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

Author

Møller, R. S., Jensen, L. R., Maas, S. M., Filmus, J., Capurro, M., Hansen, C., Marcelis, C. L. M., Ravn, K., Andrieux, J., Mathieu, M., Kirchhoff, M., Rødningen, O. K., de Leeuw, N., Yntema, H. G., Froyen, G., Vandewalle, J., Ballon, K., Klopocki, E., Joss, S., Tolmie, J., Knegt, A. C., Lund, A. M., Hjalgrim, H., Kuss, A. W., Tommerup, N., Ullmann, R., de Brouwer, A. P. M., Strømme, P., Kjaergaard, S., Tümer, Z., and Kleefstra, T.

Published
2014
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4. Sequence assembly

Author

Scheibye-Alsing, K., Hoffmann, S., Frankel, A., Jensen, P., Stadler, P.F., Mang, Y., Tommerup, N., Gilchrist, M.J., Nygård, A.-B., Cirera, S., Jørgensen, C.B., Fredholm, M., and Gorodkin, J.

Published
2009
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16. Morbidity risk of chromosomal breakpoints in topological domains enriched in non-exonic conserved elements

Author

Bak, M., Fonseca, A., Mehrjouy, M., Rasmussen, M., Halgren, C., Bache, I., Kroisel, P., Midyan, S., Vermeesch, J., Vienna-Morgante, A., Abe, K., Moretti-Ferreira, D., Angelova, L., Rajcan-Separovic, E., Sismani, C., Aristidou, C., Sedlacek, Z., Fagerberg, C., Brondum-Nielsen, K., Vogel, I., Bojesen, A., Ounap, K., Roht, L., Lespinasse, J., Beneteau, C., Kalscheuer, V., Ehmke, N., Daumer-Haas, C., Stefanou, E., Czako, M., Sheth, F., Bonaglia, C., Novelli, A., Fannemel, M., Engelen, J., Travessa, A., Kokalj-Vokac, N., Ramos-Arroyo, M., Martinez, L. R., Guitart, M., Schinzel, A., Silan, F., de Almeida, C., Akkari, Y., Batanian, J., Kim, H., Jacky, P., Tommerup, N., and Consortium, Int Breakpoint Mapping

Published
2019
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33. Position effect, cryptic complexity, and direct gene disruption as disease mechanisms in de novo apparently balanced translocation cases

Author

Aristidou, C. Theodosiou, A. Bak, M. Mehrjouy, M.M. Constantinou, E. Alexandrou, A. Papaevripidou, I. Christophidou-Anastasiadou, V. Skordis, N. Kitsiou-Tzeli, S. Tommerup, N. Sismani, C.

Abstract

The majority of apparently balanced translocation (ABT) carriers are phenotypically normal. However, several mechanisms were proposed to underlie phenotypes in affected ABT cases. In the current study, whole-genome mate-pair sequencing (WG-MPS) followed by Sanger sequencing was applied to further characterize de novo ABTs in three affected individuals. WG-MPS precisely mapped all ABT breakpoints and revealed three possible underlying molecular mechanisms. Firstly, in a t(X;1) carrier with hearing loss, a highly skewed Xinactivation pattern was observed and the der(X) breakpoint mapped ∼87kb upstream an Xlinked deafness gene namely POU3F4, thus suggesting an underlying long-range position effect mechanism. Secondly, cryptic complexity and a chromothripsis rearrangement was identified in a t(6;7;8;12) carrier with intellectual disability. Two translocations and a heterozygous deletion disrupted SOX5; a dominant nervous system development gene previously reported in similar patients. Finally, a direct gene disruption mechanism was proposed in a t (4;9) carrier with dysmorphic facial features and speech delay. In this case, the der(9) breakpoint directly disrupted NFIB, a gene involved in lung maturation and development of the pons with important functions in main speech processes. To conclude, in contrast to familial ABT cases with identical rearrangements and discordant phenotypes, where translocations are considered coincidental, translocations seem to be associated with phenotype presentation in affected de novo ABT cases. In addition, this study highlights the importance of investigating both coding and non-coding regions to decipher the underlying pathogenic mechanisms in these patients, and supports the potential introduction of low coverage WGMPS in the clinical investigation of de novo ABTs. © 2018 Aristidou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Published
2018

