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1. ARID1B-related disorder in 87 adults: Natural history and self-sustainability

Author

van der Sluijs, P.J., Gösgens, M., Dingemans, A.J.M., Striano, P., Riva, A., Mignot, C., Faudet, A., Vasileiou, G., Walther, M., Schrier Vergano, S.A., Alders, M., Alkuraya, F.S., Alorainy, I., Alsaif, H.S., Anderlid, B., Bache, I., van Beek, I., Blanluet, M., van Bon, B.W., Brunet, T., Brunner, H., Carriero, M.L., Charles, P., Chatron, N., Coccia, E., Dubourg, C., Earl, R.K., Eichler, E.E., Faivre, L., Foulds, N., Graziano, C., Guerrot, A.M., Hashem, M.O., Heide, S., Heron, D., Hickey, S.E., Hopman, S.M.J., Kattentidt-Mouravieva, A., Kerkhof, J., Klein Wassink-Ruiter, J.S., Kurtz-Nelson, E.C., Kušíková, K., Kvarnung, M., Lecoquierre, F., Leszinski, G.S., Loberti, L., Magoulas, P.L., Mari, F., Maystadt, I., Merla, G., Milunsky, J.M., Moortgat, S., Nicolas, G., Leary, M.O.’, Odent, S., Ozmore, J.R., Parbhoo, K., Pfundt, R., Piccione, M., Pinto, A.M., Popp, B., Putoux, A., Rehm, H.L., Reis, A., Renieri, A., Rosenfeld, J.A., Rossi, M., Salzano, E., Saugier-Veber, P., Seri, M., Severi, G., Sonmez, F.M., Strobl-Wildemann, G., Stuurman, K.E., Uctepe, E., Van Esch, H., Vitetta, G., de Vries, B.B.A., Wahl, D., Wang, T., Zacher, P., Heitink, K.R., Ropers, F.G., Steenbeek, D., Rybak, T., and Santen, G.W.E.

Published
2024
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2. Identification of new TRIP12 variants and detailed clinical evaluation of individuals with non-syndromic intellectual disability with or without autism

Author

Bramswig, Nuria C., Lüdecke, H.-J., Pettersson, M., Albrecht, B., Bernier, R. A., Cremer, K., Eichler, E. E., Falkenstein, D., Gerdts, J., Jansen, S., Kuechler, A., Kvarnung, M., Lindstrand, A., Nilsson, D., Nordgren, A., Pfundt, R., Spruijt, L., Surowy, H. M., de Vries, B. B. A., Wieland, T., Engels, H., Strom, T. M., Kleefstra, T., and Wieczorek, D.

Published
2017
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4. Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

Author

Wang T., Hoekzema K., Vecchio D., Wu H., Sulovari A., Coe B. P., Gillentine M. A., Wilfert A. B., Perez-Jurado L. A., Kvarnung M., Sleyp Y., Earl R. K., Rosenfeld J. A., Geisheker M. R., Han L., Du B., Barnett C., Thompson E., Shaw M., Carroll R., Friend K., Catford R., Palmer E. E., Zou X., Ou J., Li H., Guo H., Gerdts J., Avola E., Calabrese G., Elia M., Greco D., Lindstrand A., Nordgren A., Anderlid B. -M., Vandeweyer G., Van Dijck A., Van der Aa N., McKenna B., Hancarova M., Bendova S., Havlovicova M., Malerba G., Bernardina B. D., Muglia P., van Haeringen A., Hoffer M. J. V., Franke B., Cappuccio G., Delatycki M., Lockhart P. J., Manning M. A., Liu P., Scheffer I. E., Brunetti Pierri N., Rommelse N., Amaral D. G., Santen G. W. E., Trabetti E., Sedlacek Z., Michaelson J. J., Pierce K., Courchesne E., Kooy R. F., Acampado J., Ace A. J., Amatya A., Astrovskaya I., Bashar A., Brooks E., Butler M. E., Cartner L. A., Chin W., Chung W. K., Daniels A. M., Feliciano P., Fleisch C., Ganesan S., Jensen W., Lash A. E., Marini R., Myers V. J., O'Connor E., Rigby C., Robertson B. E., Shah N., Shah S., Singer E., Snyder L. A. G., Stephens A. N., Tjernagel J., Vernoia B. M., Volfovsky N., White L. C., Hsieh A., Shen Y., Zhou X., Turner T. N., Bahl E., Thomas T. R., Brueggeman L., Koomar T., Michael R. J., O'Roak B. J., Barnard R. A., Gibbs R. A., Muzny D., Sabo A., Ahmed K. L. B., Eichler E. E., Siegel M., Abbeduto L., Hilscher B. A., Li D., Smith K., Thompson S., Albright C., Butter E. M., Eldred S., Hanna N., Jones M., Coury D. L., Scherr J., Pifher T., Roby E., Dennis B., Higgins L., Brown M., Alessandri M., Gutierrez A., Hale M. N., Herbert L. M., Schneider H. L., David G., Annett R. D., Sarver D. E., Arriaga I., Camba A., Gulsrud A. C., Haley M., McCracken J. T., Sandhu S., Tafolla M., Yang W. S., Carpenter L. A., Bradley C. C., Gwynette F., Manning P., Shaffer R., Thomas C., Bernier R. A., Fox E. A., Gerdts J. A., Pepper M., Ho T., Cho D., Piven J., Lechniak H., Soorya L. V., Gordon R., Wainer A., Yeh L., Ochoa-Lubinoff C., Russo N., Berry-Kravis E., Booker S., Erickson C. A., Prock L. M., Pawlowski K. G., Matthews E. T., Brewster S. J., Hojlo M. A., Abada E., Lamarche E., Murali S. C., Harvey W. T., Kaplan H. E., Pierce K. L., DeMarco L., Horner S., Pandey J., Plate S., Sahin M., Riley K. D., Carmody E., Constantini J., Esler A., Fatemi A., Hutter H., Landa R. J., McKenzie A. P., Neely J., Singh V., Van Metre B., Wodka E. L., Fombonne E. J., Huang-Storms L. Y., Pacheco L. D., Mastel S. A., Coppola L. A., Francis S., Jarrett A., Jacob S., Lillie N., Gunderson J., Istephanous D., Simon L., Wasserberg O., Rachubinski A. L., Rosenberg C. R., Kanne S. M., Shocklee A. D., Takahashi N., Bridwell S. L., Klimczac R. L., Mahurin M. A., Cotrell H. E., Grant C. A., Hunter S. G., Martin C. L., Taylor C. M., Walsh L. K., Dent K. A., Mason A., Sziklay A., Smith C. J., Nordenskjold M., Romano C., Peeters H., Gecz J., Xia K., SPARK Consortium, Wang, T., Hoekzema, K., Vecchio, D., Wu, H., Sulovari, A., Coe, B. P., Gillentine, M. A., Wilfert, A. B., Perez-Jurado, L. A., Kvarnung, M., Sleyp, Y., Earl, R. K., Rosenfeld, J. A., Geisheker, M. R., Han, L., Du, B., Barnett, C., Thompson, E., Shaw, M., Carroll, R., Friend, K., Catford, R., Palmer, E. E., Zou, X., Ou, J., Li, H., Guo, H., Gerdts, J., Avola, E., Calabrese, G., Elia, M., Greco, D., Lindstrand, A., Nordgren, A., Anderlid, B. -M., Vandeweyer, G., Van Dijck, A., Van der Aa, N., Mckenna, B., Hancarova, M., Bendova, S., Havlovicova, M., Malerba, G., Bernardina, B. D., Muglia, P., van Haeringen, A., Hoffer, M. J. V., Franke, B., Cappuccio, G., Delatycki, M., Lockhart, P. J., Manning, M. A., Liu, P., Scheffer, I. E., Brunetti Pierri, N., Rommelse, N., Amaral, D. G., Santen, G. W. E., Trabetti, E., Sedlacek, Z., Michaelson, J. J., Pierce, K., Courchesne, E., Kooy, R. F., Acampado, J., Ace, A. J., Amatya, A., Astrovskaya, I., Bashar, A., Brooks, E., Butler, M. E., Cartner, L. A., Chin, W., Chung, W. K., Daniels, A. M., Feliciano, P., Fleisch, C., Ganesan, S., Jensen, W., Lash, A. E., Marini, R., Myers, V. J., O'Connor, E., Rigby, C., Robertson, B. E., Shah, N., Shah, S., Singer, E., Snyder, L. A. G., Stephens, A. N., Tjernagel, J., Vernoia, B. M., Volfovsky, N., White, L. C., Hsieh, A., Shen, Y., Zhou, X., Turner, T. N., Bahl, E., Thomas, T. R., Brueggeman, L., Koomar, T., Michael, R. J., O'Roak, B. J., Barnard, R. A., Gibbs, R. A., Muzny, D., Sabo, A., Ahmed, K. L. B., Eichler, E. E., Siegel, M., Abbeduto, L., Hilscher, B. A., Li, D., Smith, K., Thompson, S., Albright, C., Butter, E. M., Eldred, S., Hanna, N., Jones, M., Coury, D. L., Scherr, J., Pifher, T., Roby, E., Dennis, B., Higgins, L., Brown, M., Alessandri, M., Gutierrez, A., Hale, M. N., Herbert, L. M., Schneider, H. L., David, G., Annett, R. D., Sarver, D. E., Arriaga, I., Camba, A., Gulsrud, A. C., Haley, M., Mccracken, J. T., Sandhu, S., Tafolla, M., Yang, W. S., Carpenter, L. A., Bradley, C. C., Gwynette, F., Manning, P., Shaffer, R., Thomas, C., Bernier, R. A., Fox, E. A., Gerdts, J. A., Pepper, M., Ho, T., Cho, D., Piven, J., Lechniak, H., Soorya, L. V., Gordon, R., Wainer, A., Yeh, L., Ochoa-Lubinoff, C., Russo, N., Berry-Kravis, E., Booker, S., Erickson, C. A., Prock, L. M., Pawlowski, K. G., Matthews, E. T., Brewster, S. J., Hojlo, M. A., Abada, E., Lamarche, E., Murali, S. C., Harvey, W. T., Kaplan, H. E., Pierce, K. L., Demarco, L., Horner, S., Pandey, J., Plate, S., Sahin, M., Riley, K. D., Carmody, E., Constantini, J., Esler, A., Fatemi, A., Hutter, H., Landa, R. J., Mckenzie, A. P., Neely, J., Singh, V., Van Metre, B., Wodka, E. L., Fombonne, E. J., Huang-Storms, L. Y., Pacheco, L. D., Mastel, S. A., Coppola, L. A., Francis, S., Jarrett, A., Jacob, S., Lillie, N., Gunderson, J., Istephanous, D., Simon, L., Wasserberg, O., Rachubinski, A. L., Rosenberg, C. R., Kanne, S. M., Shocklee, A. D., Takahashi, N., Bridwell, S. L., Klimczac, R. L., Mahurin, M. A., Cotrell, H. E., Grant, C. A., Hunter, S. G., Martin, C. L., Taylor, C. M., Walsh, L. K., Dent, K. A., Mason, A., Sziklay, A., Smith, C. J., Nordenskjold, M., Romano, C., Peeters, H., Gecz, J., and Xia, K.

Subjects
0301 basic medicine, Male, CCCTC-Binding Factor, Transcription Factor, Basic Helix-Loop-Helix Transcription Factor, DNA Mutational Analysis, General Physics and Astronomy, RNA-Binding Protein, Heterogeneous-Nuclear Ribonucleoprotein U, VARIANTS, medicine.disease_cause, Cohort Studies, 0302 clinical medicine, Neurodevelopmental Disorder, Basic Helix-Loop-Helix Transcription Factors, SPARK Consortium, 2.1 Biological and endogenous factors, Copy-number variation, Aetiology, lcsh:Science, GABRG2, Genetics, Mutation, Multidisciplinary, biology, Neurodevelopmental disorders, RNA-Binding Proteins, High-Throughput Nucleotide Sequencing, Autism spectrum disorders, Multidisciplinary Sciences, DNA-Binding Proteins, Science & Technology - Other Topics, Female, Case-Control Studie, Engineering sciences. Technology, Human, Science, DNA-Binding Protein, Genetic Association Studie, COPY-NUMBER VARIATION, General Biochemistry, Genetics and Molecular Biology, DNA sequencing, Article, KCNQ3 Potassium Channel, DNA Mutational Analysi, 03 medical and health sciences, medicine, Humans, Genetic Predisposition to Disease, AUTISM, Gene, Genetic Association Studies, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Science & Technology, DISABILITY, Prevention, Case-control study, General Chemistry, Repressor Protein, medicine.disease, FRAMEWORK, Repressor Proteins, DE-NOVO MUTATION, 030104 developmental biology, CTCF, Neurodevelopmental Disorders, Case-Control Studies, biology.protein, Next-generation sequencing, Autism, lcsh:Q, Cohort Studie, 030217 neurology & neurosurgery, Transcription Factors
Abstract

Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case–control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF, For many neurodevelopmental disorder (NDD) risk genes, the significance for mutational burden is unestablished. Here, the authors sequence 125 candidate NDD genes in over 16,000 NDD cases; case-control mutational burden analysis identifies 48 genes with a significant burden of severe ultra-rare mutations.

Published
2020

5. Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders

Author

Gillentine, M.A., Wang, T., Hoekzema, K., Rosenfeld, J., Liu, P, Guo, H, Kim, C.N., Vries, B.B. de, Vissers, L.E.L.M., Nordenskjold, M., Kvarnung, M., Lindstrand, A., Nordgren, A., Gecz, J., Iascone, M., Cereda, A., Scatigno, A., Maitz, S., Zanni, G., Bertini, E., Zweier, C., Schuhmann, S., Wiesener, A., Pepper, M., Panjwani, H., Torti, E., Abid, F., Anselm, I., Srivastava, S., Atwal, P., Bacino, C.A., Bhat, G., Cobian, K., Bird, L.M., Friedman, J., Wright, M.S., Callewaert, B., Petit, F., Mathieu, S., Afenjar, A., Christensen, C.K., White, K.M., Elpeleg, O., Berger, I., Espineli, E.J., Fagerberg, C., Brasch-Andersen, C., Hansen, L.K., Feyma, T., Hughes, S., Thiffault, I., Sullivan, B., Yan, S., Keller, K., Keren, B., Mignot, C., Kooy, F., Meuwissen, M., Basinger, A., Kukolich, M., Philips, M., Ortega, L., Drummond-Borg, M., Lauridsen, M., Sorensen, K., Lehman, A., Lopez-Rangel, E., Levy, P., Lessel, D., Lotze, T., Madan-Khetarpal, S., Sebastian, J., Vento, J., Vats, D., Benman, L.M., McKee, S., Mirzaa, G.M., Muss, C., Pappas, J., Peeters, H, Romano, C, Elia, M., Galesi, O., Simon, M.E., Gassen, K.L.I. van, Simpson, K., Stratton, R., Syed, S., Thevenon, J., Palafoll, I.V., Vitobello, A., Bournez, M., Faivre, L., Xia, K., Earl, R.K., Nowakowski, T., Bernier, R.A., Eichler, E.E., Gillentine, M.A., Wang, T., Hoekzema, K., Rosenfeld, J., Liu, P, Guo, H, Kim, C.N., Vries, B.B. de, Vissers, L.E.L.M., Nordenskjold, M., Kvarnung, M., Lindstrand, A., Nordgren, A., Gecz, J., Iascone, M., Cereda, A., Scatigno, A., Maitz, S., Zanni, G., Bertini, E., Zweier, C., Schuhmann, S., Wiesener, A., Pepper, M., Panjwani, H., Torti, E., Abid, F., Anselm, I., Srivastava, S., Atwal, P., Bacino, C.A., Bhat, G., Cobian, K., Bird, L.M., Friedman, J., Wright, M.S., Callewaert, B., Petit, F., Mathieu, S., Afenjar, A., Christensen, C.K., White, K.M., Elpeleg, O., Berger, I., Espineli, E.J., Fagerberg, C., Brasch-Andersen, C., Hansen, L.K., Feyma, T., Hughes, S., Thiffault, I., Sullivan, B., Yan, S., Keller, K., Keren, B., Mignot, C., Kooy, F., Meuwissen, M., Basinger, A., Kukolich, M., Philips, M., Ortega, L., Drummond-Borg, M., Lauridsen, M., Sorensen, K., Lehman, A., Lopez-Rangel, E., Levy, P., Lessel, D., Lotze, T., Madan-Khetarpal, S., Sebastian, J., Vento, J., Vats, D., Benman, L.M., McKee, S., Mirzaa, G.M., Muss, C., Pappas, J., Peeters, H, Romano, C, Elia, M., Galesi, O., Simon, M.E., Gassen, K.L.I. van, Simpson, K., Stratton, R., Syed, S., Thevenon, J., Palafoll, I.V., Vitobello, A., Bournez, M., Faivre, L., Xia, K., Earl, R.K., Nowakowski, T., Bernier, R.A., and Eichler, E.E.

