, M., Newbury-Ecob, R., Jean-Marçais, N., Peeters, E. A.J., Smithson, S., Tomkins, S., Tranmauthem, F., Piton, A., van Haeringen, A., Sectie Morfologie/CMC, Genetica Klinische Genetica, Child Health, Martin, R., Splitt, M., Genevieve, D., Aten, E., Collins, A., de Bie, C. I., Faivre, L., Foulds, N., Giltay, J., Ibitoye, R., Joss, S., Kennedy, J., Kerr, B., Kivuva, E., Koopmans, M., Newbury-Ecob, R., Jean-Marçais, N., Peeters, E. A.J., Smithson, S., Tomkins, S., Tranmauthem, F., Piton, A., and van Haeringen, A.
Published: 2019

20. De novo translocation (1; 2)(q32; p25) associated with bilateral renal dysplasia

Author: Joss, S, Howatson, A, Trainer, A, Whiteford, M, and FitzPatrick, D R
Published: 2003

21. 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

22. 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

23. City branding in three Chinese mega-city regions: The role of ecological modernization

Author: Jong, Martin, Chen, Y, Joss, S, Lu, H, Zhao, M, Yang, Q, and Erasmus School of Law
Published: 2018

24. Inherited desmoplastic trichoepitheliomas

Author: Lovgren, M.‐L., Rajan, N., Joss, S., Melly, L., and Porter, M.
Subjects: Viewpoints in Dermatology, Viewpoints in dermatology ● Correspondence, Correspondence
Published: 2019

25. Finding Diagnostically Useful Patterns in Quantitative Phenotypic Data

Author: Aitken, Stuart, primary, Firth, Helen V., additional, McRae, Jeremy, additional, Halachev, Mihail, additional, Kini, Usha, additional, Parker, Michael J., additional, Lees, Melissa M., additional, Lachlan, Katherine, additional, Sarkar, Ajoy, additional, Joss, Shelagh, additional, Splitt, Miranda, additional, McKee, Shane, additional, Németh, Andrea H., additional, Scott, Richard H., additional, Wright, Caroline F., additional, Marsh, Joseph A., additional, Hurles, Matthew E., additional, FitzPatrick, David R., additional, Fitzgerald, T.W., additional, Gerety, S.S., additional, Jones, W.D., additional, van Kogelenberg, M., additional, King, D.A., additional, McRae, J., additional, Morley, K.I., additional, Parthiban, V., additional, Al-Turki, S., additional, Ambridge, K., additional, Barrett, D.M., additional, Bayzetinova, T., additional, Clayton, S., additional, Coomber, E.L., additional, Gribble, S., additional, Jones, P., additional, Krishnappa, N., additional, Mason, L.E., additional, Middleton, A., additional, Miller, R., additional, Prigmore, E., additional, Rajan, D., additional, Sifrim, A., additional, Tivey, A.R., additional, Ahmed, M., additional, Akawi, N., additional, Andrews, R., additional, Anjum, U., additional, Archer, H., additional, Armstrong, R., additional, Balasubramanian, M., additional, Banerjee, R., additional, Barelle, D., additional, Batstone, P., additional, Baty, D., additional, Bennett, C., additional, Berg, J., additional, Bernhard, B., additional, Bevan, A.P., additional, Blair, E., additional, Blyth, M., additional, Bohanna, D., additional, Bourdon, L., additional, Bourn, D., additional, Brady, A., additional, Bragin, E., additional, Brewer, C., additional, Brueton, L., additional, Brunstrom, K., additional, Bumpstead, S.J., additional, Bunyan, D.J., additional, Burn, J., additional, Burton, J., additional, Canham, N., additional, Castle, B., additional, Chandler, K., additional, Clasper, S., additional, Clayton-Smith, J., additional, Cole, T., additional, Collins, A., additional, Collinson, M.N., additional, Connell, F., additional, Cooper, N., additional, Cox, H., additional, Cresswell, L., additional, Cross, G., additional, Crow, Y., additional, D’Alessandro, P.M., additional, Dabir, T., additional, Davidson, R., additional, Davies, S., additional, Dean, J., additional, Deshpande, C., additional, Devlin, G., additional, Dixit, A., additional, Dominiczak, A., additional, Donnelly, C., additional, Donnelly, D., additional, Douglas, A., additional, Duncan, A., additional, Eason, J., additional, Edkins, S., additional, Ellard, S., additional, Ellis, P., additional, Elmslie, F., additional, Evans, K., additional, Everest, S., additional, Fendick, T., additional, Fisher, R., additional, Flinter, F., additional, Foulds, N., additional, Fryer, A., additional, Fu, B., additional, Gardiner, C., additional, Gaunt, L., additional, Ghali, N., additional, Gibbons, R., additional, Pereira, S.L. Gomes, additional, Goodship, J., additional, Goudie, D., additional, Gray, E., additional, Greene, P., additional, Greenhalgh, L., additional, Harrison, L., additional, Hawkins, R., additional, Hellens, S., additional, Henderson, A., additional, Hobson, E., additional, Holden, S., additional, Holder, S., additional, Hollingsworth, G., additional, Homfray, T., additional, Humphreys, M., additional, Hurst, J., additional, Ingram, S., additional, Irving, M., additional, Jarvis, J., additional, Jenkins, L., additional, Johnson, D., additional, Jones, D., additional, Jones, E., additional, Josifova, D., additional, Joss, S., additional, Kaemba, B., additional, Kazembe, S., additional, Kerr, B., additional, Kini, U., additional, Kinning, E., additional, Kirby, G., additional, Kirk, C., additional, Kivuva, E., additional, Kraus, A., additional, Kumar, D., additional, Lachlan, K., additional, Lam, W., additional, Lampe, A., additional, Langman, C., additional, Lees, M., additional, Lim, D., additional, Lowther, G., additional, Lynch, S.A., additional, Magee, A., additional, Maher, E., additional, Mansour, S., additional, Marks, K., additional, Martin, K., additional, Maye, U., additional, McCann, E., additional, McConnell, V., additional, McEntagart, M., additional, McGowan, R., additional, McKay, K., additional, McKee, S., additional, McMullan, D.J., additional, McNerlan, S., additional, Mehta, S., additional, Metcalfe, K., additional, Miles, E., additional, Mohammed, S., additional, Montgomery, T., additional, Moore, D., additional, Morgan, S., additional, Morris, A., additional, Morton, J., additional, Mugalaasi, H., additional, Murday, V., additional, Nevitt, L., additional, Newbury-Ecob, R., additional, Norman, A., additional, O’Shea, R., additional, Ogilvie, C., additional, Park, S., additional, Parker, M.J., additional, Patel, C., additional, Paterson, J., additional, Payne, S., additional, Phipps, J., additional, Pilz, D.T., additional, Porteous, D., additional, Pratt, N., additional, Prescott, K., additional, Price, S., additional, Pridham, A., additional, Proctor, A., additional, Purnell, H., additional, Ragge, N., additional, Rankin, J., additional, Raymond, L., additional, Rice, D., additional, Robert, L., additional, Roberts, E., additional, Roberts, G., additional, Roberts, J., additional, Roberts, P., additional, Ross, A., additional, Rosser, E., additional, Saggar, A., additional, Samant, S., additional, Sandford, R., additional, Sarkar, A., additional, Schweiger, S., additional, Scott, C., additional, Scott, R., additional, Selby, A., additional, Seller, A., additional, Sequeira, C., additional, Shannon, N., additional, Sharif, S., additional, Shaw-Smith, C., additional, Shearing, E., additional, Shears, D., additional, Simonic, I., additional, Simpkin, D., additional, Singzon, R., additional, Skitt, Z., additional, Smith, A., additional, Smith, B., additional, Smith, K., additional, Smithson, S., additional, Sneddon, L., additional, Splitt, M., additional, Squires, M., additional, Stewart, F., additional, Stewart, H., additional, Suri, M., additional, Sutton, V., additional, Swaminathan, G.J., additional, Sweeney, E., additional, Tatton-Brown, K., additional, Taylor, C., additional, Taylor, R., additional, Tein, M., additional, Temple, I.K., additional, Thomson, J., additional, Tolmie, J., additional, Torokwa, A., additional, Treacy, B., additional, Turner, C., additional, Turnpenny, P., additional, Tysoe, C., additional, Vandersteen, A., additional, Vasudevan, P., additional, Vogt, J., additional, Wakeling, E., additional, Walker, D., additional, Waters, J., additional, Weber, A., additional, Wellesley, D., additional, Whiteford, M., additional, Widaa, S., additional, Wilcox, S., additional, Williams, D., additional, Williams, N., additional, Woods, G., additional, Wragg, C., additional, Wright, M., additional, Yang, F., additional, Yau, M., additional, Carter, N.P., additional, Parker, M., additional, Firth, H.V., additional, FitzPatrick, D.R., additional, Wright, C.F., additional, Barrett, J.C., additional, and Hurles, M.E., additional
Published: 2019
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26. G150 Aetiological investigations and treatment outcomes in a prospective population-based cohort of children with epilepsy <3 years