35. Exon-disrupting deletions ofNRXN1in idiopathic generalized epilepsy

Author

Møller, R.S., Weber, Y.G., Klitten, L.L., Trucks, H., Muhle, H., Kunz, W.S., Mefford, H.C., Franke, A., Kautza, M., Wolf, P., Dennig, D., Schreiber, S., Rückert, I.M., Wichmann, H.E., Ernst, J.P., Schurmann, C., Grabe, H.J., Tommerup, N., Stephani, U., Lerche, H., Hjalgrim, H., Helbig, I., Sander, T., Zimprich, F., Mörzinger, M., Feucht, M., Suls, A., Weckhuysen, S., Claes, L., Deprez, L., Smets, K., Van Dyck, T., Deconinck, T., De Jonghe, P., Velizarova, R., Dimova, P., Radionova, M., Tournev, I., Kancheva, D., Kaneva, R., Jordanova, A., Kjelgaard, D.B., Lehesjoki, A.E., Siren, A., Baulac, S., Leguern, E., Von Spiczak, S., Ostertag, P., Leber, M., Leu, C., Toliat, M.R., Nürnberg, P., Hempelmann, A., Rüschendorf, F., Elger, C.E., Kleefuß Lie, A.A., Surges, R., Gaus, V., Janz, D., Schmitz, B., Klein, K.M., Reif, P.S., Oertel, W.H., Hamer, H.M., Rosenow, F., Becker, F., Marini, C., Guerrini, R., Mei, D., Norci, V., Zara, F., Striano, P., Robbiano, A., Pezzella, M., Bianchi, A., Gambardella, A., Tinuper, P., La Neve, A., Capovilla, G., Vigliano, P., Crichiutti, G., Vanadia, F., Vignoli, A., Coppola, A., Striano, S., Giallonardo, M.T., Franceschetti, S., Belcastro, V., Benna, P., Coppola, G., De Palo, A., Ferlazzo, E., Vecchi, M., Martinelli, V., Bisulli, F., Beccaria, F., Del Giudice, E., Mancardi, M., Stranci, G., Scabar, A., Gobbi, G., Giordano, I., Koeleman, B.P.C., De Kovel, C., Lindhout, D., De Haan, G.J., Ozbeck, U., Bebek, N., Baykan, B., Ozdemir, O., Ugur, S., Kocasoy Orhan, E., Yücesan, E., Cine, N., Gokyigit, A., Gurses, C., Gul, G., Yapici, Z., Ozkara, C., Caglayan, H., Yalcin, O., Yalcin, D., Turkdogan, D., Dizdarer, G., Agan, K., R. S. Møller, Y. G. Weber, L. L. Klitten, H. Truck, H. Muhle, W. S. Kunz, H. C. Mefford, A. Franke, M. Kautza, P. Wolf, D. Dennig, S. Schreiber, I. Rückert, H. Wichmann, J. P. Ernst, C. Schurmann, H. J. Grabe, N. Tommerup, U. Stephani, H. Lerche, H. Hjalgrim, I. Helbig, T. Sander, P. Tinuper, F. Bisulli, EPICURE Consortium, Suls, Arvid, Weckhuysen, Sarah, Claes, Godelieve, Deprez, Liesbet, Smets, Katrien, Van Dyck, Tine, Deconinck, Tine, De Jonghe, Peter, Jordanova, Albena, Møller, R, Weber, Yg, Klitten, Ll, Trucks, H, Muhle, H, Kunz, W, Mefford, Hc, Franke, A, Kautza, M, Wolf, P, Dennig, D, Schreiber, S, Rückert, Im, Wichmann, He, Ernst, Jp, Schurmann, C, Grabe, Hj, Tommerup, N, Stephani, U, Lerche, H, Hjalgrim, H, Helbig, I, Sander, T, Epicure, Consortium, DEL GIUDICE, Ennio, Coppola, Antonietta, and YÜCESAN, EMRAH