Abstract

Contains fulltext : 245103.pdf (Publisher’s version ) (Open Access), BACKGROUND: With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations. METHODS: We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk. RESULTS: We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare va

Published
2021

6. DLG4-related synaptopathy: a new rare brain disorder

Author

Rodríguez-Palmero, A., Boerrigter, M.M., Gómez-Andrés, D., Aldinger, K.A., Marcos-Alcalde, Í., Popp, B., Everman, D.B., Lovgren, A.K., Arpin, S., Bahrambeigi, V., Beunders, G., Bisgaard, A.M., Bjerregaard, V.A., Bruel, A.L., Challman, T.D., Cogné, B., Coubes, C., Man, S.A. de, Denommé-Pichon, A.S., Dye, T.J., Elmslie, F., Feuk, L., García-Miñaúr, S., Gertler, T., Giorgio, E., Gruchy, N., Haack, T.B., Haldeman-Englert, C.R., Haukanes, B.I., Hoyer, J., Hurst, A.C.E., Isidor, B., Soller, M.J., Kushary, S., Kvarnung, M., Landau, Y.E., Leppig, K.A., Lindstrand, A., Kleinendorst, L., Mackenzie, A., Mandrile, G., Mendelsohn, B.A., Moghadasi, S., Morton, J.E., Moutton, S., Müller, A.J., O'Leary, M., Pacio-Míguez, M., Palomares-Bralo, M., Parikh, S., Pfundt, R., Pode-Shakked, B., Rauch, A., Repnikova, E., Revah-Politi, A., Ross, M.J., Ruivenkamp, C.A.L., Sarrazin, E., Savatt, J.M., Schlüter, A., Schönewolf-Greulich, B., Shad, Z., Shaw-Smith, C., Shieh, J.T., Shohat, M., Spranger, S., Thiese, H., Mau-Them, F.T., Bon, B. van, Burgt, I. van der, Laar, I. van de, Drie, E. van, Haelst, M.M. van, Ravenswaaij-Arts, C.M.A. van, Verdura, E., Vitobello, A., Waldmüller, S., Whiting, S., Zweier, C., Prada, C.E., Vries, B.B. de, Dobyns, W.B., Reiter, S.F., Gómez-Puertas, P., Pujol, A., Tümer, Z., Rodríguez-Palmero, A., Boerrigter, M.M., Gómez-Andrés, D., Aldinger, K.A., Marcos-Alcalde, Í., Popp, B., Everman, D.B., Lovgren, A.K., Arpin, S., Bahrambeigi, V., Beunders, G., Bisgaard, A.M., Bjerregaard, V.A., Bruel, A.L., Challman, T.D., Cogné, B., Coubes, C., Man, S.A. de, Denommé-Pichon, A.S., Dye, T.J., Elmslie, F., Feuk, L., García-Miñaúr, S., Gertler, T., Giorgio, E., Gruchy, N., Haack, T.B., Haldeman-Englert, C.R., Haukanes, B.I., Hoyer, J., Hurst, A.C.E., Isidor, B., Soller, M.J., Kushary, S., Kvarnung, M., Landau, Y.E., Leppig, K.A., Lindstrand, A., Kleinendorst, L., Mackenzie, A., Mandrile, G., Mendelsohn, B.A., Moghadasi, S., Morton, J.E., Moutton, S., Müller, A.J., O'Leary, M., Pacio-Míguez, M., Palomares-Bralo, M., Parikh, S., Pfundt, R., Pode-Shakked, B., Rauch, A., Repnikova, E., Revah-Politi, A., Ross, M.J., Ruivenkamp, C.A.L., Sarrazin, E., Savatt, J.M., Schlüter, A., Schönewolf-Greulich, B., Shad, Z., Shaw-Smith, C., Shieh, J.T., Shohat, M., Spranger, S., Thiese, H., Mau-Them, F.T., Bon, B. van, Burgt, I. van der, Laar, I. van de, Drie, E. van, Haelst, M.M. van, Ravenswaaij-Arts, C.M.A. van, Verdura, E., Vitobello, A., Waldmüller, S., Whiting, S., Zweier, C., Prada, C.E., Vries, B.B. de, Dobyns, W.B., Reiter, S.F., Gómez-Puertas, P., Pujol, A., and Tümer, Z.

Abstract

Contains fulltext : 245031.pdf (Publisher’s version ) (Closed access), PURPOSE: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants. METHODS: The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing. RESULTS: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies. CONCLUSION: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.

Published
2021

7. Author Correction: Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders (Nature Communications, (2020), 11, 1, (4932), 10.1038/s41467-020-18723-y)

Author

Wang, T., Hoekzema, K., Vecchio, Davide., Wu, H., Sulovari, A., Coe, B. P., Gillentine, M. A., Wilfert, A. B., Perez-Jurado, L. A., Kvarnung, M., Sleyp, Y., Earl, R. K., Rosenfeld, J. A., Geisheker, M. R., Han, L., Du, B., Barnett, C., Thompson, E., Shaw, M., Carroll, R., Friend, K., Catford, R., Palmer, E. E., Zou, X., Ou, J., Li, H., Guo, H., Gerdts, J., Avola, E., Calabrese, Giuseppe, Elia, Maurizio., Greco, Donatella, Lindstrand, A., Nordgren, A., Anderlid, B. -M., Vandeweyer, G., Van Dijck, A., Van der Aa, N., Mckenna, B., Hancarova, M., Bendova, S., Havlovicova, M., Malerba, G., Bernardina, B. D., Muglia, P., van Haeringen, A., Hoffer, M. J. V., Franke, B., Cappuccio, G., Delatycki, M., Lockhart, P. J., Manning, M. A., Liu, P., Scheffer, I. E., Brunetti-Pierri, N., Rommelse, N., Amaral, D. G., Santen, G. W. E., Trabetti, E., Sedlacek, Z., Michaelson, J. J., Pierce, K., Courchesne, E., Kooy, R. F., Acampado, J., Ace, A. J., Amatya, A., Astrovskaya, I., Bashar, A., Brooks, E., Butler, M. E., Cartner, L. A., Chin, W., Chung, W. K., Daniels, A. M., Feliciano, P., Fleisch, C., Ganesan, S., Jensen, W., Lash, A. E., Marini, R., Myers, V. J., O'Connor, E., Rigby, C., Robertson, B. E., Shah, N., Shah, S., Singer, E., Snyder, L. A. G., Stephens, A. N., Tjernagel, J., Vernoia, B. M., Volfovsky, N., White, L. C., Hsieh, A., Shen, Y., Zhou, X., Turner, T. N., Bahl, E., Thomas, T. R., Brueggeman, L., Koomar, T., O'Roak, B. J., Barnard, R. A., Gibbs, R. A., Muzny, D., Sabo, A., Ahmed, K. L. B., Eichler, E. E., Siegel, M., Abbeduto, L., Hilscher, B. A., Li, D., Smith, K., Thompson, S., Albright, C., Butter, E. M., Eldred, S., Hanna, N., Jones, M., Coury, D. L., Scherr, J., Pifher, T., Roby, E., Dennis, B., Higgins, L., Brown, M., Alessandri, M., Gutierrez, A., Hale, M. N., Herbert, L. M., Schneider, H. L., David, G., Annett, R. D., Sarver, D. E., Arriaga, I., Camba, A., Gulsrud, A. C., Haley, M., Mccracken, J. T., Sandhu, S., Tafolla, M., Yang, W. S., Carpenter, L. A., Bradley, C. C., Gwynette, F., Manning, P., Shaffer, R., Thomas, C., Bernier, R. A., Fox, E. A., Gerdts, J. A., Pepper, M., Ho, T., Cho, D., Piven, J., Lechniak, H., Soorya, L. V., Gordon, R., Wainer, A., Yeh, L., Ochoa-Lubinoff, C., Russo, N., Berry-Kravis, E., Booker, S., Erickson, C. A., Prock, L. M., Pawlowski, K. G., Matthews, E. T., Brewster, S. J., Hojlo, M. A., Abada, E., Lamarche, E., Murali, S. C., Harvey, W. T., Kaplan, H. E., Pierce, K. L., Demarco, L., Horner, S., Pandey, J., Plate, S., Sahin, M., Riley, K. D., Carmody, E., Constantini, J., Esler, A., Fatemi, A., Hutter, H., Landa, R. J., Mckenzie, A. P., Neely, J., Singh, V., Van Metre, B., Wodka, E. L., Fombonne, E. J., Huang-Storms, L. Y., Pacheco, L. D., Mastel, S. A., Coppola, L. A., Francis, S., Jarrett, A., Jacob, S., Lillie, N., Gunderson, J., Istephanous, D., Simon, L., Wasserberg, O., Rachubinski, A. L., Rosenberg, C. R., Kanne, S. M., Shocklee, A. D., Takahashi, N., Bridwell, S. L., Klimczac, R. L., Mahurin, M. A., Cotrell, H. E., Grant, C. A., Hunter, S. G., Martin, C. L., Taylor, C. M., Walsh, L. K., Dent, K. A., Mason, A., Sziklay, A., Smith, C. J., Nordenskjold, M., Romano, Corrado, Peeters, H., Gecz, J., and Xia, K.

Published
2020

8. Phenotypic and genotypic description of 44 patients with variants in DLG4 encoding the post-synaptic density protein PSD-95

Author

Rodriguez-Palmero Seuma, A., Boerrigter, M., Mandrile, G., Pelle, A., Giorgio, E., Lindstrand, A., Johansson, M., Kvarnung, M., Everman, D., Bahrambeigi, V., MacKenzie, A., Morton, J., Ruivenkamp, C., Challman, T., Hurst, A., Hoyer, J., Elmslie, F., Dye, T., Isidor, B., Haldeman-Englert, C., Gomez-Andres, D., Schluter, A., de Man, S., Shieh, J., Prada, C., Moutton, S., Denomme-Pichon, A., Motti, S., Bruel, A., Mau-Them, F. Tran, Reiter, S., van Ravenswaaij-Arts, C., Shaw-Smith, C., Parikh, S., Aldinger, K., Lovgren, A., Rauch, A., Ross, M., Gomez-Puertas, P., de Vries, B., Pujol, A., Tumer, Z., and Clinical Cognitive Neuropsychiatry Research Program (CCNP)

Published
2020

9. Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

Author

Wang, T., Hoekzema, K., Vecchio, D., Wu, H., Sulovari, A., Coe, B.P., Gillentine, M.A., Wilfert, A.B., Perez-Jurado, L.A., Kvarnung, M., Sleyp, Y., Earl, R.K., Rosenfeld, J.A., Geisheker, M.R., Han, L., Du, B., Barnett, C., Thompson, E., Shaw, M., Carroll, R., Friend, K., Catford, R., Palmer, E.E., Zou, X., Ou, J., Li, H., Guo, H, Gerdts, J., Avola, E., Calabrese, G., Elia, M., Greco, D., Lindstrand, A., Nordgren, A., Anderlid, B.M., Vandeweyer, G., Dijck, A. Van, Aa, N. van der, McKenna, B., Hancarova, M., Bendova, S., Havlovicova, M., Malerba, G., Bernardina, B.D., Muglia, P., Haeringen, A. van, Hoffer, M.J.V., Franke, B., Cappuccio, G., Delatycki, M., Lockhart, P.J., Manning, M.A., Liu, P, Scheffer, I.E., Brunetti-Pierri, N., Rommelse, N.N.J., Amaral, D.G., Santen, G.W.E., Trabetti, E., Sedláček, Z., Michaelson, J.J., Pierce, K., Courchesne, E., Kooy, R.F., Nordenskjöld, M., Romano, C, Peeters, H, Bernier, R.A., Gecz, J., Xia, K., Eichler, E.E., Wang, T., Hoekzema, K., Vecchio, D., Wu, H., Sulovari, A., Coe, B.P., Gillentine, M.A., Wilfert, A.B., Perez-Jurado, L.A., Kvarnung, M., Sleyp, Y., Earl, R.K., Rosenfeld, J.A., Geisheker, M.R., Han, L., Du, B., Barnett, C., Thompson, E., Shaw, M., Carroll, R., Friend, K., Catford, R., Palmer, E.E., Zou, X., Ou, J., Li, H., Guo, H, Gerdts, J., Avola, E., Calabrese, G., Elia, M., Greco, D., Lindstrand, A., Nordgren, A., Anderlid, B.M., Vandeweyer, G., Dijck, A. Van, Aa, N. van der, McKenna, B., Hancarova, M., Bendova, S., Havlovicova, M., Malerba, G., Bernardina, B.D., Muglia, P., Haeringen, A. van, Hoffer, M.J.V., Franke, B., Cappuccio, G., Delatycki, M., Lockhart, P.J., Manning, M.A., Liu, P, Scheffer, I.E., Brunetti-Pierri, N., Rommelse, N.N.J., Amaral, D.G., Santen, G.W.E., Trabetti, E., Sedláček, Z., Michaelson, J.J., Pierce, K., Courchesne, E., Kooy, R.F., Nordenskjöld, M., Romano, C, Peeters, H, Bernier, R.A., Gecz, J., Xia, K., and Eichler, E.E.

Abstract

Contains fulltext : 229260.pdf (publisher's version ) (Open Access), Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E-06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E-07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype-genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.

Published
2020

10. Author Correction: Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders (Nature Communications, (2020), 11, 1, (4932), 10.1038/s41467-020-18723-y)

Author

Wang, T, Hoekzema, K, Vecchio, D, Wu, H, Sulovari, A, Coe, BP, Gillentine, MA, Wilfert, AB, Perez-Jurado, LA, Kvarnung, M, Sleyp, Y, Earl, RK, Rosenfeld, JA, Geisheker, MR, Han, L, Du, B, Barnett, C, Thompson, E, Shaw, M, Carroll, R, Friend, K, Catford, R, Palmer, EE, Zou, X, Ou, J, Li, H, Guo, H, Gerdts, J, Avola, E, Calabrese, G, Elia, M, Greco, D, Lindstrand, A, Nordgren, A, Anderlid, BM, Vandeweyer, G, Van Dijck, A, Van der Aa, N, McKenna, B, Hancarova, M, Bendova, S, Havlovicova, M, Malerba, G, Bernardina, BD, Muglia, P, van Haeringen, A, Hoffer, MJV, Franke, B, Cappuccio, G, Delatycki, M, Lockhart, PJ, Manning, MA, Liu, P, Scheffer, IE, Brunetti-Pierri, N, Rommelse, N, Amaral, DG, Santen, GWE, Trabetti, E, Sedláček, Z, Michaelson, JJ, Pierce, K, Courchesne, E, Kooy, RF, Acampado, J, Ace, AJ, Amatya, A, Astrovskaya, I, Bashar, A, Brooks, E, Butler, ME, Cartner, LA, Chin, W, Chung, WK, Daniels, AM, Feliciano, P, Fleisch, C, Ganesan, S, Jensen, W, Lash, AE, Marini, R, Myers, VJ, O’Connor, E, Rigby, C, Robertson, BE, Shah, N, Shah, S, Singer, E, Snyder, LAG, Stephens, AN, Tjernagel, J, Vernoia, BM, Volfovsky, N, White, LC, Hsieh, A, Shen, Y, Zhou, X, Turner, TN, Bahl, E, Thomas, TR, Wang, T, Hoekzema, K, Vecchio, D, Wu, H, Sulovari, A, Coe, BP, Gillentine, MA, Wilfert, AB, Perez-Jurado, LA, Kvarnung, M, Sleyp, Y, Earl, RK, Rosenfeld, JA, Geisheker, MR, Han, L, Du, B, Barnett, C, Thompson, E, Shaw, M, Carroll, R, Friend, K, Catford, R, Palmer, EE, Zou, X, Ou, J, Li, H, Guo, H, Gerdts, J, Avola, E, Calabrese, G, Elia, M, Greco, D, Lindstrand, A, Nordgren, A, Anderlid, BM, Vandeweyer, G, Van Dijck, A, Van der Aa, N, McKenna, B, Hancarova, M, Bendova, S, Havlovicova, M, Malerba, G, Bernardina, BD, Muglia, P, van Haeringen, A, Hoffer, MJV, Franke, B, Cappuccio, G, Delatycki, M, Lockhart, PJ, Manning, MA, Liu, P, Scheffer, IE, Brunetti-Pierri, N, Rommelse, N, Amaral, DG, Santen, GWE, Trabetti, E, Sedláček, Z, Michaelson, JJ, Pierce, K, Courchesne, E, Kooy, RF, Acampado, J, Ace, AJ, Amatya, A, Astrovskaya, I, Bashar, A, Brooks, E, Butler, ME, Cartner, LA, Chin, W, Chung, WK, Daniels, AM, Feliciano, P, Fleisch, C, Ganesan, S, Jensen, W, Lash, AE, Marini, R, Myers, VJ, O’Connor, E, Rigby, C, Robertson, BE, Shah, N, Shah, S, Singer, E, Snyder, LAG, Stephens, AN, Tjernagel, J, Vernoia, BM, Volfovsky, N, White, LC, Hsieh, A, Shen, Y, Zhou, X, Turner, TN, Bahl, E, and Thomas, TR

Abstract

The original version of this Article contained an error on page 5 of the Results section, which incorrectly read ‘They are characterized by craniofacial dysmorphisms (9/10), thin vermillion border and lips (4/7), and feeding difficulties (6/11), and exhibit neonatal hypotonia (10/7)’. The correct version states ‘They are characterized by craniofacial dysmorphisms (9/10), thin vermillion border and lips (4/7), and feeding difficulties (6/11), and exhibit neonatal hypotonia (7/10)’.

