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1. Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction

Author

Wesdorp, M. (Mieke), de Koning Gans, P.A.M. (P. A M), Schraders, M. (Margit), Oostrik, J. (Jaap), Huynen, M. (Martijn), Venselaar, H. (Hanka), Beynon, A.J. (Andy J.), van Gaalen, J. (Judith), Piai, V. (Vitória), Voermans, N.C. (Nicol), Rossum, M.M. (Michelle) van, Hartel, B.P. (Bas P.), Lelieveld, S.H. (Stefan H.), Wiel, L. (Laurens), Verbist, B. (Berit), Rotteveel, L.J. (Liselotte J.), Dooren, M.F. (Marieke) van, Lichtner, P. (Peter), Kunst, H.P.M. (Henricus P. M.), Feenstra, I. (Ilse), Admiraal, R.J.C. (Ronald J. C.), van Dooren, M.F. (M. F.), de Gier, H.H.W. (H. H.W.), Hoefsloot, E.H. (Lies), Schroeff, M.P. (Marc) van der, Kant, S.G. (Sarina), Rotteveel, L.J.C. (L. J.C.), Frints, S.G.M. (Suzanna), Hof, J.R. (J. R.), Stokroos, R.J. (Robert Jan), Vanhoutte, E.K. (Els), Admiraal, R.J. (Ronald), Feenstra, I. (I.), Kremer, H. (H.), Kunst, H.P.M. (Henricus P.M.), Pennings, R.J.E. (Ronald J.E.), Yntema, H.G. (H. G.), Essen, J.A. (Anthonie) van, Free, R.H. (Rolien), Klein-Wassink, J.S. (J. S.), Yntema, H.G., Pennings, R.J.E. (Ronald J. E.), Kremer, H. (Hannie), Wesdorp, M. (Mieke), de Koning Gans, P.A.M. (P. A M), Schraders, M. (Margit), Oostrik, J. (Jaap), Huynen, M. (Martijn), Venselaar, H. (Hanka), Beynon, A.J. (Andy J.), van Gaalen, J. (Judith), Piai, V. (Vitória), Voermans, N.C. (Nicol), Rossum, M.M. (Michelle) van, Hartel, B.P. (Bas P.), Lelieveld, S.H. (Stefan H.), Wiel, L. (Laurens), Verbist, B. (Berit), Rotteveel, L.J. (Liselotte J.), Dooren, M.F. (Marieke) van, Lichtner, P. (Peter), Kunst, H.P.M. (Henricus P. M.), Feenstra, I. (Ilse), Admiraal, R.J.C. (Ronald J. C.), van Dooren, M.F. (M. F.), de Gier, H.H.W. (H. H.W.), Hoefsloot, E.H. (Lies), Schroeff, M.P. (Marc) van der, Kant, S.G. (Sarina), Rotteveel, L.J.C. (L. J.C.), Frints, S.G.M. (Suzanna), Hof, J.R. (J. R.), Stokroos, R.J. (Robert Jan), Vanhoutte, E.K. (Els), Admiraal, R.J. (Ronald), Feenstra, I. (I.), Kremer, H. (H.), Kunst, H.P.M. (Henricus P.M.), Pennings, R.J.E. (Ronald J.E.), Yntema, H.G. (H. G.), Essen, J.A. (Anthonie) van, Free, R.H. (Rolien), Klein-Wassink, J.S. (J. S.), Yntema, H.G., Pennings, R.J.E. (Ronald J. E.), and Kremer, H. (Hannie)

Abstract

Unraveling the causes and pathomechanisms of progressive disorders is essential for the development of therapeutic strategies. Here, we identified heterozygous pathogenic missense variants of LMX1A in two families of Dutch origin with progressive nonsyndromic hearing impairment (HI), using whole exome sequencing. One variant, c.721G > C (p.Val241Leu), occurred de novo and is predicted to affect the homeodomain of LMX1A, which is essential for DNA binding. The second variant, c.290G > C (p.Cys97Ser), predicted to affect a zinc-binding residue of the second LIM domain that is involved in protein–protein interactions. Bi-allelic deleterious variants of Lmx1a are associated with a complex phenotype in mice, including deafness and vestibular defects, due to arrest of inner ear development. Although Lmx1a mouse mutants demonstrate neurological, skeletal, pigmentation and reproductive system abnormalities, no syndromic features were present in the participating subjects of either family. LMX1A has previously been suggested as a candidate gene for intellectual disability, but our data do not support this, as affected subjects displayed normal cognition. Large variability was observed in the age of onset (a)symmetry, severity and progression rate of HI. About half of the affected individuals displayed vestibular dysfunction and experienced symptoms thereof. The late-onset progressive phenotype and the absence of cochleovestibular malformations on computed tomography scans indicate that heterozygous defects of LMX1A do not result in severe developmental abnormalities in humans. We propose that a single LMX1A wild-type copy is sufficient for normal development but insufficient for maintenance of cochleovestibular function. Alternatively, minor cochleovestibular developmental abnormalities could eventually lead to the progressive phenotype seen in the families.