Subjects
Male, Idiopathic generalized epilepsy, Neuronal, Idiopathic Generalized Epilepsy, 1q21, 1 Microdeletion, Two-hit Hypothesis, Nrxn1, Neuropsychological Tests, Immunoglobulin E, Cell Adhesion Molecules, Neuronal/genetics, Adult, Age of Onset, Anticonvulsant, Exon, 1q21.1 microdeletion, Exons/genetics, Odds Ratio, Nerve Tissue Proteins/genetics, Copy-number variation, Valproic Acid/therapeutic use, Age of Onset, Neural Cell Adhesion Molecules, genetics, DNA Copy Number Variations, Electroencephalography, Epilepsy, Genetics, biology, Triazines, Anticonvulsants/therapeutic use, Electroencephalography, genetics, Family, Female, Fructose, Exons, Middle Aged, Settore MED/39 - Neuropsichiatria Infantile, Pedigree, therapeutic use, Valproic Acid, Neurology, Settore MED/26 - Neurologia, Anticonvulsants, Epilepsy, Generalized, Female, Adult, Case-Control Studies, Cell Adhesion Molecules, Neuronal, DNA Copy Number Variations, Family, Fructose, Gene Deletion, Genotype, Humans, Infant, Microarray Analysis, Nerve Tissue Proteins, Valproic Acid, analogs /&/ derivatives/therapeutic use, Gene Deletion, Genotype, Humans, Infant, Male, Microarray Analysis, Middle Aged, Nerve Tissue Protein, therapeutic use, Case-Control Studies, Cell Adhesion Molecule, drug therapy/genetics/psychology, Exon, genetics, Neuropsychological Tests, Odds Ratio, Pedigree, Triazine, Lamotrigine, NRXN1, Topiramate, Epilepsy, Generalized/drug therapy, medicine, Allele, Biology, Gene, Generalized, Point mutation, Calcium-Binding Proteins, Odds ratio, medicine.disease, Triazines/therapeutic use, Settore MED/03 - Genetica Medica, therapeutic use, biology.protein, Fructose/analogs & derivatives, Human medicine, Neurology (clinical), Two-hit hypothesis
Abstract

Summary Purpose Neurexins are neuronal adhesion molecules located in the presynaptic terminal, where they interact with postsynaptic neuroligins to form a transsynaptic complex required for efficient neurotransmission in the brain. Recently, deletions and point mutations of the neurexin 1 (NRXN1) gene have been associated with a broad spectrum of neuropsychiatric disorders. This study aimed to investigate if NRXN1 deletions also increase the risk of idiopathic generalized epilepsies (IGEs). Methods We screened for deletions involving the NRXN1 gene in 1,569 patients with IGE and 6,201 controls using high-density oligonucleotide microarrays. Key Findings We identified exon-disrupting deletions of NRXN1 in 5 of 1,569 patients with IGE and 2 of 6,201 control individuals (p = 0.0049; odds ratio (OR) 9.91, 95% confidence interval (CI) 1.92–51.12). A complex familial segregation pattern in the IGE families was observed, suggesting that heterozygous NRXN1 deletions are susceptibility variants. Intriguingly, we identified a second large copy number variant in three of five index patients, supporting an involvement of heterogeneous susceptibility alleles in the etiology of IGE. Significance We conclude that exon-disrupting deletions of NRXN1 represent a genetic risk factor in the genetically complex predisposition of common IGE syndromes.