Published
2020

11. Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders (vol 11, 4932, 2020)

Author

Wang, T, Hoekzema, K, Vecchio, D, Wu, H, Sulovari, A, Coe, BP, Gillentine, MA, Wilfert, AB, Perez-Jurado, LA, Kvarnung, M, Sleyp, Y, Earl, RK, Rosenfeld, JA, Geisheker, MR, Han, L, Du, B, Barnett, C, Thompson, E, Shaw, M, Carroll, R, Friend, K, Catford, R, Palmer, EE, Zou, X, Ou, J, Li, H, Guo, H, Gerdts, J, Avola, E, Calabrese, G, Elia, M, Greco, D, Lindstrand, A, Nordgren, A, Anderlid, B-M, Vandeweyer, G, Van Dijck, A, Van der Aa, N, McKenna, B, Hancarova, M, Bendova, S, Havlovicova, M, Malerba, G, Bernardina, BD, Muglia, P, van Haeringen, A, Hoffer, MJV, Franke, B, Cappuccio, G, Delatycki, M, Lockhart, PJ, Manning, MA, Liu, P, Scheffer, IE, Brunetti-Pierri, N, Rommelse, N, Amaral, DG, Santen, GWE, Trabetti, E, Sedlacek, Z, Michaelson, JJ, Pierce, K, Courchesne, E, Kooy, RF, Nordenskjold, M, Romano, C, Peeters, H, Bernier, RA, Gecz, J, Xia, K, Eichler, EE, Wang, T, Hoekzema, K, Vecchio, D, Wu, H, Sulovari, A, Coe, BP, Gillentine, MA, Wilfert, AB, Perez-Jurado, LA, Kvarnung, M, Sleyp, Y, Earl, RK, Rosenfeld, JA, Geisheker, MR, Han, L, Du, B, Barnett, C, Thompson, E, Shaw, M, Carroll, R, Friend, K, Catford, R, Palmer, EE, Zou, X, Ou, J, Li, H, Guo, H, Gerdts, J, Avola, E, Calabrese, G, Elia, M, Greco, D, Lindstrand, A, Nordgren, A, Anderlid, B-M, Vandeweyer, G, Van Dijck, A, Van der Aa, N, McKenna, B, Hancarova, M, Bendova, S, Havlovicova, M, Malerba, G, Bernardina, BD, Muglia, P, van Haeringen, A, Hoffer, MJV, Franke, B, Cappuccio, G, Delatycki, M, Lockhart, PJ, Manning, MA, Liu, P, Scheffer, IE, Brunetti-Pierri, N, Rommelse, N, Amaral, DG, Santen, GWE, Trabetti, E, Sedlacek, Z, Michaelson, JJ, Pierce, K, Courchesne, E, Kooy, RF, Nordenskjold, M, Romano, C, Peeters, H, Bernier, RA, Gecz, J, Xia, K, and Eichler, EE

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. Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

Author

Wang, T, Hoekzema, K, Vecchio, D, Wu, H, Sulovari, A, Coe, BP, Gillentine, MA, Wilfert, AB, Perez-Jurado, LA, Kvarnung, M, Sleyp, Y, Earl, RK, Rosenfeld, JA, Geisheker, MR, Han, L, Du, B, Barnett, C, Thompson, E, Shaw, M, Carroll, R, Friend, K, Catford, R, Palmer, EE, Zou, X, Ou, J, Li, H, Guo, H, Gerdts, J, Avola, E, Calabrese, G, Elia, M, Greco, D, Lindstrand, A, Nordgren, A, Anderlid, B-M, Vandeweyer, G, Van Dijck, A, Van der Aa, N, McKenna, B, Hancarova, M, Bendova, S, Havlovicova, M, Malerba, G, Dalla Bernardina, B, Muglia, P, van Haeringen, A, Hoffer, MJV, Franke, B, Cappuccio, G, Delatycki, M, Lockhart, PJ, Manning, MA, Liu, P, Scheffer, IE, Brunetti-Pierri, N, Rommelse, N, Amaral, DG, Santen, GWE, Trabetti, E, Sedlacek, Z, Michaelson, JJ, Pierce, K, Courchesne, E, Kooy, RF, Nordenskjold, M, Romano, C, Peeters, H, Bernier, RA, Gecz, J, Xia, K, Eichler, EE, Wang, T, Hoekzema, K, Vecchio, D, Wu, H, Sulovari, A, Coe, BP, Gillentine, MA, Wilfert, AB, Perez-Jurado, LA, Kvarnung, M, Sleyp, Y, Earl, RK, Rosenfeld, JA, Geisheker, MR, Han, L, Du, B, Barnett, C, Thompson, E, Shaw, M, Carroll, R, Friend, K, Catford, R, Palmer, EE, Zou, X, Ou, J, Li, H, Guo, H, Gerdts, J, Avola, E, Calabrese, G, Elia, M, Greco, D, Lindstrand, A, Nordgren, A, Anderlid, B-M, Vandeweyer, G, Van Dijck, A, Van der Aa, N, McKenna, B, Hancarova, M, Bendova, S, Havlovicova, M, Malerba, G, Dalla Bernardina, B, Muglia, P, van Haeringen, A, Hoffer, MJV, Franke, B, Cappuccio, G, Delatycki, M, Lockhart, PJ, Manning, MA, Liu, P, Scheffer, IE, Brunetti-Pierri, N, Rommelse, N, Amaral, DG, Santen, GWE, Trabetti, E, Sedlacek, Z, Michaelson, JJ, Pierce, K, Courchesne, E, Kooy, RF, Nordenskjold, M, Romano, C, Peeters, H, Bernier, RA, Gecz, J, Xia, K, and Eichler, EE

Abstract

Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E-06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E-07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype-genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.

Published
2020

13. Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP

Author

Dijck, A. van, Vulto-van Silfhout, A.T., Cappuyns, E., Werf, I.M. van der, Mancini, G.M., Tzschach, A., Bernier, R., Gozes, I., Eichler, E.E., Romano, C., Lindstrand, A., Nordgren, A., Kvarnung, M., Kleefstra, T., Vries, B.B.A. de, Kury, S., Rosenfeld, J.A., Meuwissen, M.E., Vandeweyer, G., Kooy, R.F., Bakshi, M., Wilson, M., Berman, Y., Dickson, R., Fransen, E., Helsmoortel, C., Ende, J. van den, Aa, N. van der, Wijdeven, M.J. van de, Rosenblum, J., Monteiro, F., Kok, F., Quercia, N., Bowdin, S., Dyment, D., Chitayat, D., Alkhunaizi, E., Boonen, S.E., Keren, B., Jacquette, A., Faivre, L., Bezieau, S., Isidor, B., Riess, A., Moog, U., Lynch, S.A., McVeigh, T., Elpeleg, O., Smeland, M.F., Fannemel, M., Haeringen, A. van, Maas, S.M., Veenstra-Knol, H.E., Schouten, M., Willemsen, M.H., Marcelis, C.L., Ockeloen, C., Burgt, I. van der, Feenstra, I., Smagt, J. van der, Jezela-Stanek, A., Krajewska-Walasek, M., Gonzalez-Lamuno, D., Anderlid, B.M., Malmgren, H., Nordenskjold, M., Clement, E., Hurst, J., Metcalfe, K., Mansour, S., Lachlan, K., Clayton-Smith, J., Hendon, L.G., Abdulrahman, O.A., Morrow, E., McMillan, C., Gerdts, J., Peeden, J., Vergano, S.A.S., Valentino, C., Chung, W.K., Ozmore, J.R., Bedrosian-Sermone, S., Dennis, A., Treat, K., Hughes, S.S., Safina, N., Pichon, J.B. le, McGuire, M., Infante, E., Madan-Khetarpal, S., Desai, S., Benke, P., Krokosky, A., Cristian, I., Baker, L., Gripp, K., Stessman, H.A., Eichenberger, J., Jayakar, P., Pizzino, A., Manning, M.A., Slattery, L., ADNP Consortium, Universidad de Cantabria, ADNP Consortium, Human Genetics, ANS - Complex Trait Genetics, and Clinical Genetics

Subjects
Male, 0301 basic medicine, Pediatrics, Autism Spectrum Disorder, Autism, Intellectual disability, Cohort Studies, Epilepsy, 0302 clinical medicine, Genotype-phenotype distinction, Neurodevelopmental disorder, Neurodevelopmental Disorder, Helsmoortel-Van der Aa syndrome, Child, ADNP, Syndrome, Hypotonia, Autism spectrum disorder, Child, Preschool, Cohort, Female, Abnormalities, medicine.symptom, Multiple, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Adult, medicine.medical_specialty, Adolescent, Nerve Tissue Proteins, Article, Young Adult, 03 medical and health sciences, Intellectual Disability, Helsmoortel-Van der Aa Síndrome, medicine, Genetics, Humans, Abnormalities, Multiple, Preschool, Biology, Biological Psychiatry, Homeodomain Proteins, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, Infant, medicine.disease, 030104 developmental biology, Neurodevelopmental Disorders, Mutation, Human medicine, business, 030217 neurology & neurosurgery
Abstract

Background In genome-wide screening studies for de novo mutations underlying autism and intellectual disability, mutations in the ADNP gene are consistently reported among the most frequent. ADNP mutations have been identified in children with autism spectrum disorder comorbid with intellectual disability, distinctive facial features, and deficits in multiple organ systems. However, a comprehensive clinical description of the Helsmoortel-Van der Aa syndrome is lacking. Methods We identified a worldwide cohort of 78 individuals with likely disruptive mutations in ADNP from January 2014 to October 2016 through systematic literature search, by contacting collaborators, and through direct interaction with parents. Clinicians filled in a structured questionnaire on genetic and clinical findings to enable correlations between genotype and phenotype. Clinical photographs and specialist reports were gathered. Parents were interviewed to complement the written questionnaires. Results We report on the detailed clinical characterization of a large cohort of individuals with an ADNP mutation and demonstrate a distinctive combination of clinical features, including mild to severe intellectual disability, autism, severe speech and motor delay, and common facial characteristics. Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities. Strikingly, individuals with the recurrent p.Tyr719* mutation were more severely affected. Conclusions This overview defines the full clinical spectrum of individuals with ADNP mutations, a specific autism subtype. We show that individuals with mutations in ADNP have many overlapping clinical features that are distinctive from those of other autism and/or intellectual disability syndromes. In addition, our data show preliminary evidence of a correlation between genotype and phenotype. This work was supported by grants from the European Research Area Networks Network of European Funding for Neuroscience Research through the Research Foundation–Flanders and the Chief Scientist Office–Ministry of Health (to RFK, GV, IG). This research was supported, in part, by grants from the Simons Foundation Autism Research Initiative (Grant No. SFARI 303241 to EEE) and National Institutes of Health (Grant No. R01MH101221 to EEE). This work was also supported by the Italian Ministry of Health and ‘5 per mille’ funding (to CR). For many individuals, sequencing was provided by research initiatives like the Care4Rare Research Consortium in Canada or the Deciphering Developmental Disorders (DDD) study in the UK. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (Grant No. HICF-1009–003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (Grant No. WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South Research Ethics Committee, and GEN/284/12 granted by the Republic of Ireland Research Ethics Committee). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network.

Published
2019

14. From cytogenetics to cytogenomics : whole genome sequencing as a comprehensive genetic test in rare disease diagnostics

Author

Nilsson, D., Eisfeldt, J., Lundin, J., Pettersson, M., Kvarnung, M., Lieden, A., Sahlin, E., Lagerstedt, K., Martin, M., Ygberg, S., Bjerin, O., Stranneheim, H., Wedell, A., Nordenskjold, M., Soller, M. Johansson, Nordgren, A., Wirta, Valtteri, Lindstrand, A., Nilsson, D., Eisfeldt, J., Lundin, J., Pettersson, M., Kvarnung, M., Lieden, A., Sahlin, E., Lagerstedt, K., Martin, M., Ygberg, S., Bjerin, O., Stranneheim, H., Wedell, A., Nordenskjold, M., Soller, M. Johansson, Nordgren, A., Wirta, Valtteri, and Lindstrand, A.

Abstract

Rare genetic diseases are caused by different types of genetic variants, from single nucleotide variants (SNVs) to large chromosomal rearrangements. Recent data indicates that whole genome sequencing (WGS) may be used as a comprehensive test to identify multiple types of pathologic genetic aberrations in a single analysis. We present FindSV, a bioinformatic pipeline for detection of balanced (inversions and translocations) and unbalanced (deletions and duplications) structural variants (SVs). First, FindSV was tested on 106 validated deletions and duplications with a median size of 850 kb (min: 511 bp, max: 155 Mb). All variants were detected. Second, we demonstrated the clinical utility in 138 monogenic WGS panels. SV analysis yielded 11 diagnostic findings (8%). Remarkably, a complex structural rearrangement involving two clustered deletions disrupting SCN1A, SCN2A, and SCN3A was identified in a three months old girl with epileptic encephalopathy. Finally, 100 consecutive samples referred for clinical microarray were also analyzed by WGS. The WGS data was screened for large (>2 kbp) SVs genome wide, processed for visualization in our clinical routine arrayCGH workflow with the newly developed tool vcf2cytosure, and for exonic SVs and SNVs in a panel of 700 genes linked to intellectual disability. We also applied short tandem repeat (STR) expansion detection and discovered one pathologic expansion in ATXN7. The diagnostic rate (29%) was doubled compared to clinical microarray (12%). In conclusion, using WGS we have detected a wide range of structural variation with high accuracy, confirming it a powerful comprehensive genetic test in a clinical diagnostic laboratory setting., QC 20191104

Published
2019
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15. 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