Author: Symonds, JD, primary, Elliott, KS, additional, Knight, JC, additional, Brunklaus, A, additional, Joss, S, additional, MacLeod, S, additional, Pilz, DT, additional, and Zuberi, SM, additional
Published: 2019
Full Text: View/download PDF

27. De novo and inherited mutations in the X-linked gene CLCN4 are associated with syndromic intellectual disability and behavior and seizure disorders in males and females

Author: Palmer, EE, Stuhlmann, T, Weinert, S, Haan, E, Van Esch, H, Holvoet, M, Boyle, J, Leffler, M, Raynaud, M, Moraine, C, Van Bokhoven, H, Kleefstra, T, Kahrizi, K, Najmabadi, H, Ropers, HH, Delgado, MR, Sirsi, D, Golla, S, Sommer, A, Pietryga, MP, Chung, WK, Wynn, J, Rohena, L, Bernardo, E, Hamlin, D, Faux, BM, Grange, DK, Manwaring, L, Tolmie, J, Joss, S, Study, DDD, Cobben, JM, Duijkers, FAM, Goehringer, JM, Challman, TD, Hennig, F, Fischer, U, Grimme, A, Suckow, V, Musante, L, Nicholl, J, Shaw, M, Lodh, SP, Niu, Z, Rosenfeld, JA, Stankiewicz, P, Jentsch, TJ, Gecz, J, Field, M, Kalscheuer, VM, Palmer, EE, Stuhlmann, T, Weinert, S, Haan, E, Van Esch, H, Holvoet, M, Boyle, J, Leffler, M, Raynaud, M, Moraine, C, Van Bokhoven, H, Kleefstra, T, Kahrizi, K, Najmabadi, H, Ropers, HH, Delgado, MR, Sirsi, D, Golla, S, Sommer, A, Pietryga, MP, Chung, WK, Wynn, J, Rohena, L, Bernardo, E, Hamlin, D, Faux, BM, Grange, DK, Manwaring, L, Tolmie, J, Joss, S, Study, DDD, Cobben, JM, Duijkers, FAM, Goehringer, JM, Challman, TD, Hennig, F, Fischer, U, Grimme, A, Suckow, V, Musante, L, Nicholl, J, Shaw, M, Lodh, SP, Niu, Z, Rosenfeld, JA, Stankiewicz, P, Jentsch, TJ, Gecz, J, Field, M, and Kalscheuer, VM
Abstract: Variants in CLCN4, which encodes the chloride/hydrogen ion exchanger CIC-4 prominently expressed in brain, were recently described to cause X-linked intellectual disability and epilepsy. We present detailed phenotypic information on 52 individuals from 16 families with CLCN4-related disorder: 5 affected females and 2 affected males with a de novo variant in CLCN4 (6 individuals previously unreported) and 27 affected males, 3 affected females and 15 asymptomatic female carriers from 9 families with inherited CLCN4 variants (4 families previously unreported). Intellectual disability ranged from borderline to profound. Behavioral and psychiatric disorders were common in both child-and adulthood, and included autistic features, mood disorders, obsessive-compulsive behaviors and hetero-and autoaggression. Epilepsy was common, with severity ranging from epileptic encephalopathy to well-controlled seizures. Several affected individuals showed white matter changes on cerebral neuroimaging and progressive neurological symptoms, including movement disorders and spasticity. Heterozygous females can be as severely affected as males. The variability of symptoms in females is not correlated with the X inactivation pattern studied in their blood. The mutation spectrum includes frameshift, missense and splice site variants and one single-exon deletion. All missense variants were predicted to affect CLCN4's function based on in silico tools and either segregated with the phenotype in the family or were de novo. Pathogenicity of all previously unreported missense variants was further supported by electrophysiological studies in Xenopus laevis oocytes. We compare CLCN4-related disorder with conditions related to dysfunction of other members of the CLC family.
Published: 2018

28. Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort

Author: Meester, J.A.N., Sukalo, M., Schröder, K.C., Schanze, D., Baynam, G., Borck, G., Bramswig, N.C., Duman, D., Gilbert-Dussardier, B., Holder-Espinasse, M., Itin, P., Johnson, D.S., Joss, S., Koillinen, H., McKenzie, F., Morton, J., Nelle, H., Reardon, W., Roll, C., Salih, M.A., Savarirayan, R., Scurr, I., Splitt, M., Thompson, E., Titheradge, H., Travers, C.P., Van Maldergem, L., Whiteford, M., Wieczorek, D., Vandeweyer, G., Trembath, R., Van Laer, L., Loeys, B.L., Zenker, M., Southgate, L., Wuyts, W., Meester, J.A.N., Sukalo, M., Schröder, K.C., Schanze, D., Baynam, G., Borck, G., Bramswig, N.C., Duman, D., Gilbert-Dussardier, B., Holder-Espinasse, M., Itin, P., Johnson, D.S., Joss, S., Koillinen, H., McKenzie, F., Morton, J., Nelle, H., Reardon, W., Roll, C., Salih, M.A., Savarirayan, R., Scurr, I., Splitt, M., Thompson, E., Titheradge, H., Travers, C.P., Van Maldergem, L., Whiteford, M., Wieczorek, D., Vandeweyer, G., Trembath, R., Van Laer, L., Loeys, B.L., Zenker, M., Southgate, L., and Wuyts, W.
Abstract: Adams–Oliver syndrome (AOS) is a rare developmental disorder, characterized by scalp aplasia cutis congenita (ACC) and transverse terminal limb defects (TTLD). Autosomal dominant forms of AOS are linked to mutations in ARHGAP31, DLL4, NOTCH1 or RBPJ, while DOCK6 and EOGT underlie autosomal recessive inheritance. Data on the frequency and distribution of mutations in large cohorts are currently limited. The purpose of this study was therefore to comprehensively examine the genetic architecture of AOS in an extensive cohort. Molecular diagnostic screening of 194 AOS/ACC/TTLD probands/families was conducted using next‐generation and/or capillary sequencing analyses. In total, we identified 63 (likely) pathogenic mutations, comprising 56 distinct and 22 novel mutations, providing a molecular diagnosis in 30% of patients. Taken together with previous reports, these findings bring the total number of reported disease variants to 63, with a diagnostic yield of 36% in familial cases. NOTCH1 is the major contributor, underlying 10% of AOS/ACC/TTLD cases, with DLL4 (6%), DOCK6 (6%), ARHGAP31 (3%), EOGT (3%), and RBPJ (2%) representing additional causality in this cohort. We confirm the relevance of genetic screening across the AOS/ACC/TTLD spectrum, highlighting preliminary but important genotype–phenotype correlations. This cohort offers potential for further gene identification to address missing heritability.
Published: 2018

29. Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort

Author: Meester, JAN, Sukalo, M, Schroeder, KC, Schanze, D, Baynam, G, Borck, G, Bramswig, NC, Duman, D, Gilbert-Dussardier, B, Holder-Espinasse, M, Itin, P, Johnson, DS, Joss, S, Koillinen, H, McKenzie, F, Morton, J, Nelle, H, Reardon, W, Roll, C, Salih, MA, Savarirayan, R, Scurr, I, Splitt, M, Thompson, E, Titheradge, H, Travers, CP, Van Maldergem, L, Whiteford, M, Wieczorek, D, Vandeweyer, G, Trembath, R, Van Laer, L, Loeys, BL, Zenker, M, Southgate, L, Wuyts, W, Meester, JAN, Sukalo, M, Schroeder, KC, Schanze, D, Baynam, G, Borck, G, Bramswig, NC, Duman, D, Gilbert-Dussardier, B, Holder-Espinasse, M, Itin, P, Johnson, DS, Joss, S, Koillinen, H, McKenzie, F, Morton, J, Nelle, H, Reardon, W, Roll, C, Salih, MA, Savarirayan, R, Scurr, I, Splitt, M, Thompson, E, Titheradge, H, Travers, CP, Van Maldergem, L, Whiteford, M, Wieczorek, D, Vandeweyer, G, Trembath, R, Van Laer, L, Loeys, BL, Zenker, M, Southgate, L, and Wuyts, W
Abstract: Adams-Oliver syndrome (AOS) is a rare developmental disorder, characterized by scalp aplasia cutis congenita (ACC) and transverse terminal limb defects (TTLD). Autosomal dominant forms of AOS are linked to mutations in ARHGAP31, DLL4, NOTCH1 or RBPJ, while DOCK6 and EOGT underlie autosomal recessive inheritance. Data on the frequency and distribution of mutations in large cohorts are currently limited. The purpose of this study was therefore to comprehensively examine the genetic architecture of AOS in an extensive cohort. Molecular diagnostic screening of 194 AOS/ACC/TTLD probands/families was conducted using next-generation and/or capillary sequencing analyses. In total, we identified 63 (likely) pathogenic mutations, comprising 56 distinct and 22 novel mutations, providing a molecular diagnosis in 30% of patients. Taken together with previous reports, these findings bring the total number of reported disease variants to 63, with a diagnostic yield of 36% in familial cases. NOTCH1 is the major contributor, underlying 10% of AOS/ACC/TTLD cases, with DLL4 (6%), DOCK6 (6%), ARHGAP31 (3%), EOGT (3%), and RBPJ (2%) representing additional causality in this cohort. We confirm the relevance of genetic screening across the AOS/ACC/TTLD spectrum, highlighting preliminary but important genotype-phenotype correlations. This cohort offers potential for further gene identification to address missing heritability.
Published: 2018