Published
2013
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36. Whole genome characterization of array defined clustered CNVs reveals two distinct complex rearrangement subclasses generated through either non-homologous repair or template switching

Author

Nazaryan-Petersen, L., Eisfeldt, J., Lundin, J., Pettersson, M., Nilsson, D., Wincent, J., Lieden, A., Vezzi, F., Wirta, Valtteri, Käller, Max, Duelund, T., Houssari, R., Pignata, L., Bak, M., Tommerup, N., Lundberg, E. S., Tumer, Z., Lindstrand, A., Nazaryan-Petersen, L., Eisfeldt, J., Lundin, J., Pettersson, M., Nilsson, D., Wincent, J., Lieden, A., Vezzi, F., Wirta, Valtteri, Käller, Max, Duelund, T., Houssari, R., Pignata, L., Bak, M., Tommerup, N., Lundberg, E. S., Tumer, Z., and Lindstrand, A.

Abstract

QC 20200312

Published
2018

37. Mutation of ribosomal RNA-processing protein 7 homolog A (RRP7A) cause autosomal recessive microcephaly with intellectual disability

Author

Farooq, M., Lindbaek, L., Krogh, N., Nielsen, V. S., Monnich, M., Sakthivel, S., Doganli, C., Mang, Y., Fatima, A., Hussain, M. S., Mollgard, K., Eiberg, H., Hansen, L., Kjaer, K. W., Nielsen, H., Baig, S. M., Tommerup, N., Christensen, S. T., Larsen, L. A., Farooq, M., Lindbaek, L., Krogh, N., Nielsen, V. S., Monnich, M., Sakthivel, S., Doganli, C., Mang, Y., Fatima, A., Hussain, M. S., Mollgard, K., Eiberg, H., Hansen, L., Kjaer, K. W., Nielsen, H., Baig, S. M., Tommerup, N., Christensen, S. T., and Larsen, L. A.