16. Disruptive variants of CSDE1 associate with autism and interfere with neuronal development and synaptic transmission

Author

Guo, H. (Hui), Li, Y. (Ying), Shen, L. (Lu), Wang, T. (Tianyun), Jia, X. (Xiangbin), Liu, L. (Lijuan), Xu, T. (Tao), Ou, M. (Mengzhu), Hoekzema, K. (Kendra), Wu, H. (Huidan), Gillentine, M.A. (Madelyn A.), Liu, C. (Cenying), Ni, H. (Hailun), Peng, P. (Pengwei), Zhao, R. (Rongjuan), Zhang, Y. (Yu), Phornphutkul, C. (Chanika), Stegmann, A.P.A. (Alexander P.A.), Prada, C.E. (C.), Hopkin, R., Shieh, J.T. (Joseph T.), McWalter, K. (Kirsty), Monaghan, K.G. (Kristin G.), Hasselt, P.M. (Peter) van, van Gassen, K. (Koen), Bai, T. (Ting), Long, M. (Min), Han, L. (Lin), Quan, Y. (Yingting), Chen, M. (Meilin), Zhang, Y. (Yaowen), Li, K. (Kuokuo), Zhang, Q. (Qiumeng), Tan, J. (Jieqiong), Zhu, T. (Tengfei), Liu, Y. (Yaning), Pang, N. (Nan), Peng, J. (Jing), Scott, D.A., Lalani, S.R. (Seema R.), Azamian, M. (Mahshid), Mancini, G.M.S. (Grazia), Adams, D.J. (Darius J.), Kvarnung, M. (Malin), Lindstrand, A. (Anna), Nordgren, A. (Ann), Pevsner, J. (Jonathan), Osei-Owusu, I.A. (Ikeoluwa A.), Romano, C. (Corrado), Calabrese, G. (Giuseppe), Galesi, O. (O.), Gecz, J. (Jozef), Haan, E. (Eric), Ranells, J. (Judith), Racobaldo, M. (Melissa), Nordenskjöld, M., Madan-Khetarpal, S. (Suneeta), Sebastian, J. (Jessica), Ball, S. (Susie), Zou, X. (Xiaobing), Zhao, J. (Jingping), Hu, Z. (Zhengmao), Xia, F. (Fan), Liu, P. (Pengfei), Rosenfeld, J.A. (Jill), Vries, B. (Boukje) de, Bernier, R.A. (Raphael A.), Xu, Z.-Q.D. (Zhi-Qing David), Li, H. (Honghui), Xie, W. (Wei), Hufnagel, R.B. (Robert B.), Eichler, E.E. (Evan), Xia, K. (Kun), Guo, H. (Hui), Li, Y. (Ying), Shen, L. (Lu), Wang, T. (Tianyun), Jia, X. (Xiangbin), Liu, L. (Lijuan), Xu, T. (Tao), Ou, M. (Mengzhu), Hoekzema, K. (Kendra), Wu, H. (Huidan), Gillentine, M.A. (Madelyn A.), Liu, C. (Cenying), Ni, H. (Hailun), Peng, P. (Pengwei), Zhao, R. (Rongjuan), Zhang, Y. (Yu), Phornphutkul, C. (Chanika), Stegmann, A.P.A. (Alexander P.A.), Prada, C.E. (C.), Hopkin, R., Shieh, J.T. (Joseph T.), McWalter, K. (Kirsty), Monaghan, K.G. (Kristin G.), Hasselt, P.M. (Peter) van, van Gassen, K. (Koen), Bai, T. (Ting), Long, M. (Min), Han, L. (Lin), Quan, Y. (Yingting), Chen, M. (Meilin), Zhang, Y. (Yaowen), Li, K. (Kuokuo), Zhang, Q. (Qiumeng), Tan, J. (Jieqiong), Zhu, T. (Tengfei), Liu, Y. (Yaning), Pang, N. (Nan), Peng, J. (Jing), Scott, D.A., Lalani, S.R. (Seema R.), Azamian, M. (Mahshid), Mancini, G.M.S. (Grazia), Adams, D.J. (Darius J.), Kvarnung, M. (Malin), Lindstrand, A. (Anna), Nordgren, A. (Ann), Pevsner, J. (Jonathan), Osei-Owusu, I.A. (Ikeoluwa A.), Romano, C. (Corrado), Calabrese, G. (Giuseppe), Galesi, O. (O.), Gecz, J. (Jozef), Haan, E. (Eric), Ranells, J. (Judith), Racobaldo, M. (Melissa), Nordenskjöld, M., Madan-Khetarpal, S. (Suneeta), Sebastian, J. (Jessica), Ball, S. (Susie), Zou, X. (Xiaobing), Zhao, J. (Jingping), Hu, Z. (Zhengmao), Xia, F. (Fan), Liu, P. (Pengfei), Rosenfeld, J.A. (Jill), Vries, B. (Boukje) de, Bernier, R.A. (Raphael A.), Xu, Z.-Q.D. (Zhi-Qing David), Li, H. (Honghui), Xie, W. (Wei), Hufnagel, R.B. (Robert B.), Eichler, E.E. (Evan), and Xia, K. (Kun)

Abstract

RNA binding proteins are key players in posttranscriptional regulation and have been implicated in neurodevelopmental and neuropsychiatric disorders. Here, we report a significant burden of heterozygous, likely genedisrupting variants in CSDE1 (encoding a highly constrained RNA binding protein) among patients with autism and related neurodevelopmental disabilities. Analysis of 17 patients identifies common phenotypes including autism, intellectual disability, language and motor delay, seizures, macrocephaly, and variable ocular abnormalities. HITSCLIP revealed that Csde1binding targets are enriched in autismassociated gene sets, especially FMRP targets, and in neuronal development and synaptic plasticity–related pathways. Csde1 knockdown in primary mouse cortical neurons leads to an overgrowth of the neurites and abnormal dendritic spine morphology/synapse formation and impaired synaptic transmission, whereas mutant and knockdown experiments in Drosophila result in defects in synapse growth and synaptic transmission. Our study defines a new autismrelated syndrome and highlights the functional role of CSDE1 in synapse development and synaptic transmission.

Published
2019
Full Text
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17. Disruptive variants of CSDE1 associate with autism and interfere with neuronal development and synaptic transmission

Author

Guo, H, Li, Y, Shen, Lucy, Wang, TY, Jia, XB, Liu, LJ, Xu, T, Ou, MZ, Hoekzema, K, Wu, HD, Gillentine, MA, Liu, CY, Ni, HL, Peng, PW, Zhao, RJ, Zhang, Y, Phornphutkul, C, Stegmann, APA, Prada, CE, Hopkin, RJ, Shieh, JT, McWalter, K, Monaghan, K G, van Hasselt, PM, van Gassen, K, Bai, T, Long, M, Han, L, Quan, YT, Chen, ML, Zhang, YW, Li, KKW, Zhang, QM, Tan, JQ, Zhu, TF, Liu, YN, Pang, N, Peng, J, Scott, DA, Lalani, SR, Azamian, M, Verheijen - Mancini, Grazia, Adams, DJ, Kvarnung, M, Lindstrand, A, Nordgren, A, Pevsner, J, Osei-Owusu, IA, Romano, C, Calabrese, G, Galesi, O, Gecz, J, Haan, E, Ranells, J, Racobaldo, M, Nordenskjold, M, Madan-Khetarpal, S, Sebastian, J, Ball, S, Zou, XB, Zhao, JP, Hu, ZM, Xia, F, Liu, PF, Rosenfeld, JA, de Vries, BBA, Bernier, RA, Xu, ZQD, Li, HH, Xie, W, Hufnagel, RB, Eichler, EE, Xia, K, Guo, H, Li, Y, Shen, Lucy, Wang, TY, Jia, XB, Liu, LJ, Xu, T, Ou, MZ, Hoekzema, K, Wu, HD, Gillentine, MA, Liu, CY, Ni, HL, Peng, PW, Zhao, RJ, Zhang, Y, Phornphutkul, C, Stegmann, APA, Prada, CE, Hopkin, RJ, Shieh, JT, McWalter, K, Monaghan, K G, van Hasselt, PM, van Gassen, K, Bai, T, Long, M, Han, L, Quan, YT, Chen, ML, Zhang, YW, Li, KKW, Zhang, QM, Tan, JQ, Zhu, TF, Liu, YN, Pang, N, Peng, J, Scott, DA, Lalani, SR, Azamian, M, Verheijen - Mancini, Grazia, Adams, DJ, Kvarnung, M, Lindstrand, A, Nordgren, A, Pevsner, J, Osei-Owusu, IA, Romano, C, Calabrese, G, Galesi, O, Gecz, J, Haan, E, Ranells, J, Racobaldo, M, Nordenskjold, M, Madan-Khetarpal, S, Sebastian, J, Ball, S, Zou, XB, Zhao, JP, Hu, ZM, Xia, F, Liu, PF, Rosenfeld, JA, de Vries, BBA, Bernier, RA, Xu, ZQD, Li, HH, Xie, W, Hufnagel, RB, Eichler, EE, and Xia, K

Published
2019

18. De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias

Author

Helbig, K.L., Lauerer, R.J., Bahr, J.C., Souza, I.A., Myers, C.T., Uysal, B., Schwarz, N., Gandini, M.A., Huang, S., Keren, B., Mignot, C., Afenjar, A., Villemeur, T. Billette de, Heron, D., Nava, C., Valence, S., Buratti, J., Fagerberg, C.R., Soerensen, K.P., Kibaek, M., Kamsteeg, E.J., Koolen, D.A., Gunning, B., Schelhaas, H.J., Kruer, M.C., Fox, J., Bakhtiari, S., Jarrar, R., Padilla-Lopez, S., Lindstrom, K., Jin, S.C., Zeng, X., Bilguvar, K., Papavasileiou, A., Xin, Q., Zhu, C., Boysen, K., Vairo, F., Lanpher, B.C., Klee, E.W., Tillema, J.M., Payne, E.T., Cousin, M.A., Kruisselbrink, T.M., Wick, M.J., Baker, J., Haan, E., Smith, N., Corbett, M.A., MacLennan, A.H., Gecz, J., Biskup, S., Goldmann, E., Rodan, L.H., Kichula, E., Segal, E., Jackson, K.E., Asamoah, A., Dimmock, D., McCarrier, J., Botto, L.D., Filloux, F., Tvrdik, T., Cascino, G.D., Klingerman, S., Neumann, C., Wang, R., Jacobsen, J.C., Nolan, M.A., Snell, R.G., Lehnert, K., Sadleir, L.G., Anderlid, B.M., Kvarnung, M., Guerrini, R., Friez, M.J., Lyons, M.J., Leonhard, J., Kringlen, G., Casas, K., Achkar, C.M. El, Smith, L.A., Rotenberg, A., Poduri, A., Sanchis-Juan, A., Carss, K.J., Rankin, J., Zeman, A., Raymond, F.L., Blyth, M., Kerr, B., Ruiz, K., Urquhart, J., Hughes, I., Banka, S., Hedrich, U.B.S., Scheffer, I.E., Helbig, I., Zamponi, G.W., Lerche, H., et al., Helbig, K.L., Lauerer, R.J., Bahr, J.C., Souza, I.A., Myers, C.T., Uysal, B., Schwarz, N., Gandini, M.A., Huang, S., Keren, B., Mignot, C., Afenjar, A., Villemeur, T. Billette de, Heron, D., Nava, C., Valence, S., Buratti, J., Fagerberg, C.R., Soerensen, K.P., Kibaek, M., Kamsteeg, E.J., Koolen, D.A., Gunning, B., Schelhaas, H.J., Kruer, M.C., Fox, J., Bakhtiari, S., Jarrar, R., Padilla-Lopez, S., Lindstrom, K., Jin, S.C., Zeng, X., Bilguvar, K., Papavasileiou, A., Xin, Q., Zhu, C., Boysen, K., Vairo, F., Lanpher, B.C., Klee, E.W., Tillema, J.M., Payne, E.T., Cousin, M.A., Kruisselbrink, T.M., Wick, M.J., Baker, J., Haan, E., Smith, N., Corbett, M.A., MacLennan, A.H., Gecz, J., Biskup, S., Goldmann, E., Rodan, L.H., Kichula, E., Segal, E., Jackson, K.E., Asamoah, A., Dimmock, D., McCarrier, J., Botto, L.D., Filloux, F., Tvrdik, T., Cascino, G.D., Klingerman, S., Neumann, C., Wang, R., Jacobsen, J.C., Nolan, M.A., Snell, R.G., Lehnert, K., Sadleir, L.G., Anderlid, B.M., Kvarnung, M., Guerrini, R., Friez, M.J., Lyons, M.J., Leonhard, J., Kringlen, G., Casas, K., Achkar, C.M. El, Smith, L.A., Rotenberg, A., Poduri, A., Sanchis-Juan, A., Carss, K.J., Rankin, J., Zeman, A., Raymond, F.L., Blyth, M., Kerr, B., Ruiz, K., Urquhart, J., Hughes, I., Banka, S., Hedrich, U.B.S., Scheffer, I.E., Helbig, I., Zamponi, G.W., and Lerche, H., et al.

Abstract

Item does not contain fulltext, Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the alpha1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.

Published
2018

19. Clinical and molecular consequences of disease-associated de novo mutations in SATB2

Author

Bengani, Hemant, Handley, Mark, Alvi, Mohsan, Ibitoye, Rita, Lees, Melissa, Lynch, Sally Ann, Lam, Wayne, Fannemel, Madeleine, Nordgren, Ann, Malmgren, H, Kvarnung, M, Mehta, Sarju, McKee, Shane, Whiteford, Margo, Stewart, Fiona, Connell, Fiona, Clayton-Smith, Jill, Mansour, Sahar, Mohammed, Shehla, Fryer, Alan, Morton, Jenny, UK10K Consortium, Grozeva, Detelina, Asam, Tara, Moore, David, Sifrim, Alejandro, McRae, Jeremy, Hurles, Matthew E, Firth, Helen V, Raymond, F Lucy, Kini, Usha, Nellåker, Christoffer, Ddd Study, FitzPatrick, David R, Alvi, Mohsan [0000-0003-4331-7078], Ibitoye, Rita [0000-0002-2887-2068], Lynch, Sally Ann [0000-0003-0287-4134], Nordgren, Ann [0000-0003-3338-8382], Malmgren, H [0000-0003-3285-4281], McKee, Shane [0000-0003-0446-3435], Whiteford, Margo [0000-0002-1772-0106], Connell, Fiona [0000-0002-0444-8203], Mohammed, Shehla [0000-0001-6629-4118], Sifrim, Alejandro [0000-0001-9308-5741], McRae, Jeremy [0000-0001-8247-4020], Kini, Usha [0000-0003-2652-3355], FitzPatrick, David R [0000-0001-7609-3504], and Apollo - University of Cambridge Repository

Subjects
Cohort Studies, Whole Genome Sequencing, Loss of Function Mutation, Intellectual Disability, Mutation, Missense, Humans, Haploinsufficiency, Matrix Attachment Region Binding Proteins, Genetic Association Studies, Cell Line, HeLa Cells, Protein Binding, Transcription Factors
Abstract

PURPOSE: To characterize features associated with de novo mutations affecting SATB2 function in individuals ascertained on the basis of intellectual disability. METHODS: Twenty previously unreported individuals with 19 different SATB2 mutations (11 loss-of-function and 8 missense variants) were studied. Fibroblasts were used to measure mutant protein production. Subcellular localization and mobility of wild-type and mutant SATB2 were assessed using fluorescently tagged protein. RESULTS: Recurrent clinical features included neurodevelopmental impairment (19/19), absent/near absent speech (16/19), normal somatic growth (17/19), cleft palate (9/19), drooling (12/19), and dental anomalies (8/19). Six of eight missense variants clustered in the first CUT domain. Sibling recurrence due to gonadal mosaicism was seen in one family. A nonsense mutation in the last exon resulted in production of a truncated protein retaining all three DNA-binding domains. SATB2 nuclear mobility was mutation-dependent; p.Arg389Cys in CUT1 increased mobility and both p.Gly515Ser in CUT2 and p.Gln566Lys between CUT2 and HOX reduced mobility. The clinical features in individuals with missense variants were indistinguishable from those with loss of function. CONCLUSION: SATB2 haploinsufficiency is a common cause of syndromic intellectual disability. When mutant SATB2 protein is produced, the protein appears functionally inactive with a disrupted pattern of chromatin or matrix association.Genet Med advance online publication 02 February 2017.

Published
2017

20. Identification of new TRIP12 variants and detailed clinical evaluation of individuals with non-syndromic intellectual disability with or without autism

Author

Bramswig, N.C., Ludecke, H.J., Pettersson, M., Albrecht, B., Bernier, R.A., Cremer, K., Eichler, E.E., Falkenstein, D., Gerdts, J., Jansen, S, Kuechler, A., Kvarnung, M., Lindstrand, A., Nilsson, D., Nordgren, A., Pfundt, R.P., Spruijt, L., Surowy, H.M., Vries, B.B. de, Wieland, T., Engels, H., Strom, T.M., Kleefstra, T., Wieczorek, D., Bramswig, N.C., Ludecke, H.J., Pettersson, M., Albrecht, B., Bernier, R.A., Cremer, K., Eichler, E.E., Falkenstein, D., Gerdts, J., Jansen, S, Kuechler, A., Kvarnung, M., Lindstrand, A., Nilsson, D., Nordgren, A., Pfundt, R.P., Spruijt, L., Surowy, H.M., Vries, B.B. de, Wieland, T., Engels, H., Strom, T.M., Kleefstra, T., and Wieczorek, D.