30. 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

31. Prevalence and architecture of de novo mutations in developmental disorders

Author: McRae, JF, Clayton, S, Fitzgerald, TW, Kaplanis, J, Prigmore, E, Rajan, D, Sifrim, A, Aitken, S, Akawi, N, Alvi, M, Ambridge, K, Barrett, DM, Bayzetinova, T, Jones, P, Jones, WD, King, D, Krishnappa, N, Mason, LE, Singh, T, Tivey, AR, Ahmed, M, Anjum, U, Archer, H, Armstrong, R, Awada, J, Balasubramanian, M, Banka, S, Baralle, D, Barnicoat, A, Batstone, P, Baty, D, Bennett, C, Berg, J, Bernhard, B, Bevan, AP, Bitner-Glindzicz, M, Blair, E, Blyth, M, Bohanna, D, Bourdon, L, Bourn, D, Bradley, L, Brady, A, Brent, S, Brewer, C, Brunstrom, K, Bunyan, DJ, Burn, J, Canham, N, Castle, B, Chandler, K, Chatzimichali, E, Cilliers, D, Clarke, A, Clasper, S, Clayton-Smith, J, Clowes, V, Coates, A, Cole, T, Colgiu, I, 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, de Vries, D, Dean, J, Deshpande, C, Devlin, G, Dixit, A, Dobbie, A, Donaldson, A, Donnai, D, Donnelly, D, Donnelly, C, Douglas, A, Douzgou, S, Duncan, A, Eason, J, Ellard, S, Ellis, I, Elmslie, F, Evans, K, Everest, S, Fendick, T, Fisher, R, Flinter, F, Foulds, N, Fry, A, Fryer, A, Gardiner, C, Gaunt, L, Ghali, N, Gibbons, R, Gill, H, Goodship, J, Goudie, D, Gray, E, Green, A, Greene, P, Greenhalgh, L, Gribble, S, Harrison, R, Harrison, L, Harrison, V, Hawkins, R, He, L, Hellens, S, Henderson, A, Hewitt, S, Hildyard, L, Hobson, E, Holden, S, Holder, M, Holder, S, Hollingsworth, G, Homfray, T, Humphreys, M, Hurst, J, Hutton, B, Ingram, S, Irving, M, Islam, L, Jackson, A, Jarvis, J, Jenkins, L, Johnson, D, Jones, E, Josifova, D, Joss, S, Kaemba, B, Kazembe, S, Kelsell, R, Kerr, B, Kingston, H, Kini, U, Kinning, E, Kirby, G, Kirk, C, Kivuva, E, Kraus, A, Kumar, D, Kumar, VKA, Lachlan, K, Lam, W, Lampe, A, Langman, C, Lees, M, Lim, D, Longman, C, Lowther, G, Lynch, SA, Magee, A, Maher, E, Male, A, Mansour, S, Marks, K, Martin, K, Maye, U, McCann, E, McConnell, V, McEntagart, M, McGowan, R, McKay, K, McKee, S, McMullan, DJ, McNerlan, S, McWilliam, C, Mehta, S, Metcalfe, K, Middleton, A, Miedzybrodzka, Z, Miles, E, Mohammed, S, Montgomery, T, Moore, D, Morgan, S, Morton, J, Mugalaasi, H, Murday, V, Murphy, H, Naik, S, Nemeth, A, Nevitt, L, Newbury-Ecob, R, Norman, A, O’Shea, R, Ogilvie, C, Ong, K-R, Park, S-M, Parker, MJ, Patel, C, Paterson, J, Payne, S, Perrett, D, Phipps, J, Pilz, DT, Pollard, M, Pottinger, C, Poulton, J, Pratt, N, Prescott, K, Price, S, Pridham, A, Procter, A, Purnell, H, Quarrell, O, Ragge, N, Rahbari, R, Randall, J, Rankin, J, Raymond, L, Rice, D, Robert, L, Roberts, E, Roberts, J, Roberts, P, Roberts, G, Ross, A, Rosser, E, Saggar, A, Samant, S, Sampson, J, Sandford, R, Sarkar, A, Schweiger, S, Scott, R, Scurr, I, Selby, A, Seller, A, Sequeira, C, Shannon, N, Sharif, S, Shaw-Smith, C, Shearing, E, Shears, D, Sheridan, E, Simonic, I, Singzon, R, Skitt, Z, Smith, A, Smith, K, Smithson, S, Sneddon, L, Splitt, M, Squires, M, Stewart, F, Stewart, H, Straub, V, Suri, M, Sutton, V, Swaminathan, GJ, Sweeney, E, Tatton-Brown, K, Taylor, C, Taylor, R, Tein, M, Temple, IK, Thomson, J, Tischkowitz, M, Tomkins, S, Torokwa, A, Treacy, B, Turner, C, Turnpenny, P, Tysoe, C, Vandersteen, A, Varghese, V, Vasudevan, P, Vijayarangakannan, P, Vogt, J, Wakeling, E, Wallwark, S, Waters, J, Weber, A, Wellesley, D, Whiteford, M, Widaa, S, Wilcox, S, Wilkinson, E, Williams, D, Williams, N, Wilson, L, Woods, G, Wragg, C, Wright, M, Yates, L, Yau, M, Nellåker, C, Parker, M, Firth, HV, Wright, CF, FitzPatrick, DR, Barrett, JC, and Hurles, ME
Subjects: Male, Parents, Heredity, Developmental Disabilities, GRIN2B, POGZ, Autoantigens, SMAD4, CASK, GATAD2B, 0302 clinical medicine, TRIO, SMARCA2, KCNH1, Average Faces, CTNNB1, SCN1A, Young adult, Casein Kinase II, Child, AUTS2, MEF2C, Exome, ADNP, Exome sequencing, EP300, KCNQ2, KCNQ3, EHMT1, CNKSR2, CREBBP, MYT1L, MED13L, CSNK2A1, Protein Phosphatase 2C, PPP2R1A, ZBTB18, CDKL5, WAC, HNRNPU, Cohort, STXBP1, Medical genetics, SYNGAP1, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Sex characteristics, AHDC1, SCN8A, medicine.medical_specialty, SLC6A1, FOXP1, USP9X, Article, ANKRD11, PUF60, BRAF, 03 medical and health sciences, SATB2, SMC1A, Intellectual Disability, BCL11A, GABRB3, IQSEC2, Humans, TBL1XR1, TCF4, MSL3, TCF20, DNM1, EEF1A2, SUV420H1, DYRK1A, SETD5, COL4A3BP, CTCF, CHD2, R1, CHD4, 030104 developmental biology, NAA10, HDAC8, Mutation, KDM5B, CHAMP1, PhenIcons, 030217 neurology & neurosurgery, Transcription Factors, 0301 basic medicine, ZMYND11, PTEN, De novo mutation, Chromosomal Proteins, Non-Histone, PTPN11, ASXL1, Bioinformatics, medicine.disease_cause, ASXL3, Cohort Studies, DEAD-box RNA Helicases, CHD8, Prevalence, QRICH1, KIF1A, Genetics, Sex Characteristics, GNAI1, Multidisciplinary, WDR45, Middle Aged, KMT2A, PPM1D, MECP2, DNA-Binding Proteins, PPP2R5D, Phenotype, PACS1, ras GTPase-Activating Proteins, DDX3X, Female, FOXG1, SET, Myeloid-Lymphoid Leukemia Protein, Developmental Disease, Adult, KANSL1, Adolescent, NFIX, Nerve Tissue Proteins, PURA, Biology, KAT6B, KAT6A, NSD1, PDHA1, ALG13, Young Adult, Seizures, CDC2 Protein Kinase, medicine, Journal Article, QH426, Homeodomain Proteins, ITPR1, DYNC1H1, GNAO1, Histone-Lysine N-Methyltransferase, Sequence Analysis, DNA, ZC4H2, ARID1B, Repressor Proteins, CNOT3, SCN2A, SLC35A2, CDK13
Abstract: Children with severe, undiagnosed developmental disorders (DDs) are enriched for damaging de novo mutations (DNMs) in developmentally important genes. We exome sequenced 4,294 families with children with DDs, and meta-analysed these data with published data on 3,287 children with similar disorders. We show that the most significant factors influencing the diagnostic yield of de novo mutations are the sex of the child, the relatedness of their parents and the age of both father and mother. We identified 95 genes enriched for damaging de novo mutation at genome-wide significance (P < 5 x 10-7), including fourteen genes for which compelling data for causation was previously lacking. The large number of genome-wide significant findings allow us to demonstrate that, at current cost differentials, exome sequencing has much greater power than genome sequencing for novel gene discovery in genetically heterogeneous disorders. We estimate that 42.5% of our cohort likely carry pathogenic de novo single nucleotide variants (SNVs) and indels in coding sequences, with approximately half operating by a loss-of-function mechanism, and the remainder being gain-of-function. We established that most haploinsufficient developmental disorders have already been identified, but that many gain-of-function disorders remain to be discovered. Extrapolating from the DDD cohort to the general population, we estimate that de novo dominant developmental disorders have an average birth prevalence of 1 in 168 to 1 in 377, depending on parental age.
Published: 2017

32. SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome

Author: Shaw, N.D., Brand, H., Kupchinsky, Z.A., Bengani, H., Plummer, L., Jones, T.I., Erdin, S., Williamson, K.A., Rainger, J., Stortchevoi, A., Samocha, K., Currall, B.B., Dunican, D.S., Collins, R.L., Willer, J.R., Lek, A., Lek, M., Nassan, M., Pereira, S., Kammin, T., Lucente, D., Silva, A., Seabra, C.M., Chiang, C., An, Y., Ansari, M., Rainger, J.K., Joss, S., Smith, J.C., Lippincott, M.F., Singh, S.S., Patel, N., Jing, J.W., Law, J.R., Ferraro, N., Verloes, A., Rauch, A., Steindl, K., Zweier, M., Scheer, I., Sato, D., Okamoto, N., Jacobsen, C., Tryggestad, J., Chernausek, S., Schimmenti, L.A., Brasseur, B., Cesaretti, C., Garcia-Ortiz, J.E., Buitrago, T.P., Silva, O.P., Hoffman, J.D., Muhlbauer, W., Ruprecht, K.W., Loeys, B.L., Shino, M., Kaindl, A.M., Cho, C.H., Morton, C.C., Meehan, R.R., Heyningen, V. van, Liao, E.C., Balasubramanian, R., Hall, J.E., Seminara, S.B., Macarthur, D., Moore, S.A., Yoshiura, K.I., Gusella, J.F., Marsh, J.A., Graham, J.M., Lin, A.E., Katsanis, N., Jones, P.L., Crowley, W.F., Davis, E.E., FitzPatrick, D.R., Talkowski, M.E., Shaw, N.D., Brand, H., Kupchinsky, Z.A., Bengani, H., Plummer, L., Jones, T.I., Erdin, S., Williamson, K.A., Rainger, J., Stortchevoi, A., Samocha, K., Currall, B.B., Dunican, D.S., Collins, R.L., Willer, J.R., Lek, A., Lek, M., Nassan, M., Pereira, S., Kammin, T., Lucente, D., Silva, A., Seabra, C.M., Chiang, C., An, Y., Ansari, M., Rainger, J.K., Joss, S., Smith, J.C., Lippincott, M.F., Singh, S.S., Patel, N., Jing, J.W., Law, J.R., Ferraro, N., Verloes, A., Rauch, A., Steindl, K., Zweier, M., Scheer, I., Sato, D., Okamoto, N., Jacobsen, C., Tryggestad, J., Chernausek, S., Schimmenti, L.A., Brasseur, B., Cesaretti, C., Garcia-Ortiz, J.E., Buitrago, T.P., Silva, O.P., Hoffman, J.D., Muhlbauer, W., Ruprecht, K.W., Loeys, B.L., Shino, M., Kaindl, A.M., Cho, C.H., Morton, C.C., Meehan, R.R., Heyningen, V. van, Liao, E.C., Balasubramanian, R., Hall, J.E., Seminara, S.B., Macarthur, D., Moore, S.A., Yoshiura, K.I., Gusella, J.F., Marsh, J.A., Graham, J.M., Lin, A.E., Katsanis, N., Jones, P.L., Crowley, W.F., Davis, E.E., FitzPatrick, D.R., and Talkowski, M.E.
Abstract: Item does not contain fulltext, Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of-function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes. Transcriptome and protein analyses in arhinia probands and controls showed no differences in SMCHD1 mRNA or protein abundance but revealed regulatory changes in genes and pathways associated with craniofacial patterning. Mutations in SMCHD1 thus contribute to distinct phenotypic spectra, from craniofacial malformation and reproductive disorders to muscular dystrophy, which we speculate to be consistent with oligogenic mechanisms resulting in pleiotropic outcomes.
Published: 2017

33. Pricing Inflation Linked Bonds and Hedging Bond Portfolios: A Comparative Analysis Applied to French Oat Indexed Bonds

Author: Joss S da Fonseca
Published: 2016

34. Genetic and immune findings in complex febrile seizures and the epidemiology of Dravet syndrome: A nationwide cohort study.

Author: Symonds, J.D., primary, Lang, B., additional, Vincent, A., additional, Brunklaus, A., additional, Dorris, L., additional, Ellis, R., additional, Jollands, A., additional, Joss, S., additional, Kirkpatrick, M., additional, McLellan, A., additional, MacLeod, S., additional, O'Regan, M., additional, Pilz, D.T., additional, Reavey, E., additional, Stewart, K., additional, Williams, N., additional, and Zuberi, S.M., additional
Published: 2017
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35. Portfolio Selection in Euro Area with CAPM and Lower Partial Moments Models

Author: da Fonseca, Joss S., primary
Published: 2017
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36. ASPP2 deficiency causes features of 1q41q42 microdeletion syndrome

Author: Zak, J, primary, Vives, V, additional, Szumska, D, additional, Vernet, A, additional, Schneider, J E, additional, Miller, P, additional, Slee, E A, additional, Joss, S, additional, Lacassie, Y, additional, Chen, E, additional, Escobar, L F, additional, Tucker, M, additional, Aylsworth, A S, additional, Dubbs, H A, additional, Collins, A T, additional, Andrieux, J, additional, Dieux-Coeslier, A, additional, Haberlandt, E, additional, Kotzot, D, additional, Scott, D A, additional, Parker, M J, additional, Zakaria, Z, additional, Choy, Y S, additional, Wieczorek, D, additional, Innes, A M, additional, Jun, K R, additional, Zinner, S, additional, Prin, F, additional, Lygate, C A, additional, Pretorius, P, additional, Rosenfeld, J A, additional, Mohun, T J, additional, and Lu, X, additional
Published: 2016
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37. Pricing Inflation Linked Bonds and Hedging Bond Portfolios: A Comparative Analysis Applied to French OAT Indexed Bonds

Author: da Fonseca, Joss S, primary and de SSverac, BBatrice, additional
Published: 2016
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38. Refinement of the critical 2p25.3 deletion region: the role of MYT1L in intellectual disability and obesity