Published
2018

38. Abstracts of Selected Posters

Author

Albanese, R., Antoine, J. L., Dutrillaux, B., Ashley, T., Avivi, L., Kariv, I., Barigozzi, C., Baratelli, L., Profeta, S., Bartram, C. R., de Klein, A., Hagemeijer, A., Grosveld, G., Bootsma, D., Bennett, Michael D., Smith, J. B., Ward, J. P., Heslop-Harrison, J. S., Blin, N., Kopun, M., Buys, C. H. C. M., Koerts, T., van der Veen, A. Y., de Leij, L., Civitelli, M. V., Capanna, E., Couturier, J., Arnason, U., Mandahl, N., Créau-Goldberg, N., Turleau, C., Cochet, C., de Grouchy, J., Dietrich, A. J. J., Delhanty, J. D. A., Mazzullo, H. A., Cooke, H. M. G., Dotan, A., Dresser, M. E., Moses, M. J., Evans, E. P., Burgoyne, P. B., Ferraro, M., Lavia, P., Fonatsch, C., Kirchner, H. H., Pajunk, A., Schaadt, M., Burrichter, H., Diehl, V., Ford, J. H., Roberts, C. G., Friebe, B., Vogel, R., Friedländer, M., Gamperl, R., Amtmann, E., Pfister, H., Gebhart, E., Wagner, H., Goetz, P., Chandley, A. C., Speed, R. M., Goyanes, V. J., Schvartzman, J. B., Graeven, U., Weh, H. J., Hossfeld, D. K., Greenblatt, I. M., Gripenberg, U., Söderlund, V., Wahlberg, C., Blomqvist, L., Guichaoua, M. R., Delafontaine, D., Taillemite, J. L., Luciani, J. M., Naaf, T., Grunert, D., Schmid, M., Hameister, H., Sperling, K., Hamers, A., Jongbloet, P., Peeters, G., Geraedts, J., Hartley-Asp, B., Heneen, W. K., Hens, L., Kirsch-Volders, M., Susanne, C., Herbst, E. W., Winking, H., Claussen, C. P., Putz, B., Sellin, D., Kolbus, U., Gropp, A., Bennett, M. D., Heyting, C., Koperdraad, F., Redeker, E. J. W., Holmquist, G., Goldman, M., Jaworska, Halina, Johannisson, R., Kerem, B., Goitein, R., Richier, C., Marcus, M., Cedar, H., Koch, H., Hoehn, H., Kubbies, Manfred, Rabinovitch, Peter S., Kunz, W., Franz, G., Lacadena, J. R., Cermeno, M. C., Orellana, J., Santos, J. L., Lemeunier, F., Derbin, C., Lin, C. C., Hoar, D. I., Hoo, J. J., Macgregor, H. C., Sims, S., Horner, H. A., Pellatt, P., Mackay, J. M., Fox, D. P., Brunt, P. W., Johnston, A. W., Magenis, R. E., Chamberlin, J., Allen, L., Tomar, D., Olson, S., Donlon, T., Marlekaj, P., Balcini, A., Fantoni, A., de Capoa, A., Martinsson, T., Dahllöf, B., Levan, G., Matsukuma, S., Utakoji, T., del Mazo, J., Avila, J., Miller, D. A., Feinstein, S. I., Miller, O. J., Morita, T., Delarbre, C., Gachelin, G., Kourilsky, P., Moritz, K., Moriwaki, K., Miyashita, N., Imai, H. T., Wang, C. H., Bonhomme, F., Murer-Orlando, M., Peterson, A. C., Neitzel, H., Bogenberger, J., Fittler, F., Gaenge, M., Schulze, C., Nietzel, H., Nürnberger, F., Höhn, H., van Ommen, G. J. B., Baas, F., Arnberg, A. C., Pearson, P. L., De Vijilder, J. J. M., Bakker, E., Hofker, M., Wapenaar, M. C., Parrington, J. M., West, L. F., Povey, S., Pasquali, F., Casalone, R., Bernasconi, P., Paul, J., Froster-Iskenius, U., Schwinger, E., Moje, W., Pearson, P. O., Beverstock, G. C., Veenema, H., v.d Kamp, J. J., Petitpierre, E., Philip, J., Lundsteen, C., van der Ploeg, M., van Prooijen-Knegt, A. C., Bauman, J. G. J., van Duijn, P., Puertas, M. J., de la Pena, A., Estades, B., Merino, F., Rao, S. R. V., Vasantha, K., Thelma, B. K., Juyal, R. C., Jhanwar, S. C., Ratomponirina, Ch, Hamilton, A., Rumpler, Y., Moses, M., Raveh, D., Ben-Zeoev, A., Redi, C. A., Garagna, S., Italy, C. N. R., Robert-Nicoud, M., Streichhan, I., Möhr, E., Westermann, R., Grossbach, U., Sandberg, P., Levan, A., Schäfer, Mireille, Schempp, W., Scheres, J. M. J. C., Hustinx, T. W. J., Holdrinet, R. S. G., Tice, R. R., Schwarzacher, T., Finch, R. A., Searle, J. B., Sharma, T., Sen, S., Cheong, N., Siebert, E., Loidl, J., Slater, R. M., de Kraker, J., Voute, P. A., Delemarre, J. F. M., Smeets, D. F. C. M., Smits, A. P. T., Solleder, E., Inglin, B., Geile, B., Somssich, I., Schwarz, E., Speit, G., Mehnert, K., Vogel, W., Stahl, A., Hartung, M., Devictor, M., Guichaoua, M., Stoll, C., Roth, M.-P., Dott, B., Tabor, A., Madsen, M., Tommerup, N., Traut, W., Chavin-Colin, F., Junien, C., Vekemans, M., Esseltine, D., Venegas, W., Lasne, Cl, Chouroulinkov, I., Vidal, F., Navarro, J., Templado, C., Egozcue, J., Viegas-Péquignot, E., Malfoy, B., Taillandier, E., Leng, M., Viinikka, Y., Spielmann, H., Boldin, S., Volobouev, V. T., Webb, G. C., Krumins, E., Wegner, R.-D., Lüdtke, E.-L., Weith, A., Westerman, M., Thomson, R., Sinclair, A., Yacobi, Y. Z., Feldman, M., Yoon, J. S., Bennett, M. D., editor, Gropp, A., editor, and Wolf, U., editor