Abstract

Contains fulltext : 169702.pdf (publisher's version ) (Closed access), The ubiquitin pathway is an enzymatic cascade including activating E1, conjugating E2, and ligating E3 enzymes, which governs protein degradation and sorting. It is crucial for many physiological processes. Compromised function of members of the ubiquitin pathway leads to a wide range of human diseases, such as cancer, neurodegenerative diseases, and neurodevelopmental disorders. Mutations in the thyroid hormone receptor interactor 12 (TRIP12) gene (OMIM 604506), which encodes an E3 ligase in the ubiquitin pathway, have been associated with autism spectrum disorder (ASD). In addition to autistic features, TRIP12 mutation carriers showed intellectual disability (ID). More recently, TRIP12 was postulated as a novel candidate gene for intellectual disability in a meta-analysis of published ID cohorts. However, detailed clinical information characterizing the phenotype of these individuals was not provided. In this study, we present seven novel individuals with private TRIP12 mutations including two splice site mutations, one nonsense mutation, three missense mutations, and one translocation case with a breakpoint in intron 1 of the TRIP12 gene and clinically review four previously published cases. The TRIP12 mutation-positive individuals presented with mild to moderate ID (10/11) or learning disability [intelligence quotient (IQ) 76 in one individual], ASD (8/11) and some of them with unspecific craniofacial dysmorphism and other anomalies. In this study, we provide detailed clinical information of 11 TRIP12 mutation-positive individuals and thereby expand the clinical spectrum of the TRIP12 gene in non-syndromic intellectual disability with or without ASD.

Published
2017

21. Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases

Author

Stessman, H.A., Xiong, B., Coe, B.P., Wang, T., Hoekzema, K., Fenckova, M., Kvarnung, M., Gerdts, J., Trinh, S., Cosemans, N., Vives, L., Lin, J., Turner, T.N., Santen, G., Ruivenkamp, C., Kriek, M., Haeringen, A. van, Aten, E., Friend, K., Liebelt, J., Barnett, C., Haan, E., Shaw, M., Gecz, J., Anderlid, B.M., Nordgren, A., Lindstrand, A., Schwartz, C., Kooy, R.F., Vandeweyer, G., Helsmoortel, C., Romano, C, Alberti, A., Vinci, M., Avola, E., Giusto, S., Courchesne, E., Pramparo, T., Pierce, K., Nalabolu, S., Amaral, D.G., Scheffer, I.E., Delatycki, M.B., Lockhart, P.J., Hormozdiari, F., Harich, B., Castells Nobau, A., Xia, K., Peeters, H., Nordenskjold, M., Schenck, A., Bernier, R.A., Eichler, E.E., Stessman, H.A., Xiong, B., Coe, B.P., Wang, T., Hoekzema, K., Fenckova, M., Kvarnung, M., Gerdts, J., Trinh, S., Cosemans, N., Vives, L., Lin, J., Turner, T.N., Santen, G., Ruivenkamp, C., Kriek, M., Haeringen, A. van, Aten, E., Friend, K., Liebelt, J., Barnett, C., Haan, E., Shaw, M., Gecz, J., Anderlid, B.M., Nordgren, A., Lindstrand, A., Schwartz, C., Kooy, R.F., Vandeweyer, G., Helsmoortel, C., Romano, C, Alberti, A., Vinci, M., Avola, E., Giusto, S., Courchesne, E., Pramparo, T., Pierce, K., Nalabolu, S., Amaral, D.G., Scheffer, I.E., Delatycki, M.B., Lockhart, P.J., Hormozdiari, F., Harich, B., Castells Nobau, A., Xia, K., Peeters, H., Nordenskjold, M., Schenck, A., Bernier, R.A., and Eichler, E.E.

Abstract

Item does not contain fulltext, Gene-disruptive mutations contribute to the biology of neurodevelopmental disorders (NDDs), but most of the related pathogenic genes are not known. We sequenced 208 candidate genes from >11,730 cases and >2,867 controls. We identified 91 genes, including 38 new NDD genes, with an excess of de novo mutations or private disruptive mutations in 5.7% of cases. Drosophila functional assays revealed a subset with increased involvement in NDDs. We identified 25 genes showing a bias for autism versus intellectual disability and highlighted a network associated with high-functioning autism (full-scale IQ >100). Clinical follow-up for NAA15, KMT5B, and ASH1L highlighted new syndromic and nonsyndromic forms of disease.

Published
2017

22. De Novo Truncating Mutations in the Last and Penultimate Exons of PPM1D Cause an Intellectual Disability Syndrome

Author

Jansen, S, Geuer, S., Pfundt, R.P., Brough, R., Ghongane, P., Herkert, J.C., Marco, E.J., Willemsen, M.H., Kleefstra, T., Hannibal, M., Shieh, J.T., Lynch, S.A., Flinter, F., FitzPatrick, D.R., Gardham, A., Bernhard, B., Ragge, N., Newbury-Ecob, R., Bernier, R., Kvarnung, M., Magnusson, E.A., Wessels, M.W., Slegtenhorst, M.A. van, Monaghan, K.G., Vries, P.F. de, Veltman, J.A., Lord, C.J., Vissers, L.E.L.M., Vries, B.B. de, Jansen, S, Geuer, S., Pfundt, R.P., Brough, R., Ghongane, P., Herkert, J.C., Marco, E.J., Willemsen, M.H., Kleefstra, T., Hannibal, M., Shieh, J.T., Lynch, S.A., Flinter, F., FitzPatrick, D.R., Gardham, A., Bernhard, B., Ragge, N., Newbury-Ecob, R., Bernier, R., Kvarnung, M., Magnusson, E.A., Wessels, M.W., Slegtenhorst, M.A. van, Monaghan, K.G., Vries, P.F. de, Veltman, J.A., Lord, C.J., Vissers, L.E.L.M., and Vries, B.B. de

Abstract

Contains fulltext : 174535.pdf (publisher's version ) (Closed access), Intellectual disability (ID) is a highly heterogeneous disorder involving at least 600 genes, yet a genetic diagnosis remains elusive in approximately 35%-40% of individuals with moderate to severe ID. Recent meta-analyses statistically analyzing de novo mutations in >7,000 individuals with neurodevelopmental disorders highlighted mutations in PPM1D as a possible cause of ID. PPM1D is a type 2C phosphatase that functions as a negative regulator of cellular stress-response pathways by mediating a feedback loop of p38-p53 signaling, thereby contributing to growth inhibition and suppression of stress-induced apoptosis. We identified 14 individuals with mild to severe ID and/or developmental delay and de novo truncating PPM1D mutations. Additionally, deep phenotyping revealed overlapping behavioral problems (ASD, ADHD, and anxiety disorders), hypotonia, broad-based gait, facial dysmorphisms, and periods of fever and vomiting. PPM1D is expressed during fetal brain development and in the adult brain. All mutations were located in the last or penultimate exon, suggesting escape from nonsense-mediated mRNA decay. Both PPM1D expression analysis and cDNA sequencing in EBV LCLs of individuals support the presence of a stable truncated transcript, consistent with this hypothesis. Exposure of cells derived from individuals with PPM1D truncating mutations to ionizing radiation resulted in normal p53 activation, suggesting that p53 signaling is unaffected. However, a cell-growth disadvantage was observed, suggesting a possible effect on the stress-response pathway. Thus, we show that de novo truncating PPM1D mutations in the last and penultimate exons cause syndromic ID, which provides additional insight into the role of cell-cycle checkpoint genes in neurodevelopmental disorders.

Published
2017

23. De Novo Truncating Mutations in the Last and Penultimate Exons of PPM1D Cause an Intellectual Disability Syndrome

Author

Jansen, S. (Sandra), Geuer, S. (Sinje), Pfundt, R. (Rolph), Brough, R. (Rachel), Ghongane, P. (Priyanka), Herkert, J.C. (Johanna), Marco, E.J. (Elysa J.), Willemsen, M.H. (Marjolein), Kleefstra, T. (Tjitske), Hannibal, M. (Mark), Shieh, J.T. (Joseph T.), Lynch, S.A., Flinter, F. (Frances), Fitzpatrick, D.R. (David), Gardham, A. (Alice), Bernhard, B. (Birgitta), Ragge, N. (Nicola), Newbury-Ecob, R. (Ruth), Bernier, R. (Raphael), Kvarnung, M. (Malin), Magnusson, E.A.H. (E.A. Helena), Wessels, M.W. (Marja), Slegtenhorst, M.A. (Marjon) van, Monaghan, K.G. (Kristin G.), de Vries, P. (Petra), Veltman, J.A. (Joris), Lord, C.J. (Christopher ), Vissers, L.E.L.M., Vries, B. (Boukje) de, Jansen, S. (Sandra), Geuer, S. (Sinje), Pfundt, R. (Rolph), Brough, R. (Rachel), Ghongane, P. (Priyanka), Herkert, J.C. (Johanna), Marco, E.J. (Elysa J.), Willemsen, M.H. (Marjolein), Kleefstra, T. (Tjitske), Hannibal, M. (Mark), Shieh, J.T. (Joseph T.), Lynch, S.A., Flinter, F. (Frances), Fitzpatrick, D.R. (David), Gardham, A. (Alice), Bernhard, B. (Birgitta), Ragge, N. (Nicola), Newbury-Ecob, R. (Ruth), Bernier, R. (Raphael), Kvarnung, M. (Malin), Magnusson, E.A.H. (E.A. Helena), Wessels, M.W. (Marja), Slegtenhorst, M.A. (Marjon) van, Monaghan, K.G. (Kristin G.), de Vries, P. (Petra), Veltman, J.A. (Joris), Lord, C.J. (Christopher ), Vissers, L.E.L.M., and Vries, B. (Boukje) de

Abstract

Intellectual disability (ID) is a highly heterogeneous disorder involving at least 600 genes, yet a genetic diagnosis remains elusive in ∼35%-40% of individuals with moderate to severe ID. Recent meta-analyses statistically analyzing de novo mutations in >7,000 individuals with neurodevelopmental disorders highlighted mutations in PPM1D as a possible cause of ID. PPM1D is a type 2C phosphatase that functions as a negative regulator of cellular stress-response pathways by mediating a feedback loop of p38-p53 signaling, thereby contributing to growth inhibition and suppression of stress-induced apoptosis. We identified 14 individuals with mild to severe ID and/or developmental delay and de novo truncating PPM1D mutations. Additionally, deep phenotyping revealed overlapping behavioral problems (ASD, ADHD, and anxiety disorders), hypotonia, broad-based gait, facial dysmorphisms, and periods of fever and vomiting. PPM1D is expressed during fetal brain development and in the adult brain. All mutations were located in the last or penultimate exon, suggesting escape from nonsense-mediated mRNA decay. Both PPM1D expression analysis and cDNA sequencing in EBV LCLs of individuals support the presence of a stable truncated transcript, consistent with this hypothesis. Exposure of cells derived from individuals with PPM1D truncating mutations to ionizing radiation resulted in normal p53 activation, suggesting that p53 signaling is unaffected. However, a cell-growth disadvantage was observed, suggesting a possible effect on the stress-response pathway. Thus, we show that de novo truncating PPM1D mutations in the last and penultimate exons cause syndromic ID, which provides additional insight into the role of cell-cycle checkpoint genes in neurodevelopmental disorders.

Published
2017
Full Text
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24. Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases

Author

Stessman, HAF, Xiong, B, Coe, BP, Wang, T, Hoekzema, K, Fenckova, M, Kvarnung, M, Gerdts, J, Trinh, S, Cosemans, N, Vives, L, Lin, J, Turner, TN, Santen, G, Ruivenkamp, C, Kriek, M, van Haeringen, A, Aten, E, Friend, K, Liebelt, J, Barnett, C, Haan, E, Shaw, M, Gecz, J, Anderlid, B-M, Nordgren, A, Lindstrand, A, Schwartz, C, Kooy, RF, Vandeweyer, G, Helsmoortel, C, Romano, C, Alberti, A, Vinci, M, Avola, E, Giusto, S, Courchesne, E, Pramparo, T, Pierce, K, Nalabolu, S, Amaral, DG, Scheffer, IE, Delatycki, MB, Lockhart, PJ, Hormozdiari, F, Harich, B, Castells-Nobau, A, Xia, K, Peeters, H, Nordenskjold, M, Schenck, A, Bernier, RA, Eichler, EE, Stessman, HAF, Xiong, B, Coe, BP, Wang, T, Hoekzema, K, Fenckova, M, Kvarnung, M, Gerdts, J, Trinh, S, Cosemans, N, Vives, L, Lin, J, Turner, TN, Santen, G, Ruivenkamp, C, Kriek, M, van Haeringen, A, Aten, E, Friend, K, Liebelt, J, Barnett, C, Haan, E, Shaw, M, Gecz, J, Anderlid, B-M, Nordgren, A, Lindstrand, A, Schwartz, C, Kooy, RF, Vandeweyer, G, Helsmoortel, C, Romano, C, Alberti, A, Vinci, M, Avola, E, Giusto, S, Courchesne, E, Pramparo, T, Pierce, K, Nalabolu, S, Amaral, DG, Scheffer, IE, Delatycki, MB, Lockhart, PJ, Hormozdiari, F, Harich, B, Castells-Nobau, A, Xia, K, Peeters, H, Nordenskjold, M, Schenck, A, Bernier, RA, and Eichler, EE

Abstract

Gene-disruptive mutations contribute to the biology of neurodevelopmental disorders (NDDs), but most of the related pathogenic genes are not known. We sequenced 208 candidate genes from >11,730 cases and >2,867 controls. We identified 91 genes, including 38 new NDD genes, with an excess of de novo mutations or private disruptive mutations in 5.7% of cases. Drosophila functional assays revealed a subset with increased involvement in NDDs. We identified 25 genes showing a bias for autism versus intellectual disability and highlighted a network associated with high-functioning autism (full-scale IQ >100). Clinical follow-up for NAA15, KMT5B, and ASH1L highlighted new syndromic and nonsyndromic forms of disease.

Published
2017

25. Disruption of POGZ Is Associated with Intellectual Disability and Autism Spectrum Disorders

Author

Stessman, H.A., Willemsen, M.H., Fenckova, M., Penn, O., Hoischen, A., Xiong, B., Wang, T., Hoekzema, K., Vives, L., Vogel, I., Brunner, H.G., Burgt, I. van der, Ockeloen, C.W., Schuurs-Hoeijmakers, J.H.M., Wassink-Ruiter, J.S., Stumpel, C., Stevens, S.J., Vles, H.S., Marcelis, C.M., Bokhoven, H. van, Cantagrel, V., Colleaux, L., Nicouleau, M., Lyonnet, S., Bernier, R.A., Gerdts, J., Coe, B.P., Romano, C, Alberti, A., Grillo, L., Scuderi, C., Nordenskjold, M., Kvarnung, M., Guo, H., Xia, K., Piton, A., Gerard, B., Genevieve, D., Delobel, B., Lehalle, D., Perrin, L., Prieur, F., Thevenon, J., Gecz, J., Shaw, M., Pfundt, R., Keren, B., Jacquette, A., Schenck, A., Eichler, E.E., Kleefstra, T., Stessman, H.A., Willemsen, M.H., Fenckova, M., Penn, O., Hoischen, A., Xiong, B., Wang, T., Hoekzema, K., Vives, L., Vogel, I., Brunner, H.G., Burgt, I. van der, Ockeloen, C.W., Schuurs-Hoeijmakers, J.H.M., Wassink-Ruiter, J.S., Stumpel, C., Stevens, S.J., Vles, H.S., Marcelis, C.M., Bokhoven, H. van, Cantagrel, V., Colleaux, L., Nicouleau, M., Lyonnet, S., Bernier, R.A., Gerdts, J., Coe, B.P., Romano, C, Alberti, A., Grillo, L., Scuderi, C., Nordenskjold, M., Kvarnung, M., Guo, H., Xia, K., Piton, A., Gerard, B., Genevieve, D., Delobel, B., Lehalle, D., Perrin, L., Prieur, F., Thevenon, J., Gecz, J., Shaw, M., Pfundt, R., Keren, B., Jacquette, A., Schenck, A., Eichler, E.E., and Kleefstra, T.