Author: Rocker, N. de, Vergult, S., Koolen, D.A., Jacobs, E., Hoischen, A., Zeesman, S., Bang, B., Bena, F., Bockaert, N., Bongers, E.M.H.F., Ravel, T. de, Devriendt, K., Giglio, S., Faivre, L., Joss, S., Maas, S., Marle, N., Novara, F., Nowaczyk, M.J., Peeters, H., Polstra, A., Roelens, F., Rosenberg, C., Thevenon, J., Tumer, Z., Vanhauwaert, S., Varvagiannis, K., Willaert, A., Willemsen, M.H., Willems, M., Zuffardi, O., Coucke, P., Speleman, F., Eichler, E.E., Kleefstra, T., Menten, B., Rocker, N. de, Vergult, S., Koolen, D.A., Jacobs, E., Hoischen, A., Zeesman, S., Bang, B., Bena, F., Bockaert, N., Bongers, E.M.H.F., Ravel, T. de, Devriendt, K., Giglio, S., Faivre, L., Joss, S., Maas, S., Marle, N., Novara, F., Nowaczyk, M.J., Peeters, H., Polstra, A., Roelens, F., Rosenberg, C., Thevenon, J., Tumer, Z., Vanhauwaert, S., Varvagiannis, K., Willaert, A., Willemsen, M.H., Willems, M., Zuffardi, O., Coucke, P., Speleman, F., Eichler, E.E., Kleefstra, T., and Menten, B.
Abstract: Item does not contain fulltext, PURPOSE: Submicroscopic deletions of chromosome band 2p25.3 are associated with intellectual disability and/or central obesity. Although MYT1L is believed to be a critical gene responsible for intellectual disability, so far no unequivocal data have confirmed this hypothesis. METHODS: In this study we evaluated a cohort of 22 patients (15 sporadic patients and two families) with a 2p25.3 aberration to further refine the clinical phenotype and to delineate the role of MYT1L in intellectual disability and obesity. In addition, myt1l spatiotemporal expression in zebrafish embryos was analyzed by quantitative polymerase chain reaction and whole-mount in situ hybridization. RESULTS: Complete MYT1L deletion, intragenic deletion, or duplication was observed in all sporadic patients, in addition to two patients with a de novo point mutation in MYT1L. The familial cases comprise a 6-Mb deletion in a father and his three children and a 5' MYT1L overlapping duplication in a father and his two children. Expression analysis in zebrafish embryos shows specific myt1l expression in the developing brain. CONCLUSION: Our data strongly strengthen the hypothesis that MYT1L is the causal gene for the observed syndromal intellectual disability. Moreover, because 17 patients present with obesity/overweight, haploinsufficiency of MYT1L might predispose to weight problems with childhood onset.Genet Med 17 6, 460-466.
Published: 2015

39. 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

40. De novo variants in CNOT3cause a variable neurodevelopmental disorder

Author: Martin, R., Splitt, M., Genevieve, D., Aten, E., Collins, A., de Bie, C. I., Faivre, L., Foulds, N., Giltay, J., Ibitoye, R., Joss, S., Kennedy, J., Kerr, B., Kivuva, E., Koopmans, M., Newbury-Ecob, R., Jean-Marçais, N., Peeters, E. A. J., Smithson, S., Tomkins, S., Tranmauthem, F., Piton, A., and van Haeringen, A.
Abstract: As a result of exome-based sequencing work performed by the DDD study, de novo variants in CNOT3have emerged as a newly recognised cause of a developmental disorder. This paper describes molecular and clinical details of 16 probands with developmental disorders and de novo CNOT3 variants. It is the first such description of the developmental phenotype associated with CNOT3variants. Eight of these cases were discovered as part of the DDD study, while the other eight were found as a result of large-scale sequencing work performed by other groups. A highly specific phenotype was not recognised in these 16 cases. The most consistent phenotypic features seen in subjects with de novo variants in CNOT3were hypotonia, relatively small stature, developmental delay, behavioural problems and intellectual disability. There is no easily recognisable facial phenotype, but some common dysmorphic features such as anteverted nares, thin upper lip and low set eyebrows were shared among some of the probands. Haploinsufficiency appears to be the most likely mechanism of action, with eight cases found to have protein-truncating variants. Of the other eight cases (all missense variants), three share an amino acid substitution at the same position which may therefore represent an important functional domain.
Published: 2019
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41. A homozygous STIM1 mutation impairs store-operated calcium entry and natural killer cell effector function without clinical immunodeficiency

Author: Parry, DA, Holmes, TD, Gamper, N, El-Sayed, W, Hettiarachchi, NT, Ahmed, M, Cook, GP, Logan, CV, Johnson, CA, Joss, S, Peers, C, Prescott, K, Savic, S, Inglehearn, CF, and Mighell, AJ
Subjects: Immunology, Homozygote, Membrane Proteins, Genes, Recessive, Neoplasm Proteins, Killer Cells, Natural, Consanguinity, Phenotype, Mutation, Immunology and Allergy, Humans, Calcium, Family, Stromal Interaction Molecule 1, Letter to the Editor, Genetic Association Studies
Published: 2016

42. X-linked congenital ptosis and associated intellectual disability, short stature, microcephaly, cleft palate, digital and genital abnormalities define novel Xq25q26 duplication syndrome

Author: Moller, R.S., Jensen, L.R., Maas, S.M., Filmus, J., Capurro, M., Hansen, C., Marcelis, C.L.M., Ravn, K., Andrieux, J., Mathieu, M., Kirchhoff, M., Rodningen, O.K., Leeuw, N. de, Yntema, H.G., Froyen, G., Vandewalle, J., Ballon, K., Klopocki, E., Joss, S., Tolmie, J., Knegt, A.C., Lund, A.M., Hjalgrim, H., Kuss, A.W., Tommerup, N., Ullmann, R., Brouwer, A.P.M. de, Stromme, P., Kjaergaard, S., Tumer, Z., Kleefstra, T., Moller, R.S., Jensen, L.R., Maas, S.M., Filmus, J., Capurro, M., Hansen, C., Marcelis, C.L.M., Ravn, K., Andrieux, J., Mathieu, M., Kirchhoff, M., Rodningen, O.K., Leeuw, N. de, Yntema, H.G., Froyen, G., Vandewalle, J., Ballon, K., Klopocki, E., Joss, S., Tolmie, J., Knegt, A.C., Lund, A.M., Hjalgrim, H., Kuss, A.W., Tommerup, N., Ullmann, R., Brouwer, A.P.M. de, Stromme, P., Kjaergaard, S., Tumer, Z., and Kleefstra, T.
Abstract: Item does not contain fulltext, Submicroscopic duplications along the long arm of the X-chromosome with known phenotypic consequences are relatively rare events. The clinical features resulting from such duplications are various, though they often include intellectual disability, microcephaly, short stature, hypotonia, hypogonadism and feeding difficulties. Female carriers are often phenotypically normal or show a similar but milder phenotype, as in most cases the X-chromosome harbouring the duplication is subject to inactivation. Xq28, which includes MECP2 is the major locus for submicroscopic X-chromosome duplications, whereas duplications in Xq25 and Xq26 have been reported in only a few cases. Using genome-wide array platforms we identified overlapping interstitial Xq25q26 duplications ranging from 0.2 to 4.76 Mb in eight unrelated families with in total five affected males and seven affected females. All affected males shared a common phenotype with intrauterine- and postnatal growth retardation and feeding difficulties in childhood. Three had microcephaly and two out of five suffered from epilepsy. In addition, three males had a distinct facial appearance with congenital bilateral ptosis and large protruding ears and two of them showed a cleft palate. The affected females had various clinical symptoms similar to that of the males with congenital bilateral ptosis in three families as most remarkable feature. Comparison of the gene content of the individual duplications with the respective phenotypes suggested three critical regions with candidate genes (AIFM1, RAB33A, GPC3 and IGSF1) for the common phenotypes, including candidate loci for congenital bilateral ptosis, small head circumference, short stature, genital and digital defects.
Published: 2014