Published
1984
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39. A Cohort of Balanced Reciprocal Translocations Associated with Dyslexia: Identification of Two Putative Candidate Genes at DYX1

Author

Buonincontri, R., Bache, I., Silahtaroglu, A., Elbro, C., Veber Nilsen, A., Ullmann, R., Arkesteijn, G., Tommerup, N., and Dep Infectieziekten Immunologie

Subjects
Adult, Male, Candidate gene, Denmark, Nerve Tissue Proteins, Chromosomal translocation, Biology, Polymorphism, Single Nucleotide, behavioral disciplines and activities, Translocation, Genetic, Cohort Studies, Dyslexia, Pregnancy, mental disorders, Basic Helix-Loop-Helix Transcription Factors, Genetics, medicine, Humans, Child, Gene, Genetic Association Studies, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, Linkage (software), Chromosomes, Human, Pair 15, Cyclic Nucleotide Phosphodiesterases, Type 7, Genetic Carrier Screening, Breakpoint, Chromosome Mapping, Nuclear Proteins, Zinc Fingers, Karyotype, medicine.disease, Phenotype, Pedigree, nervous system diseases, Cytoskeletal Proteins, Karyotyping, Amniocentesis, Chromosomes, Human, Pair 6, Female
Abstract

Dyslexia is one of the most common neurodevelopmental disorders where likely many genes are involved in the pathogenesis. So far six candidate dyslexia genes have been proposed, and two of these were identified by rare chromosomal translocations in affected individuals. By systematic re-examination of all translocation carriers in Denmark, we have identified 16 different translocations associated with dyslexia. In four families, where the translocation co-segregated with the phenotype, one of the breakpoints concurred (at the cytogenetic level) with either a known dyslexia linkage region--at 15q21 (DYX1), 2p13 (DYX3) and 1p36 (DYX8)--or an unpublished linkage region at 19q13. As a first exploitation of this unique cohort, we identify three novel candidate dyslexia genes, ZNF280D and TCF12 at 15q21, and PDE7B at 6q23.3, by molecular mapping of the familial translocation with the 15q21 breakpoint.

Published
2010
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40. Erratum: Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy (Epilepsia (2013) 54 (256-264) DOI:10.1111/epi.12517)