Abstract

Item does not contain fulltext, Intellectual disability (ID) and autism spectrum disorders (ASD) are genetically heterogeneous, and a significant number of genes have been associated with both conditions. A few mutations in POGZ have been reported in recent exome studies; however, these studies do not provide detailed clinical information. We collected the clinical and molecular data of 25 individuals with disruptive mutations in POGZ by diagnostic whole-exome, whole-genome, or targeted sequencing of 5,223 individuals with neurodevelopmental disorders (ID primarily) or by targeted resequencing of this locus in 12,041 individuals with ASD and/or ID. The rarity of disruptive mutations among unaffected individuals (2/49,401) highlights the significance (p = 4.19 x 10(-13); odds ratio = 35.8) and penetrance (65.9%) of this genetic subtype with respect to ASD and ID. By studying the entire cohort, we defined common phenotypic features of POGZ individuals, including variable levels of developmental delay (DD) and more severe speech and language delay in comparison to the severity of motor delay and coordination issues. We also identified significant associations with vision problems, microcephaly, hyperactivity, a tendency to obesity, and feeding difficulties. Some features might be explained by the high expression of POGZ, particularly in the cerebellum and pituitary, early in fetal brain development. We conducted parallel studies in Drosophila by inducing conditional knockdown of the POGZ ortholog row, further confirming that dosage of POGZ, specifically in neurons, is essential for normal learning in a habituation paradigm. Combined, the data underscore the pathogenicity of loss-of-function mutations in POGZ and define a POGZ-related phenotype enriched in specific features.

Published
2016

26. Identification of new TRIP12 variants and detailed clinical evaluation of individuals with non-syndromic intellectual disability with or without autism

Author

Bramswig, Nuria C., primary, Lüdecke, H.-J., additional, Pettersson, M., additional, Albrecht, B., additional, Bernier, R. A., additional, Cremer, K., additional, Eichler, E. E., additional, Falkenstein, D., additional, Gerdts, J., additional, Jansen, S., additional, Kuechler, A., additional, Kvarnung, M., additional, Lindstrand, A., additional, Nilsson, D., additional, Nordgren, A., additional, Pfundt, R., additional, Spruijt, L., additional, Surowy, H. M., additional, de Vries, B. B. A., additional, Wieland, T., additional, Engels, H., additional, Strom, T. M., additional, Kleefstra, T., additional, and Wieczorek, D., additional

Published
2016
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30. Pushing the boundaries of rare disease diagnostics with the help of the first Undiagnosed Hackathon.

Author

Delgado-Vega AM, Cederroth H, Taylan F, Ekholm K, Ek M, Thonberg H, Jemt A, Nilsson D, Eisfeldt J, Bilgrav Saether K, Höijer I, Akgun-Dogan O, Asano Y, Barakat TS, Batkovskyte D, Baynam G, Bodamer O, Chetruengchai W, Corcoran P, Couse M, Danis D, Demidov G, Dohi E, Erhardsson M, Fernandez-Luna L, Fujiwara T, Garg N, Giugliani R, Gonzaga-Jauregui C, Grigelioniene G, Groza T, Gunnarsson C, Hammarsjö A, Hammond CK, Hatirnaz Ng Ö, Hesketh S, Hettiarachchi D, Johansson Soller M, Kirmani UA, Kjellberg M, Kvarnung M, Kvlividze O, Lagerstedt-Robinson K, Lasko P, Lassmann T, Lau LYS, Laurie S, Lim WK, Liu Z, Lysenkova Wiklander M, Makay P, Maiga AB, Maya-González C, Meyn MS, Neethiraj R, Nigro V, Nordgren F, Nordlund J, Orrsjö S, Ottosson J, Ozbek U, Özdemir Ö, Partin C, Pearce DA, Peck R, Pedersen A, Pettersson M, Pongpanich M, Posada de la Paz M, Ramani A, Romero JA, Romero VI, Rosenquist R, Saw AM, Spencer M, Stattin EL, Srichomthong C, Tapia-Paez I, Taruscio D, Taylor JP, Tkemaladze T, Tully I, Tümer Z, van Zelst-Stams WAG, Verloes A, Västerviga E, Wang S, Yang R, Yamamoto S, Yépez VA, Zhang Q, Shotelersuk V, Wiafe SA, Alanay Y, Botto LD, Kirmani S, Lumaka A, Palmer EE, Puri RD, Wirta V, Lindstrand A, Buske OJ, Cederroth M, and Nordgren A

Published
2024
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31. Unraveling GRIA1 neurodevelopmental disorders: Lessons learned from the p.(Ala636Thr) variant.

Author

Tvergaard NK, Tkemaladze T, Stödberg T, Kvarnung M, Tatton-Brown K, Baralle D, Tümer Z, and Bayat A

Subjects
Humans, Female, Male, Child, Adult, Child, Preschool, Adolescent, Phenotype, Mutation, Intellectual Disability genetics, Genetic Predisposition to Disease, Young Adult, Neurodevelopmental Disorders genetics, Receptors, AMPA genetics
Abstract

Ionotropic glutamate receptors (iGluRs), specifically α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs), play a crucial role in orchestrating excitatory neurotransmission in the brain. AMPARs are intricate assemblies of subunits encoded by four paralogous genes: GRIA1-4. Functional studies have established that rare GRIA variants can alter AMPAR currents leading to a loss- or gain-of-function. Patients affected by rare heterozygous GRIA variants tend to have family specific variants and only few recurrent variants have been reported. We deep-phenotyped a cohort comprising eight unrelated children and adults, harboring a recurrent and well-established disease-causing GRIA1 variant (NM&#95;001114183.1: c.1906G>A, p.(Ala636Thr)). Recurrent symptoms included motor and/or language delay, mild-severe intellectual disability, behavioral and psychiatric comorbidities, hypotonia and epilepsy. We also report challenges in social skills, autonomy, living and work situation, and occupational levels. Furthermore, we compared their clinical manifestations in relation to those documented in patients presenting with rare heterozygous variants at analogous positions within paralogous genes. This study provides unprecedented details on the neurodevelopmental outcomes, cognitive abilities, seizure profiles, and behavioral abnormalities associated with p.(Ala636Thr) refining and broadening the clinical phenotype., (© 2024 The Author(s). Clinical Genetics published by John Wiley & Sons Ltd.)

Published
2024
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32. Ataxia Syndrome With Hearing Loss and Nephronophthisis Associated With a Novel Homozygous Variant in XPNPEP3 .

Author

Ben-Shabat I, Kvarnung M, Sperker W, Bruhn H, Wredenberg A, Wibom R, Nennesmo I, Engvall M, and Paucar M

Abstract

Objectives: Biallelic variants in XPNPEP3 are associated with a rare mitochondrial syndrome characterized by nephronophthisis leading to kidney failure, essential tremor, hearing loss, seizures, and intellectual disability. Only 2 publications on this condition are available. We report a man with a complex ataxia syndrome, hearing loss, and kidney failure associated with a new biallelic variant in XPNPEP3 ., Methods: Clinical evaluation, neuroimaging studies, a kidney biopsy, and whole genome sequencing (WGS) were applied. Since the phenotype was compatible with a mitochondrial disease, a muscle biopsy with morphological and mitochondrial biochemical investigations was performed., Results: Axial ataxia, cerebellar atrophy, hearing loss, myopathy, ptosis, supranuclear palsy, and kidney failure because of nephronophthisis were the prominent features in this case. WGS revealed the novel biallelic variant c.766C>T (p.Gln256*) in XPNPEP3 . A muscle biopsy revealed COX negative fibers, a few ragged red fibers, and ultrastructural mitochondrial changes. Enzyme activity in respiratory chain complex IV was reduced in muscle and fibroblasts., Discussion: This is the first report of a slowly progressive cerebellar ataxia associated with a novel biallelic variant in XPNPEP3 . Abnormalities typical for mitochondrial disease and the slow progression of kidney disease are also striking. Our report expands the spectrum of XPNPEP3 -related diseases., Competing Interests: The authors report no relevant disclosures. Go to Neurology.org/NG for full disclosures., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Published
2023
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33. Pathogenic variants in SMARCA1 cause an X-linked neurodevelopmental disorder modulated by NURF complex composition.

Author

Picketts D, Mirzaa G, Yan K, Relator R, Timpano S, Yalcin B, Collins S, Ziegler A, Pao E, Oyama N, Brischoux-Boucher E, Piard J, Monaghan K, Sacoto MG, Dobyns W, Park K, Fernández-Mayoralas D, Fernández-Jaén A, Jayakar P, Brusco A, Antona V, Giorgio E, Kvarnung M, Isidor B, Conrad S, Cogné B, Deb W, Stuurman KE, Sterbova K, Smal N, Weckhuysen S, Oegema R, Innes M, Latsko M, Ben-Omran T, Yeh R, Kruer M, Bakhtiari S, Papavasiliou A, Moutton S, Nambot S, Chanprasert S, Paolucci S, Miller K, Burton B, Kim K, O'Heir E, Bruwer Z, Donald K, Kleefstra T, Goldstein A, Angle B, Bontempo K, Miny P, Joset P, Demurger F, Hobson E, Pang L, Carpenter L, Li D, Bonneau D, and Sadikovic B

Abstract

Pathogenic variants in ATP-dependent chromatin remodeling proteins are a recurrent cause of neurodevelopmental disorders (NDDs). The NURF complex consists of BPTF and either the SNF2H ( SMARCA5 ) or SNF2L ( SMARCA1 ) ISWI-chromatin remodeling enzyme. Pathogenic variants in BPTF and SMARCA5 were previously implicated in NDDs. Here, we describe 40 individuals from 30 families with de novo or maternally inherited pathogenic variants in SMARCA1 . This novel NDD was associated with mild to severe ID/DD, delayed or regressive speech development, and some recurrent facial dysmorphisms. Individuals carrying SMARCA1 loss-of-function variants exhibited a mild genome-wide DNA methylation profile and a high penetrance of macrocephaly. Genetic dissection of the NURF complex using Smarca1, Smarca5 , and Bptfsingle and double mouse knockouts revealed the importance of NURF composition and dosage for proper forebrain development. Finally, we propose that genetic alterations affecting different NURF components result in a NDD with a broad clinical spectrum., Competing Interests: KGM and MJGS are employees of GeneDX, LLC. All remaining authors declare no competing financial interests.

Published
2023
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34. Genome sequencing with comprehensive variant calling identifies structural variants and repeat expansions in a large fraction of individuals with ataxia and/or neuromuscular disorders.

Author

Ek M, Nilsson D, Engvall M, Malmgren H, Thonberg H, Pettersson M, Anderlid BM, Hammarsjö A, Helgadottir HT, Arnardottir S, Naess K, Nennesmo I, Paucar M, Hjartarson HT, Press R, Solders G, Sejersen T, Lindstrand A, and Kvarnung M

Abstract

Introduction: Neuromuscular disorders (NMDs) have a heterogeneous etiology. A genetic diagnosis is key to personalized healthcare and access to targeted treatment for the affected individuals., Methods: In this study, 861 patients with NMDs were analyzed with genome sequencing and comprehensive variant calling including single nucleotide variants, small insertions/deletions (SNVs/INDELs), and structural variants (SVs) in a panel of 895 NMD genes, as well as short tandem repeat expansions (STRs) at 28 loci. In addition, for unsolved cases with an unspecific clinical presentation, the analysis of a panel with OMIM disease genes was added., Results: In the cohort, 27% (232/861) of the patients harbored pathogenic variants, of which STRs and SVs accounted for one-third of the patients (71/232). The variants were found in 107 different NMD genes. Furthermore, 18 pediatric patients harbored pathogenic variants in non-NMD genes., Discussion: Our results highlight that for children with unspecific hypotonia, a genome-wide analysis rather than a disease-based gene panel should be considered as a diagnostic approach. More importantly, our results clearly show that it is crucial to include STR- and SV-analyses in the diagnostics of patients with neuromuscular disorders., Competing Interests: AL has received honoraria from Illumina Inc., and has been an advisor for Oxford Nanopore Technologies, both unrelated to the content in this article. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ek, Nilsson, Engvall, Malmgren, Thonberg, Pettersson, Anderlid, Hammarsjö, Helgadottir, Arnardottir, Naess, Nennesmo, Paucar, Hjartarson, Press, Solders, Sejersen, Lindstrand and Kvarnung.)

Published
2023
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35. Genome sequencing is a sensitive first-line test to diagnose individuals with intellectual disability.

Author

Lindstrand A, Ek M, Kvarnung M, Anderlid BM, Björck E, Carlsten J, Eisfeldt J, Grigelioniene G, Gustavsson P, Hammarsjö A, Helgadóttir HT, Hellström-Pigg M, Kuchinskaya E, Lagerstedt-Robinson K, Levin LÅ, Lieden A, Lindelöf H, Malmgren H, Nilsson D, Svensson E, Paucar M, Sahlin E, Tesi B, Tham E, Winberg J, Winerdal M, Wincent J, Johansson Soller M, Pettersson M, and Nordgren A

Subjects
Child, Humans, Developmental Disabilities genetics, Genetic Testing methods, Microarray Analysis, Fragile X Mental Retardation Protein genetics, Intellectual Disability diagnosis, Intellectual Disability genetics, Neurodevelopmental Disorders genetics
Abstract

Purpose: Individuals with intellectual disability (ID) and/or neurodevelopment disorders (NDDs) are currently investigated with several different approaches in clinical genetic diagnostics., Methods: We compared the results from 3 diagnostic pipelines in patients with ID/NDD: genome sequencing (GS) first (N = 100), GS as a secondary test (N = 129), or chromosomal microarray (CMA) with or without FMR1 analysis (N = 421)., Results: The diagnostic yield was 35% (GS-first), 26% (GS as a secondary test), and 11% (CMA/FMR1). Notably, the age of diagnosis was delayed by 1 year when GS was performed as a secondary test and the cost per diagnosed individual was 36% lower with GS first than with CMA/FMR1. Furthermore, 91% of those with a negative result after CMA/FMR1 analysis (338 individuals) have not yet been referred for additional genetic testing and remain undiagnosed., Conclusion: Our findings strongly suggest that genome analysis outperforms other testing strategies and should replace traditional CMA and FMR1 analysis as a first-line genetic test in individuals with ID/NDD. GS is a sensitive, time- and cost-effective method that results in a confirmed molecular diagnosis in 35% of all referred patients., Competing Interests: Conflict of Interest An.L. received honoraria from Illumina, Inc. All other authors declare no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2022
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36. Multi-Omic Investigations of a 17-19 Translocation Links MINK1 Disruption to Autism, Epilepsy and Osteoporosis.

Author

Eisfeldt J, Schuy J, Stattin EL, Kvarnung M, Falk A, Feuk L, and Lindstrand A

Subjects
Chromosome Mapping, Humans, Translocation, Genetic, Autistic Disorder genetics, Epilepsy genetics, Osteoporosis genetics, Protein Serine-Threonine Kinases genetics
Abstract

Balanced structural variants, such as reciprocal translocations, are sometimes hard to detect with sequencing, especially when the breakpoints are located in repetitive or insufficiently mapped regions of the genome. In such cases, long-range information is required to resolve the rearrangement, identify disrupted genes and, in symptomatic carriers, pinpoint the disease-causing mechanisms. Here, we report an individual with autism, epilepsy and osteoporosis and a de novo balanced reciprocal translocation: t(17;19) (p13;p11). The genomic DNA was analyzed by short-, linked- and long-read genome sequencing, as well as optical mapping. Transcriptional consequences were assessed by transcriptome sequencing of patient-specific neuroepithelial stem cells derived from induced pluripotent stem cells (iPSC). The translocation breakpoints were only detected by long-read sequencing, the first on 17p13, located between exon 1 and exon 2 of MINK1 (Misshapen-like kinase 1), and the second in the chromosome 19 centromere. Functional validation in induced neural cells showed that MINK1 expression was reduced by >50% in the patient’s cells compared to healthy control cells. Furthermore, pathway analysis revealed an enrichment of changed neural pathways in the patient’s cells. Altogether, our multi-omics experiments highlight MINK1 as a candidate monogenic disease gene and show the advantages of long-read genome sequencing in capturing centromeric translocations.

Published
2022
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37. On Spinocerebellar Ataxia 21 as a Mimicker of Cerebral Palsy.