43. X-linked congenital ptosis and associated intellectual disability, short stature, microcephaly, cleft palate, digital and genital abnormalities define novel Xq25q26 duplication syndrome

Author: Møller, R S, Jensen, L R, Maas, S M, Filmus, J, Capurro, M, Hansen, Claus, Marcelis, C L M, Ravn, K, Andrieux, J, Mathieu, M, Kirchhoff, M, Rødningen, O K, de Leeuw, N, Yntema, H G, Froyen, G, Vandewalle, J, Ballon, K, Klopocki, E, Joss, S, Tolmie, J, Knegt, A C, Lund, A M, Hjalgrim, H, Kuss, A W, Tommerup, N, Ullmann, R, de Brouwer, A P M, Strømme, P, Kjaergaard, S, Tümer, Z, Kleefstra, T, Møller, R S, Jensen, L R, Maas, S M, Filmus, J, Capurro, M, Hansen, Claus, Marcelis, C L M, Ravn, K, Andrieux, J, Mathieu, M, Kirchhoff, M, Rødningen, O K, de Leeuw, N, Yntema, H G, Froyen, G, Vandewalle, J, Ballon, K, Klopocki, E, Joss, S, Tolmie, J, Knegt, A C, Lund, A M, Hjalgrim, H, Kuss, A W, Tommerup, N, Ullmann, R, de Brouwer, A P M, Strømme, P, Kjaergaard, S, Tümer, Z, and Kleefstra, T
Abstract: Submicroscopic duplications along the long arm of the X-chromosome with known phenotypic consequences are relatively rare events. The clinical features resulting from such duplications are various, though they often include intellectual disability, microcephaly, short stature, hypotonia, hypogonadism and feeding difficulties. Female carriers are often phenotypically normal or show a similar but milder phenotype, as in most cases the X-chromosome harbouring the duplication is subject to inactivation. Xq28, which includes MECP2 is the major locus for submicroscopic X-chromosome duplications, whereas duplications in Xq25 and Xq26 have been reported in only a few cases. Using genome-wide array platforms we identified overlapping interstitial Xq25q26 duplications ranging from 0.2 to 4.76 Mb in eight unrelated families with in total five affected males and seven affected females. All affected males shared a common phenotype with intrauterine- and postnatal growth retardation and feeding difficulties in childhood. Three had microcephaly and two out of five suffered from epilepsy. In addition, three males had a distinct facial appearance with congenital bilateral ptosis and large protruding ears and two of them showed a cleft palate. The affected females had various clinical symptoms similar to that of the males with congenital bilateral ptosis in three families as most remarkable feature. Comparison of the gene content of the individual duplications with the respective phenotypes suggested three critical regions with candidate genes (AIFM1, RAB33A, GPC3 and IGSF1) for the common phenotypes, including candidate loci for congenital bilateral ptosis, small head circumference, short stature, genital and digital defects.
Published: 2014

44. Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype

Author: Tatton-Brown, K., Murray, A., Hanks, S., Douglas, J., Armstrong, R., Banka, S., Bird, L.M., Clericuzio, C.L., Cormier-Daire, V., Cushing, T., Flinter, F., Jacquemont, M-L, Joss, S., Kinning, E., Lynch, S.A., Magee, A., McConnell, V., Medeira, A., Ozono, K., Patton, M., Rankin, J., Shears, D., Simon, M., Splitt, M., Strenger, V., Stuurman, K., Taylor, C., Titheradge, H., Van Maldergem, L., Temple, I.K., Cole, T., Seal, S., Rahman, N., Baynam, G., Tatton-Brown, K., Murray, A., Hanks, S., Douglas, J., Armstrong, R., Banka, S., Bird, L.M., Clericuzio, C.L., Cormier-Daire, V., Cushing, T., Flinter, F., Jacquemont, M-L, Joss, S., Kinning, E., Lynch, S.A., Magee, A., McConnell, V., Medeira, A., Ozono, K., Patton, M., Rankin, J., Shears, D., Simon, M., Splitt, M., Strenger, V., Stuurman, K., Taylor, C., Titheradge, H., Van Maldergem, L., Temple, I.K., Cole, T., Seal, S., Rahman, N., and Baynam, G.
Abstract: Weaver syndrome, first described in 1974, is characterized by tall stature, a typical facial appearance, and variable intellectual disability. In 2011, mutations in the histone methyltransferase, EZH2, were shown to cause Weaver syndrome. To date, we have identified 48 individuals with EZH2 mutations. The mutations were primarily missense mutations occurring throughout the gene, with some clustering in the SET domain (12/48). Truncating mutations were uncommon (4/48) and only identified in the final exon, after the SET domain. Through analyses of clinical data and facial photographs of EZH2 mutation-positive individuals, we have shown that the facial features can be subtle and the clinical diagnosis of Weaver syndrome is thus challenging, especially in older individuals. However, tall stature is very common, reported in >90% of affected individuals. Intellectual disability is also common, present in ~80%, but is highly variable and frequently mild. Additional clinical features which may help in stratifying individuals to EZH2 mutation testing include camptodactyly, soft, doughy skin, umbilical hernia, and a low, hoarse cry. Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident. The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes. As mutation testing becomes increasingly accessible and larger numbers of EZH2 mutation-positive individuals are identified, knowledge of the clinical spectrum and prognostic implications of EZH2 mutations should improve.
Published: 2013

45. Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype

Author: Tatton-Brown, K. (Katrina), Murray, A. (Anna), Hanks, S. (Sandra), Douglas, J. (Jenny), Armstrong, R. (Ruth), Banka, S. (Siddharth), Bird, L.M. (Lynne), Clericuzio, C.L. (Carol), Cormier-Daire, V. (Valerie), Cushing, T. (Tom), Flinter, F. (Frances), Jacquemont, S. (Sébastien), Joss, S. (Shelagh), Kinning, E. (Esther), Lynch, S.A., Magee, A. (Alex), Mcconnell, V. (Vivienne), Medeira, A. (Ana), Ozono, K. (Keiichi), Patton, M. (Michael), Rankin, J. (Julia), Shears, D.J. (Deborah), Simon, M.E.H. (Marleen), Splitt, M. (M.), Strenger, V. (Volker), Stuurman, K.E. (Kyra), Taylor, C.J. (Clare), Titheradge, H. (Hannah), Maldergem, L. (Lionel) van, Temple, I.K., Cole, T.J. (Trevor), Seal, S. (Sheila), Rahman, N. (Nazneen), Tatton-Brown, K. (Katrina), Murray, A. (Anna), Hanks, S. (Sandra), Douglas, J. (Jenny), Armstrong, R. (Ruth), Banka, S. (Siddharth), Bird, L.M. (Lynne), Clericuzio, C.L. (Carol), Cormier-Daire, V. (Valerie), Cushing, T. (Tom), Flinter, F. (Frances), Jacquemont, S. (Sébastien), Joss, S. (Shelagh), Kinning, E. (Esther), Lynch, S.A., Magee, A. (Alex), Mcconnell, V. (Vivienne), Medeira, A. (Ana), Ozono, K. (Keiichi), Patton, M. (Michael), Rankin, J. (Julia), Shears, D.J. (Deborah), Simon, M.E.H. (Marleen), Splitt, M. (M.), Strenger, V. (Volker), Stuurman, K.E. (Kyra), Taylor, C.J. (Clare), Titheradge, H. (Hannah), Maldergem, L. (Lionel) van, Temple, I.K., Cole, T.J. (Trevor), Seal, S. (Sheila), and Rahman, N. (Nazneen)
Abstract: Weaver syndrome, first described in 1974, is characterized by tall stature, a typical facial appearance, and variable intellectual disability. In 2011, mutations in the histone methyltransferase, EZH2, were shown to cause Weaver syndrome. To date, we have identified 48 individuals with EZH2 mutations. The mutations were primarily missense mutations occurring throughout the gene, with some clustering in the SET domain (12/48). Truncating mutations were uncommon (4/48) and only identified in the final exon, after the SET domain. Through analyses of clinical data and facial photographs of EZH2 mutation-positive individuals, we have shown that the facial features can be subtle and the clinical diagnosis of Weaver syndrome is thus challenging, especially in older individuals. However, tall stature is very common, reported in >90% of affected individuals. Intellectual disability is also common, present in ~80%, but is highly variable and frequently mild. Additional clinical features which may help in stratifying individuals to EZH2 mutation testing include camptodactyly, soft, doughy skin, umbilical hernia, and a low, hoarse cry. Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident. The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes. As mutation testing becomes increasingly accessible and larger numbers of EZH2 mutation-positive individuals are identified, knowledge of the clinical spectrum and prognostic implications of EZH2 mutations should improve.
Published: 2013
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46. De novo and inherited mutations in the X-linked gene CLCN4 are associated with syndromic intellectual disability and behavior and seizure disorders in males and females

Author: Palmer, E E, Stuhlmann, T, Weinert, S, Haan, E, Van Esch, H, Holvoet, M, Boyle, J, Leffler, M, Raynaud, M, Moraine, C, van Bokhoven, H, Kleefstra, T, Kahrizi, K, Najmabadi, H, Ropers, H-H, Delgado, M R, Sirsi, D, Golla, S, Sommer, A, Pietryga, M P, Chung, W K, Wynn, J, Rohena, L, Bernardo, E, Hamlin, D, Faux, B M, Grange, D K, Manwaring, L, Tolmie, J, Joss, S, Cobben, J M, Duijkers, F A M, Goehringer, J M, Challman, T D, Hennig, F, Fischer, U, Grimme, A, Suckow, V, Musante, L, Nicholl, J, Shaw, M, Lodh, S P, Niu, Z, Rosenfeld, J A, Stankiewicz, P, Jentsch, T J, Gecz, J, Field, M, and Kalscheuer, V M
Abstract: Variants in CLCN4, which encodes the chloride/hydrogen ion exchanger CIC-4 prominently expressed in brain, were recently described to cause X-linked intellectual disability and epilepsy. We present detailed phenotypic information on 52 individuals from 16 families with CLCN4-related disorder: 5 affected females and 2 affected males with a de novo variant in CLCN4 (6 individuals previously unreported) and 27 affected males, 3 affected females and 15 asymptomatic female carriers from 9 families with inherited CLCN4 variants (4 families previously unreported). Intellectual disability ranged from borderline to profound. Behavioral and psychiatric disorders were common in both child- and adulthood, and included autistic features, mood disorders, obsessive–compulsive behaviors and hetero- and autoaggression. Epilepsy was common, with severity ranging from epileptic encephalopathy to well-controlled seizures. Several affected individuals showed white matter changes on cerebral neuroimaging and progressive neurological symptoms, including movement disorders and spasticity. Heterozygous females can be as severely affected as males. The variability of symptoms in females is not correlated with the X inactivation pattern studied in their blood. The mutation spectrum includes frameshift, missense and splice site variants and one single-exon deletion. All missense variants were predicted to affect CLCN4’s function based on in silico tools and either segregated with the phenotype in the family or were de novo. Pathogenicity of all previously unreported missense variants was further supported by electrophysiological studies in Xenopus laevis oocytes. We compare CLCN4-related disorder with conditions related to dysfunction of other members of the CLC family.
Published: 2018
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47. X-linked congenital ptosis and associated intellectual disability, short stature, microcephaly, cleft palate, digital and genital abnormalities define novel Xq25q26 duplication syndrome

Author: Møller, R. S., primary, Jensen, L. R., additional, Maas, S. M., additional, Filmus, J., additional, Capurro, M., additional, Hansen, C., additional, Marcelis, C. L. M., additional, Ravn, K., additional, Andrieux, J., additional, Mathieu, M., additional, Kirchhoff, M., additional, Rødningen, O. K., additional, de Leeuw, N., additional, Yntema, H. G., additional, Froyen, G., additional, Vandewalle, J., additional, Ballon, K., additional, Klopocki, E., additional, Joss, S., additional, Tolmie, J., additional, Knegt, A. C., additional, Lund, A. M., additional, Hjalgrim, H., additional, Kuss, A. W., additional, Tommerup, N., additional, Ullmann, R., additional, de Brouwer, A. P. M., additional, Strømme, P., additional, Kjaergaard, S., additional, Tümer, Z., additional, and Kleefstra, T., additional
Published: 2013
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48. The Netherlands : seeking to involve wider publics in technology assessment

Author: Est, van, R., Eijndhoven, van, J., Aarts, W., Loeber, A., Joss, S., and Bellucci, S.
Published: 2002

49. The choice of participatory Technology Assessment methods

Author: Eijndhoven, van, J., Est, van, R., Joss, S., and Bellucci, S.
Published: 2002

50. EUROpTA: European Participatory Technology Assessment - Participatory Methods in Technology Assessment and Technology Decision-Making

Author: Klüver, L., Bellucci, S., Bütschi, D., Eijndhoven, van, J., Est, van, R., Gloede, F., Hennen, L., Joss, S., Nentwich, M., Peissl, W., and Torgersen, H.
Published: 2000

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