Author

Møller, R. S., Weber, Y. G., Klitten, L. L., Trucks, H., Muhle, H., Kunz, W. S., Mefford, H. C., Franke, A., Kautza, M., Wolf, P., Dennig, D., Schreiber, S., Rückert, I. -M., Wichmann, H. -E., Ernst, J. P., Schurmann, C., Grabe, H. J., Tommerup, N., Stephani, U., Lerche, H., Hjalgrim, H., Helbig, I., Sander, T., Zimprich, F., Mörzinger, M., Feucht, M., Suls, A., Weckhuysen, S., Claes, L., Deprez, L., Smets, K., Van Dyck, T., Deconinck, T., De Jonghe, P., Velizarova, R., Dimova, P., Radionova, M., Tournev, I., Kancheva, D., Kaneva, R., Jordanova, A., Kjelgaard, D. B., Lehesjoki, A. -E., Siren, A., Baulac, S., Leguern, E., Von Spiczak, S., Ostertag, P., Leber, M., Leu, C., Toliat, M. R., Nürnberg, P., Hempelmann, A., Rüschendorf, F., Elger, C. E., Kleefuß-Lie, A. A., Surges, R., Gaus, V., Janz, D., Schmitz, B., Klein, K. M., Reif, P. S., Oertel, W. H., Hamer, H. M., Rosenow, F., Becker, F., Marini, C., Guerrini, R., Mei, D., Norci, V., Zara, F., Striano, P., Robbiano, A., Pezzella, M., Bianchi, A., Gambardella, A., Tinuper, P., La Neve, A., Capovilla, G., Vigliano, P., Crichiutti, G., Vanadia, F., Vignoli, A., Coppola, A., Striano, S., Giallonardo, M. T., Franceschetti, S., Belcastro, V., Benna, P., Coppola, G., De Palo, A., Ferlazzo, E., Vecchi, M., Martinelli, V., Bisulli, F., Beccaria, F., Del Giudice, E., Mancardi, M., Stranci, G., Scabar, A., Gobbi, G., Giordano, I., Koeleman, B. P. C., De Kovel, C., Lindhout, D., De Haan, G. -J., Ozbeck, U., Bebek, N., Baykan, B., Ozdemir, O., Ugur, S., Kocasoy-Orhan, E., Yücesan, E., Cine, N., Gokyigit, A., Gurses, C., Gul, G., Yapici, Z., Ozkara, C., Caglayan, H., Yalcin, O., Yalcin, D., Turkdogan, D., Dizdarer, G., Agan, K., Møller, R. S., Weber, Y. G., Klitten, L. L., Trucks, H., Muhle, H., Kunz, W. S., Mefford, H. C., Franke, A., Kautza, M., Wolf, P., Dennig, D., Schreiber, S., Rückert, I. -M., Wichmann, H. -E., Ernst, J. P., Schurmann, C., Grabe, H. J., Tommerup, N., Stephani, U., Lerche, H., Hjalgrim, H., Helbig, I., Sander, T., Zimprich, F., Mörzinger, M., Feucht, M., Suls, A., Weckhuysen, S., Claes, L., Deprez, L., Smets, K., Van Dyck, T., Deconinck, T., De Jonghe, P., Velizarova, R., Dimova, P., Radionova, M., Tournev, I., Kancheva, D., Kaneva, R., Jordanova, A., Kjelgaard, D. B., Lehesjoki, A. -E., Siren, A., Baulac, S., Leguern, E., Von Spiczak, S., Ostertag, P., Leber, M., Leu, C., Toliat, M. R., Nürnberg, P., Hempelmann, A., Rüschendorf, F., Elger, C. E., Kleefuß-Lie, A. A., Surges, R., Gaus, V., Janz, D., Schmitz, B., Klein, K. M., Reif, P. S., Oertel, W. H., Hamer, H. M., Rosenow, F., Becker, F., Marini, C., Guerrini, R., Mei, D., Norci, V., Zara, F., Striano, P., Robbiano, A., Pezzella, M., Bianchi, A., Gambardella, A., Tinuper, P., La Neve, A., Capovilla, G., Vigliano, P., Crichiutti, G., Vanadia, F., Vignoli, A., Coppola, A., Striano, S., Giallonardo, M. T., Franceschetti, S., Belcastro, V., Benna, P., Coppola, G., De Palo, A., Ferlazzo, E., Vecchi, M., Martinelli, V., Bisulli, F., Beccaria, F., Del Giudice, E., Mancardi, M., Stranci, G., Scabar, A., Gobbi, G., Giordano, I., Koeleman, B. P. C., De Kovel, C., Lindhout, D., De Haan, G. -J., Ozbeck, U., Bebek, N., Baykan, B., Ozdemir, O., Ugur, S., Kocasoy-Orhan, E., Yücesan, E., Cine, N., Gokyigit, A., Gurses, C., Gul, G., Yapici, Z., Ozkara, C., Caglayan, H., Yalcin, O., Yalcin, D., Turkdogan, D., Dizdarer, G., and Agan, K.