Author

van der Put J, Daugeliene D, Bergendal Å, Kvarnung M, Svenningsson P, and Paucar M

Abstract

Objectives: Sporadic variants in ataxia genes may mimic cerebral palsy (CP). Spinocerebellar ataxia 21 (SCA21), a very rare autosomal dominant disease, was discovered to be associated with variants in the transmembrane protein 240 ( TMEM240 ) gene in 2014. In this report, we present 2 patients with sporadic SCA21, one of them diagnosed with ataxic CP., Methods: Patients provided oral and written consent. Comprehensive clinical evaluation, neuroimaging studies, review of previous psychometric evaluations, and whole-genome sequencing were applied in both cases., Results: Both patients presented with early-onset ataxia and exhibited mild parkinsonian features. Patient 1 experienced motor and speech delay, autism, and dyslexia, whereas patient 2 experienced dyslexia. Neuroimaging was normal in both cases. In patient 1, the previously reported pathogenic c.509C>T (Pro170Leu) variant in TMEM240 was detected, whereas patient 2 harbored the novel c.182&#95;188delinsGGAT (Val61&#95;Pro63delinsGlyMet) variant in the same gene. Both genetic variants were sporadic., Discussion: Our findings support the notion that SCA21 is a neurodevelopmental syndrome and a mimicker of ataxic CP. Both lack of a family history of ataxia and congenital presentation were reasonable arguments to consider ataxic CP. However, lack of convincing perinatal incidents, progressive symptoms, and the common presence of cerebellar atrophy should alert neurologists about SCA21., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Published
2022
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38. TUBB3 Arg262His causes a recognizable syndrome including CFEOM3, facial palsy, joint contractures, and early-onset peripheral neuropathy.

Author

Whitman MC, Barry BJ, Robson CD, Facio FM, Van Ryzin C, Chan WM, Lehky TJ, Thurm A, Zalewski C, King KA, Brewer C, Almpani K, Lee JS, Delaney A, FitzGibbon EJ, Lee PR, Toro C, Paul SM, Abdul-Rahman OA, Webb BD, Jabs EW, Moller HU, Larsen DA, Antony JH, Troedson C, Ma A, Ragnhild G, Wirgenes KV, Tham E, Kvarnung M, Maarup TJ, MacKinnon S, Hunter DG, Collins FS, Manoli I, and Engle EC

Subjects
Abnormalities, Multiple genetics, Adolescent, Adult, Amino Acid Substitution, Arginine, Child, Child, Preschool, Facial Paralysis diagnosis, Facial Paralysis physiopathology, Female, Fibrosis diagnosis, Fibrosis physiopathology, Histidine, Humans, Infant, Male, Ophthalmoplegia diagnosis, Ophthalmoplegia physiopathology, Peripheral Nervous System Diseases diagnosis, Peripheral Nervous System Diseases physiopathology, Syndrome, Young Adult, Facial Paralysis genetics, Fibrosis genetics, Mutation, Ophthalmoplegia genetics, Peripheral Nervous System Diseases genetics, Tubulin genetics
Abstract

Microtubules are formed from heterodimers of alpha- and beta-tubulin, each of which has multiple isoforms encoded by separate genes. Pathogenic missense variants in multiple different tubulin isoforms cause brain malformations. Missense mutations in TUBB3, which encodes the neuron-specific beta-tubulin isotype, can cause congenital fibrosis of the extraocular muscles type 3 (CFEOM3) and/or malformations of cortical development, with distinct genotype-phenotype correlations. Here, we report fourteen individuals from thirteen unrelated families, each of whom harbors the identical NM&#95;006086.4 (TUBB3):c.785G>A (p.Arg262His) variant resulting in a phenotype we refer to as the TUBB3 R262H syndrome. The affected individuals present at birth with ptosis, ophthalmoplegia, exotropia, facial weakness, facial dysmorphisms, and, in most cases, distal congenital joint contractures, and subsequently develop intellectual disabilities, gait disorders with proximal joint contractures, Kallmann syndrome (hypogonadotropic hypogonadism and anosmia), and a progressive peripheral neuropathy during the first decade of life. Subsets may also have vocal cord paralysis, auditory dysfunction, cyclic vomiting, and/or tachycardia at rest. All fourteen subjects share a recognizable set of brain malformations, including hypoplasia of the corpus callosum and anterior commissure, basal ganglia malformations, absent olfactory bulbs and sulci, and subtle cerebellar malformations. While similar, individuals with the TUBB3 R262H syndrome can be distinguished from individuals with the TUBB3 E410K syndrome by the presence of congenital and acquired joint contractures, an earlier onset peripheral neuropathy, impaired gait, and basal ganglia malformations., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Published
2021
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39. DLG4-related synaptopathy: a new rare brain disorder.

Author

Rodríguez-Palmero A, Boerrigter MM, Gómez-Andrés D, Aldinger KA, Marcos-Alcalde Í, Popp B, Everman DB, Lovgren AK, Arpin S, Bahrambeigi V, Beunders G, Bisgaard AM, Bjerregaard VA, Bruel AL, Challman TD, Cogné B, Coubes C, de Man SA, Denommé-Pichon AS, Dye TJ, Elmslie F, Feuk L, García-Miñaúr S, Gertler T, Giorgio E, Gruchy N, Haack TB, Haldeman-Englert CR, Haukanes BI, Hoyer J, Hurst ACE, Isidor B, Soller MJ, Kushary S, Kvarnung M, Landau YE, Leppig KA, Lindstrand A, Kleinendorst L, MacKenzie A, Mandrile G, Mendelsohn BA, Moghadasi S, Morton JE, Moutton S, Müller AJ, O'Leary M, Pacio-Míguez M, Palomares-Bralo M, Parikh S, Pfundt R, Pode-Shakked B, Rauch A, Repnikova E, Revah-Politi A, Ross MJ, Ruivenkamp CAL, Sarrazin E, Savatt JM, Schlüter A, Schönewolf-Greulich B, Shad Z, Shaw-Smith C, Shieh JT, Shohat M, Spranger S, Thiese H, Mau-Them FT, van Bon B, van de Burgt I, van de Laar IMBH, van Drie E, van Haelst MM, van Ravenswaaij-Arts CM, Verdura E, Vitobello A, Waldmüller S, Whiting S, Zweier C, Prada CE, de Vries BBA, Dobyns WB, Reiter SF, Gómez-Puertas P, Pujol A, and Tümer Z

Subjects
Brain, Disks Large Homolog 4 Protein genetics, Humans, Phenotype, Autism Spectrum Disorder diagnosis, Autism Spectrum Disorder genetics, Brain Diseases, Intellectual Disability, Neurodevelopmental Disorders diagnosis, Neurodevelopmental Disorders genetics
Abstract

Purpose: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants., Methods: The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing., Results: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies., Conclusion: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.

Published
2021
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40. Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders.

Author

Gillentine MA, Wang T, Hoekzema K, Rosenfeld J, Liu P, Guo H, Kim CN, De Vries BBA, Vissers LELM, Nordenskjold M, Kvarnung M, Lindstrand A, Nordgren A, Gecz J, Iascone M, Cereda A, Scatigno A, Maitz S, Zanni G, Bertini E, Zweier C, Schuhmann S, Wiesener A, Pepper M, Panjwani H, Torti E, Abid F, Anselm I, Srivastava S, Atwal P, Bacino CA, Bhat G, Cobian K, Bird LM, Friedman J, Wright MS, Callewaert B, Petit F, Mathieu S, Afenjar A, Christensen CK, White KM, Elpeleg O, Berger I, Espineli EJ, Fagerberg C, Brasch-Andersen C, Hansen LK, Feyma T, Hughes S, Thiffault I, Sullivan B, Yan S, Keller K, Keren B, Mignot C, Kooy F, Meuwissen M, Basinger A, Kukolich M, Philips M, Ortega L, Drummond-Borg M, Lauridsen M, Sorensen K, Lehman A, Lopez-Rangel E, Levy P, Lessel D, Lotze T, Madan-Khetarpal S, Sebastian J, Vento J, Vats D, Benman LM, Mckee S, Mirzaa GM, Muss C, Pappas J, Peeters H, Romano C, Elia M, Galesi O, Simon MEH, van Gassen KLI, Simpson K, Stratton R, Syed S, Thevenon J, Palafoll IV, Vitobello A, Bournez M, Faivre L, Xia K, Earl RK, Nowakowski T, Bernier RA, and Eichler EE

Subjects
Brain metabolism, DNA Copy Number Variations genetics, Gene Expression Regulation, Genetic Association Studies, Genetic Variation, Heterogeneous-Nuclear Ribonucleoproteins metabolism, Humans, Inheritance Patterns genetics, Mutation, Missense genetics, Phenotype, RNA Processing, Post-Transcriptional genetics, Single-Cell Analysis, Genetic Predisposition to Disease, Heterogeneous-Nuclear Ribonucleoproteins genetics, Mutation genetics, Neurodevelopmental Disorders genetics
Abstract

Background: With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations., Methods: We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk., Results: We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs., Conclusions: Overall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.

Published
2021
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41. Integration of whole genome sequencing into a healthcare setting: high diagnostic rates across multiple clinical entities in 3219 rare disease patients.

Author

Stranneheim H, Lagerstedt-Robinson K, Magnusson M, Kvarnung M, Nilsson D, Lesko N, Engvall M, Anderlid BM, Arnell H, Johansson CB, Barbaro M, Björck E, Bruhn H, Eisfeldt J, Freyer C, Grigelioniene G, Gustavsson P, Hammarsjö A, Hellström-Pigg M, Iwarsson E, Jemt A, Laaksonen M, Enoksson SL, Malmgren H, Naess K, Nordenskjöld M, Oscarson M, Pettersson M, Rasi C, Rosenbaum A, Sahlin E, Sardh E, Stödberg T, Tesi B, Tham E, Thonberg H, Töhönen V, von Döbeln U, Vassiliou D, Vonlanthen S, Wikström AC, Wincent J, Winqvist O, Wredenberg A, Ygberg S, Zetterström RH, Marits P, Soller MJ, Nordgren A, Wirta V, Lindstrand A, and Wedell A

Subjects
Cohort Studies, DNA Copy Number Variations genetics, Genetic Heterogeneity, Genomics, High-Throughput Nucleotide Sequencing, Humans, Information Dissemination, Inheritance Patterns genetics, Microsatellite Repeats genetics, Mutation genetics, Sweden, Uniparental Disomy genetics, Delivery of Health Care, Rare Diseases diagnosis, Rare Diseases genetics, Whole Genome Sequencing
Abstract

Background: We report the findings from 4437 individuals (3219 patients and 1218 relatives) who have been analyzed by whole genome sequencing (WGS) at the Genomic Medicine Center Karolinska-Rare Diseases (GMCK-RD) since mid-2015. GMCK-RD represents a long-term collaborative initiative between Karolinska University Hospital and Science for Life Laboratory to establish advanced, genomics-based diagnostics in the Stockholm healthcare setting., Methods: Our analysis covers detection and interpretation of SNVs, INDELs, uniparental disomy, CNVs, balanced structural variants, and short tandem repeat expansions. Visualization of results for clinical interpretation is carried out in Scout-a custom-developed decision support system. Results from both singleton (84%) and trio/family (16%) analyses are reported. Variant interpretation is done by 15 expert teams at the hospital involving staff from three clinics. For patients with complex phenotypes, data is shared between the teams., Results: Overall, 40% of the patients received a molecular diagnosis ranging from 19 to 54% for specific disease groups. There was heterogeneity regarding causative genes (n = 754) with some of the most common ones being COL2A1 (n = 12; skeletal dysplasia), SCN1A (n = 8; epilepsy), and TNFRSF13B (n = 4; inborn errors of immunity). Some causative variants were recurrent, including previously known founder mutations, some novel mutations, and recurrent de novo mutations. Overall, GMCK-RD has resulted in a large number of patients receiving specific molecular diagnoses. Furthermore, negative cases have been included in research studies that have resulted in the discovery of 17 published, novel disease-causing genes. To facilitate the discovery of new disease genes, GMCK-RD has joined international data sharing initiatives, including ClinVar, UDNI, Beacon, and MatchMaker Exchange., Conclusions: Clinical WGS at GMCK-RD has provided molecular diagnoses to over 1200 individuals with a broad range of rare diseases. Consolidation and spread of this clinical-academic partnership will enable large-scale national collaboration.

Published
2021
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42. Increasing involvement of CAPN1 variants in spastic ataxias and phenotype-genotype correlations.

Author

Méreaux JL, Firanescu C, Coarelli G, Kvarnung M, Rodrigues R, Pegoraro E, Tazir M, Taithe F, Valter R, Huin V, Lidström K, Banneau G, Morais S, Parodi L, Coutelier M, Papin M, Svenningsson P, Azulay JP, Alonso I, Nilsson D, Brice A, Le Guern E, Press R, Vazza G, Loureiro JL, Goizet C, Durr A, Paucar M, and Stevanin G

Subjects
Adult, Age of Onset, Cerebellar Ataxia genetics, Child, Female, Genetic Association Studies, Humans, Intellectual Disability diagnosis, Male, Muscle Spasticity diagnosis, Optic Atrophy diagnosis, Pedigree, Phenotype, Spinocerebellar Ataxias diagnosis, Young Adult, Calpain genetics, Intellectual Disability genetics, Muscle Spasticity genetics, Mutation genetics, Optic Atrophy genetics, Spastic Paraplegia, Hereditary genetics, Spinocerebellar Ataxias genetics
Abstract

Spastic ataxias are rare neurogenetic disorders involving spinocerebellar and pyramidal tracts. Many genes are involved. Among them, CAPN1, when mutated, is responsible for a complex inherited form of spastic paraplegia (SPG76). We report the largest published series of 21 novel patients with nine new CAPN1 disease-causing variants and their clinical characteristics from two European university hospitals (Paris and Stockholm). After a formal clinical examination, causative variants were identified by next-generation sequencing and confirmed by Sanger sequencing. CAPN1 variants are a rare cause (~ 1.4%) of young-adult-onset spastic ataxia; however, together with all published cases, they allowed us to better describe the clinical and genetic spectra of this form. Truncating variants are the most frequent, and missense variants lead to earlier age at onset in favor of an additional deleterious effect. Cerebellar ataxia with cerebellar atrophy, dysarthria and lower limb weakness are often associated with spasticity. We also suggest that cognitive impairment and depression should be assessed specifically in the follow-up of SPG76 cases.

Published
2021
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43. Author Correction: Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders.

Author

Wang T, Hoekzema K, Vecchio D, Wu H, Sulovari A, Coe BP, Gillentine MA, Wilfert AB, Perez-Jurado LA, Kvarnung M, Sleyp Y, Earl RK, Rosenfeld JA, Geisheker MR, Han L, Du B, Barnett C, Thompson E, Shaw M, Carroll R, Friend K, Catford R, Palmer EE, Zou X, Ou J, Li H, Guo H, Gerdts J, Avola E, Calabrese G, Elia M, Greco D, Lindstrand A, Nordgren A, Anderlid BM, Vandeweyer G, Van Dijck A, Van der Aa N, McKenna B, Hancarova M, Bendova S, Havlovicova M, Malerba G, Bernardina BD, Muglia P, van Haeringen A, Hoffer MJV, Franke B, Cappuccio G, Delatycki M, Lockhart PJ, Manning MA, Liu P, Scheffer IE, Brunetti-Pierri N, Rommelse N, Amaral DG, Santen GWE, Trabetti E, Sedláček Z, Michaelson JJ, Pierce K, Courchesne E, Kooy RF, Nordenskjöld M, Romano C, Peeters H, Bernier RA, Gecz J, Xia K, and Eichler EE

Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2020
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44. Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders.

Author

Wang T, Hoekzema K, Vecchio D, Wu H, Sulovari A, Coe BP, Gillentine MA, Wilfert AB, Perez-Jurado LA, Kvarnung M, Sleyp Y, Earl RK, Rosenfeld JA, Geisheker MR, Han L, Du B, Barnett C, Thompson E, Shaw M, Carroll R, Friend K, Catford R, Palmer EE, Zou X, Ou J, Li H, Guo H, Gerdts J, Avola E, Calabrese G, Elia M, Greco D, Lindstrand A, Nordgren A, Anderlid BM, Vandeweyer G, Van Dijck A, Van der Aa N, McKenna B, Hancarova M, Bendova S, Havlovicova M, Malerba G, Bernardina BD, Muglia P, van Haeringen A, Hoffer MJV, Franke B, Cappuccio G, Delatycki M, Lockhart PJ, Manning MA, Liu P, Scheffer IE, Brunetti-Pierri N, Rommelse N, Amaral DG, Santen GWE, Trabetti E, Sedláček Z, Michaelson JJ, Pierce K, Courchesne E, Kooy RF, Nordenskjöld M, Romano C, Peeters H, Bernier RA, Gecz J, Xia K, and Eichler EE

Subjects
Basic Helix-Loop-Helix Transcription Factors genetics, CCCTC-Binding Factor genetics, Case-Control Studies, Cohort Studies, DNA Mutational Analysis, DNA-Binding Proteins genetics, Female, Genetic Association Studies, Heterogeneous-Nuclear Ribonucleoprotein U genetics, High-Throughput Nucleotide Sequencing, Humans, KCNQ3 Potassium Channel genetics, Male, Mutation, RNA-Binding Proteins genetics, Repressor Proteins genetics, Transcription Factors genetics, Genetic Predisposition to Disease, Neurodevelopmental Disorders genetics
Abstract

Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E-06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E-07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype-genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.