Published
2013

45. A Novel Locus Harbouring a Functional CD164 Nonsense Mutation Identified in a Large Danish Family with Nonsyndromic Hearing Impairment

Author

Nyegaard, M., Rendtorff, N.D., Nielsen, M.S., Corydon, T.J., Demontis, D., Starnawska, A., Hedemand, A., Buniello, A., Niola, F., Overgaard, M.T., Leal, S.M., Ahmad, W., Wikman, F.P., Petersen, K.B., Cruger, D.G., Oostrik, J., Kremer, H., Tommerup, N., Frodin, M., Steel, K.P., Tranebjaerg, L., Borglum, A.D., Nyegaard, M., Rendtorff, N.D., Nielsen, M.S., Corydon, T.J., Demontis, D., Starnawska, A., Hedemand, A., Buniello, A., Niola, F., Overgaard, M.T., Leal, S.M., Ahmad, W., Wikman, F.P., Petersen, K.B., Cruger, D.G., Oostrik, J., Kremer, H., Tommerup, N., Frodin, M., Steel, K.P., Tranebjaerg, L., and Borglum, A.D.

Abstract

Contains fulltext : 154690.PDF (publisher's version ) (Open Access), Nonsyndromic hearing impairment (NSHI) is a highly heterogeneous condition with more than eighty known causative genes. However, in the clinical setting, a large number of NSHI families have unexplained etiology, suggesting that there are many more genes to be identified. In this study we used SNP-based linkage analysis and follow up microsatellite markers to identify a novel locus (DFNA66) on chromosome 6q15-21 (LOD 5.1) in a large Danish family with dominantly inherited NSHI. By locus specific capture and next-generation sequencing, we identified a c.574C>T heterozygous nonsense mutation (p.R192*) in CD164. This gene encodes a 197 amino acid transmembrane sialomucin (known as endolyn, MUC-24 or CD164), which is widely expressed and involved in cell adhesion and migration. The mutation segregated with the phenotype and was absent in 1200 Danish control individuals and in databases with whole-genome and exome sequence data. The predicted effect of the mutation was a truncation of the last six C-terminal residues of the cytoplasmic tail of CD164, including a highly conserved canonical sorting motif (YXXcapital EF, Cyrillic). In whole blood from an affected individual, we found by RT-PCR both the wild-type and the mutated transcript suggesting that the mutant transcript escapes nonsense mediated decay. Functional studies in HEK cells demonstrated that the truncated protein was almost completely retained on the plasma cell membrane in contrast to the wild-type protein, which targeted primarily to the endo-lysosomal compartments, implicating failed endocytosis as a possible disease mechanism. In the mouse ear, we found CD164 expressed in the inner and outer hair cells of the organ of Corti, as well as in other locations in the cochlear duct. In conclusion, we have identified a new DFNA locus located on chromosome 6q15-21 and implicated CD164 as a novel gene for hearing impairment.

Published
2015

46. The first mutation in CNGA2 in two brothers with anosmia

Author

Karstensen, H G, Mang, Y, Fark, T, Hummel, T, Tommerup, N, Karstensen, H G, Mang, Y, Fark, T, Hummel, T, and Tommerup, N

Abstract

Isolated congenital anosmia (ICA) is a rare disorder, where otherwise healthy individuals present with an inability to smell since birth. A list of studies have described the genes involved in syndromic anosmia; however, the genetics of ICA is still in its infancy. Studies in mice show that the cyclic nucleotide-gated channel subunit CNGA2, expressed in the olfactory epithelium has a crucial role in olfactory signal transduction. We have identified a novel X-linked stop mutation in CNGA2 (c.634C>T, p.R212*) in two brothers with ICA using exome sequencing. No additional mutations in CNGA2 were identified in a cohort of 31 non-related ICA individuals. Magnetic resonance brain imaging revealed diminished olfactory bulbs and flattened olfactory sulci. This is the first report of a mutation in the cyclic nucleotide-gated gene CNGA2 and supports the critical role of this gene in human olfaction.

Published
2015

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