Published
2020
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45. Pathogenic variants in TNRC6B cause a genetic disorder characterised by developmental delay/intellectual disability and a spectrum of neurobehavioural phenotypes including autism and ADHD.

Author

Granadillo JL, P A Stegmann A, Guo H, Xia K, Angle B, Bontempo K, Ranells JD, Newkirk P, Costin C, Viront J, Stumpel CT, Sinnema M, Panis B, Pfundt R, Krapels IPC, Klaassens M, Nicolai J, Li J, Jiang Y, Marco E, Canton A, Latronico AC, Montenegro L, Leheup B, Bonnet C, M Amudhavalli S, Lawson CE, McWalter K, Telegrafi A, Pearson R, Kvarnung M, Wang X, Bi W, Rosenfeld JA, and Shinawi M

Subjects
Attention Deficit Disorder with Hyperactivity complications, Attention Deficit Disorder with Hyperactivity pathology, Autistic Disorder complications, Autistic Disorder pathology, Child, Child, Preschool, Developmental Disabilities genetics, Developmental Disabilities pathology, Female, Heterozygote, Humans, Intellectual Disability complications, Intellectual Disability genetics, Intellectual Disability pathology, Language Development Disorders genetics, Language Development Disorders pathology, Male, Motor Skills Disorders genetics, Motor Skills Disorders pathology, Mutation genetics, Phenotype, Exome Sequencing, Attention Deficit Disorder with Hyperactivity genetics, Autistic Disorder genetics, Genetic Predisposition to Disease, RNA-Binding Proteins genetics
Abstract

Background: Rare variants in hundreds of genes have been implicated in developmental delay (DD), intellectual disability (ID) and neurobehavioural phenotypes. TNRC6B encodes a protein important for RNA silencing. Heterozygous truncating variants have been reported in three patients from large cohorts with autism, but no full phenotypic characterisation was described., Methods: Clinical and molecular characterisation was performed on 17 patients with TNRC6B variants. Clinical data were obtained by retrospective chart review, parent interviews, direct patient interaction with providers and formal neuropsychological evaluation., Results: Clinical findings included DD/ID (17/17) (speech delay in 94% (16/17), fine motor delay in 82% (14/17) and gross motor delay in 71% (12/17) of subjects), autism or autistic traits (13/17), attention deficit and hyperactivity disorder (ADHD) (11/17), other behavioural problems (7/17) and musculoskeletal findings (12/17). Other congenital malformations or clinical findings were occasionally documented. The majority of patients exhibited some dysmorphic features but no recognisable gestalt was identified. 17 heterozygous TNRC6B variants were identified in 12 male and five female unrelated subjects by exome sequencing (14), a targeted panel (2) and a chromosomal microarray (1). The variants were nonsense (7), frameshift (5), splice site (2), intragenic deletions (2) and missense (1)., Conclusions: Variants in TNRC6B cause a novel genetic disorder characterised by recurrent neurocognitive and behavioural phenotypes featuring DD/ID, autism, ADHD and other behavioural abnormalities. Our data highly suggest that haploinsufficiency is the most likely pathogenic mechanism. TNRC6B should be added to the growing list of genes of the RNA-induced silencing complex associated with ID/DD, autism and ADHD., Competing Interests: Competing interests: KM, AT and RP are employed by GeneDx, and XW, WB, JAR receive salary support from Baylor Genetics Laboratory. Both laboratories offer extensive genetic laboratory testing, including exome sequencing and derive revenue from this activity., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2020
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46. From cytogenetics to cytogenomics: whole-genome sequencing as a first-line test comprehensively captures the diverse spectrum of disease-causing genetic variation underlying intellectual disability.

Author

Lindstrand A, Eisfeldt J, Pettersson M, Carvalho CMB, Kvarnung M, Grigelioniene G, Anderlid BM, Bjerin O, Gustavsson P, Hammarsjö A, Georgii-Hemming P, Iwarsson E, Johansson-Soller M, Lagerstedt-Robinson K, Lieden A, Magnusson M, Martin M, Malmgren H, Nordenskjöld M, Norling A, Sahlin E, Stranneheim H, Tham E, Wincent J, Ygberg S, Wedell A, Wirta V, Nordgren A, Lundin J, and Nilsson D

Subjects
Child, Chromosome Aberrations, DNA Copy Number Variations, Diagnostic Tests, Routine, Female, Humans, Male, Pilot Projects, Prospective Studies, Retrospective Studies, Cytogenetic Analysis methods, Genetic Markers, Genome, Human, Intellectual Disability diagnosis, Intellectual Disability genetics, Polymorphism, Single Nucleotide, Whole Genome Sequencing methods
Abstract

Background: Since different types of genetic variants, from single nucleotide variants (SNVs) to large chromosomal rearrangements, underlie intellectual disability, we evaluated the use of whole-genome sequencing (WGS) rather than chromosomal microarray analysis (CMA) as a first-line genetic diagnostic test., Methods: We analyzed three cohorts with short-read WGS: (i) a retrospective cohort with validated copy number variants (CNVs) (cohort 1, n = 68), (ii) individuals referred for monogenic multi-gene panels (cohort 2, n = 156), and (iii) 100 prospective, consecutive cases referred to our center for CMA (cohort 3). Bioinformatic tools developed include FindSV, SVDB, Rhocall, Rhoviz, and vcf2cytosure., Results: First, we validated our structural variant (SV)-calling pipeline on cohort 1, consisting of three trisomies and 79 deletions and duplications with a median size of 850 kb (min 500 bp, max 155 Mb). All variants were detected. Second, we utilized the same pipeline in cohort 2 and analyzed with monogenic WGS panels, increasing the diagnostic yield to 8%. Next, cohort 3 was analyzed by both CMA and WGS. The WGS data was processed for large (> 10 kb) SVs genome-wide and for exonic SVs and SNVs in a panel of 887 genes linked to intellectual disability as well as genes matched to patient-specific Human Phenotype Ontology (HPO) phenotypes. This yielded a total of 25 pathogenic variants (SNVs or SVs), of which 12 were detected by CMA as well. We also applied short tandem repeat (STR) expansion detection and discovered one pathologic expansion in ATXN7. Finally, a case of Prader-Willi syndrome with uniparental disomy (UPD) was validated in the WGS data. Important positional information was obtained in all cohorts. Remarkably, 7% of the analyzed cases harbored complex structural variants, as exemplified by a ring chromosome and two duplications found to be an insertional translocation and part of a cryptic unbalanced translocation, respectively., Conclusion: The overall diagnostic rate of 27% was more than doubled compared to clinical microarray (12%). Using WGS, we detected a wide range of SVs with high accuracy. Since the WGS data also allowed for analysis of SNVs, UPD, and STRs, it represents a powerful comprehensive genetic test in a clinical diagnostic laboratory setting.

Published
2019
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47. Disruptive variants of CSDE1 associate with autism and interfere with neuronal development and synaptic transmission.

Author

Guo H, Li Y, Shen L, Wang T, Jia X, Liu L, Xu T, Ou M, Hoekzema K, Wu H, Gillentine MA, Liu C, Ni H, Peng P, Zhao R, Zhang Y, Phornphutkul C, Stegmann APA, Prada CE, Hopkin RJ, Shieh JT, McWalter K, Monaghan KG, van Hasselt PM, van Gassen K, Bai T, Long M, Han L, Quan Y, Chen M, Zhang Y, Li K, Zhang Q, Tan J, Zhu T, Liu Y, Pang N, Peng J, Scott DA, Lalani SR, Azamian M, Mancini GMS, Adams DJ, Kvarnung M, Lindstrand A, Nordgren A, Pevsner J, Osei-Owusu IA, Romano C, Calabrese G, Galesi O, Gecz J, Haan E, Ranells J, Racobaldo M, Nordenskjold M, Madan-Khetarpal S, Sebastian J, Ball S, Zou X, Zhao J, Hu Z, Xia F, Liu P, Rosenfeld JA, de Vries BBA, Bernier RA, Xu ZD, Li H, Xie W, Hufnagel RB, Eichler EE, and Xia K

Subjects
Adolescent, Animals, Autistic Disorder psychology, Child, Child, Preschool, DNA-Binding Proteins metabolism, Disease Models, Animal, Female, Genetic Association Studies, Genetic Loci, Humans, Male, Mice, Neurons metabolism, Pedigree, Phenotype, RNA-Binding Proteins metabolism, Synapses genetics, Synapses metabolism, Young Adult, Autistic Disorder diagnosis, Autistic Disorder genetics, DNA-Binding Proteins genetics, Genetic Predisposition to Disease, Genetic Variation, Neurogenesis genetics, RNA-Binding Proteins genetics, Synaptic Transmission genetics
Abstract

RNA binding proteins are key players in posttranscriptional regulation and have been implicated in neurodevelopmental and neuropsychiatric disorders. Here, we report a significant burden of heterozygous, likely gene-disrupting variants in CSDE1 (encoding a highly constrained RNA binding protein) among patients with autism and related neurodevelopmental disabilities. Analysis of 17 patients identifies common phenotypes including autism, intellectual disability, language and motor delay, seizures, macrocephaly, and variable ocular abnormalities. HITS-CLIP revealed that Csde1-binding targets are enriched in autism-associated gene sets, especially FMRP targets, and in neuronal development and synaptic plasticity-related pathways. Csde1 knockdown in primary mouse cortical neurons leads to an overgrowth of the neurites and abnormal dendritic spine morphology/synapse formation and impaired synaptic transmission, whereas mutant and knockdown experiments in Drosophila result in defects in synapse growth and synaptic transmission. Our study defines a new autism-related syndrome and highlights the functional role of CSDE1 in synapse development and synaptic transmission., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).)

Published
2019
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48. Ataxia in Patients With Bi-Allelic NFASC Mutations and Absence of Full-Length NF186.

Author

Kvarnung M, Shahsavani M, Taylan F, Moslem M, Breeuwsma N, Laan L, Schuster J, Jin Z, Nilsson D, Lieden A, Anderlid BM, Nordenskjöld M, Syk Lundberg E, Birnir B, Dahl N, Nordgren A, Lindstrand A, and Falk A

Abstract

The etiology of hereditary ataxia syndromes is heterogeneous, and the mechanisms underlying these disorders are often unknown. Here, we utilized exome sequencing in two siblings with progressive ataxia and muscular weakness and identified a novel homozygous splice mutation (c.3020-1G > A) in neurofascin ( NFASC ). In RNA extracted from fibroblasts, we showed that the mutation resulted in inframe skipping of exon 26, with a deprived expression of the full-length transcript that corresponds to NFASC isoform NF186. To further investigate the disease mechanisms, we reprogrammed fibroblasts from one affected sibling to induced pluripotent stem cells, directed them to neuroepithelial stem cells and finally differentiated to neurons. In early neurogenesis, differentiating cells with selective depletion of the NF186 isoform showed significantly reduced neurite outgrowth as well as fewer emerging neurites. Furthermore, whole-cell patch-clamp recordings of patient-derived neuronal cells revealed a lower threshold for openings, indicating altered Na + channel kinetics, suggesting a lower threshold for openings as compared to neuronal cells without the NFASC mutation. Taken together, our results suggest that loss of the full-length NFASC isoform NF186 causes perturbed neurogenesis and impaired neuronal biophysical properties resulting in a novel early-onset autosomal recessive ataxia syndrome., (Copyright © 2019 Kvarnung, Shahsavani, Taylan, Moslem, Breeuwsma, Laan, Schuster, Jin, Nilsson, Lieden, Anderlid, Nordenskjöld, Syk Lundberg, Birnir, Dahl, Nordgren, Lindstrand and Falk.)

Published
2019
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49. De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.

Author

Helbig KL, Lauerer RJ, Bahr JC, Souza IA, Myers CT, Uysal B, Schwarz N, Gandini MA, Huang S, Keren B, Mignot C, Afenjar A, Billette de Villemeur T, Héron D, Nava C, Valence S, Buratti J, Fagerberg CR, Soerensen KP, Kibaek M, Kamsteeg EJ, Koolen DA, Gunning B, Schelhaas HJ, Kruer MC, Fox J, Bakhtiari S, Jarrar R, Padilla-Lopez S, Lindstrom K, Jin SC, Zeng X, Bilguvar K, Papavasileiou A, Xing Q, Zhu C, Boysen K, Vairo F, Lanpher BC, Klee EW, Tillema JM, Payne ET, Cousin MA, Kruisselbrink TM, Wick MJ, Baker J, Haan E, Smith N, Sadeghpour A, Davis EE, Katsanis N, Corbett MA, MacLennan AH, Gecz J, Biskup S, Goldmann E, Rodan LH, Kichula E, Segal E, Jackson KE, Asamoah A, Dimmock D, McCarrier J, Botto LD, Filloux F, Tvrdik T, Cascino GD, Klingerman S, Neumann C, Wang R, Jacobsen JC, Nolan MA, Snell RG, Lehnert K, Sadleir LG, Anderlid BM, Kvarnung M, Guerrini R, Friez MJ, Lyons MJ, Leonhard J, Kringlen G, Casas K, El Achkar CM, Smith LA, Rotenberg A, Poduri A, Sanchis-Juan A, Carss KJ, Rankin J, Zeman A, Raymond FL, Blyth M, Kerr B, Ruiz K, Urquhart J, Hughes I, Banka S, Hedrich UBS, Scheffer IE, Helbig I, Zamponi GW, Lerche H, and Mefford HC

Published
2019
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50. Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability.

Author

Cogné B, Ehresmann S, Beauregard-Lacroix E, Rousseau J, Besnard T, Garcia T, Petrovski S, Avni S, McWalter K, Blackburn PR, Sanders SJ, Uguen K, Harris J, Cohen JS, Blyth M, Lehman A, Berg J, Li MH, Kini U, Joss S, von der Lippe C, Gordon CT, Humberson JB, Robak L, Scott DA, Sutton VR, Skraban CM, Johnston JJ, Poduri A, Nordenskjöld M, Shashi V, Gerkes EH, Bongers EMHF, Gilissen C, Zarate YA, Kvarnung M, Lally KP, Kulch PA, Daniels B, Hernandez-Garcia A, Stong N, McGaughran J, Retterer K, Tveten K, Sullivan J, Geisheker MR, Stray-Pedersen A, Tarpinian JM, Klee EW, Sapp JC, Zyskind J, Holla ØL, Bedoukian E, Filippini F, Guimier A, Picard A, Busk ØL, Punetha J, Pfundt R, Lindstrand A, Nordgren A, Kalb F, Desai M, Ebanks AH, Jhangiani SN, Dewan T, Coban Akdemir ZH, Telegrafi A, Zackai EH, Begtrup A, Song X, Toutain A, Wentzensen IM, Odent S, Bonneau D, Latypova X, Deb W, Redon S, Bilan F, Legendre M, Troyer C, Whitlock K, Caluseriu O, Murphree MI, Pichurin PN, Agre K, Gavrilova R, Rinne T, Park M, Shain C, Heinzen EL, Xiao R, Amiel J, Lyonnet S, Isidor B, Biesecker LG, Lowenstein D, Posey JE, Denommé-Pichon AS, Férec C, Yang XJ, Rosenfeld JA, Gilbert-Dussardier B, Audebert-Bellanger S, Redon R, Stessman HAF, Nellaker C, Yang Y, Lupski JR, Goldstein DB, Eichler EE, Bolduc F, Bézieau S, Küry S, and Campeau PM

Subjects
Adolescent, Adult, Amino Acid Sequence, Autistic Disorder metabolism, Autistic Disorder pathology, Child, Child, Preschool, Female, Genetic Association Studies, Humans, Infant, Intellectual Disability metabolism, Intellectual Disability pathology, Male, Prognosis, Sequence Homology, Syndrome, Young Adult, Adaptor Proteins, Signal Transducing genetics, Autistic Disorder etiology, Intellectual Disability etiology, Mutation, Missense, Nuclear Proteins genetics
Abstract

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., (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Published
2019
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