Published
2018
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2. Novel irf6 mutations detected in orofacial cleft patients by targeted massively parallel sequencing

Author

Khandelwal, K., Ishorst, N., Zhou, H., Ludwig, K.U., Venselaar, H., Gilissen, C.F., Thonissen, M., Rooij, I.A.L.M. van, Dreesen, K., Steehouwer, M., Vorst, J.M. van de, Bloemen, M., Beusekom, E. van, Roosenboom, J., Borstlap, W.A., Admiraal, R.J., Dormaar, T., Schoenaers, J., Poorten, V. Van der, Hens, G., Verdonck, A., Berge, S.J., Roeleveld, N., Vriend, G., Devriendt, K., Brunner, H.G., Mangold, E., Hoischen, A., Bokhoven, H. van, Carels, C.E.L., Khandelwal, K., Ishorst, N., Zhou, H., Ludwig, K.U., Venselaar, H., Gilissen, C.F., Thonissen, M., Rooij, I.A.L.M. van, Dreesen, K., Steehouwer, M., Vorst, J.M. van de, Bloemen, M., Beusekom, E. van, Roosenboom, J., Borstlap, W.A., Admiraal, R.J., Dormaar, T., Schoenaers, J., Poorten, V. Van der, Hens, G., Verdonck, A., Berge, S.J., Roeleveld, N., Vriend, G., Devriendt, K., Brunner, H.G., Mangold, E., Hoischen, A., Bokhoven, H. van, and Carels, C.E.L.

Abstract

Contains fulltext : 191986.pdf (publisher's version ) (Closed access)

Published
2017

3. Novel irf6 mutations detected in orofacial cleft patients by targeted massively parallel sequencing

Author

Khandelwal, K., Ishorst, N., Zhou, H., Ludwig, K.U., Venselaar, H., Gilissen, C.F., Thonissen, M., Rooij, I.A.L.M. van, Dreesen, K., Steehouwer, M., Vorst, J.M. van de, Bloemen, M., Beusekom, E. van, Roosenboom, J., Borstlap, W.A., Admiraal, R.J., Dormaar, T., Schoenaers, J., Poorten, V. Van der, Hens, G., Verdonck, A., Berge, S.J., Roeleveld, N., Vriend, G., Devriendt, K., Brunner, H.G., Mangold, E., Hoischen, A., Bokhoven, H. van, Carels, C.E.L., Khandelwal, K., Ishorst, N., Zhou, H., Ludwig, K.U., Venselaar, H., Gilissen, C.F., Thonissen, M., Rooij, I.A.L.M. van, Dreesen, K., Steehouwer, M., Vorst, J.M. van de, Bloemen, M., Beusekom, E. van, Roosenboom, J., Borstlap, W.A., Admiraal, R.J., Dormaar, T., Schoenaers, J., Poorten, V. Van der, Hens, G., Verdonck, A., Berge, S.J., Roeleveld, N., Vriend, G., Devriendt, K., Brunner, H.G., Mangold, E., Hoischen, A., Bokhoven, H. van, and Carels, C.E.L.

Abstract

Item does not contain fulltext

Published
2017

4. The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in the Netherlands

Author

Seco, C.Z. (Celia Zazo), Wesdorp, M. (Mieke), Feenstra, I. (Ilse), Pfundt, R. (Rolph), Hehir-Kwa, J. (Jayne), Lelieveld, S.H. (Stefan H.), Castelein, S. (Steven), Gilissen, C. (Christian), Wijs, I.J. (Ilse) de, Admiraal, R.J. (Ronald), Pennings, R.J.E. (Ronald J.E.), Kunst, H.P.M. (Henricus P.M.), van de Kamp, J.M. (Jiddeke M.), Tamminga, S. (Saskia), Houweling, A.C. (Arjan), Plomp, A. (Astrid), Maas, S.M. (Saskia), de Koning Gans, P.A.M. (P. A M), Kant, S.G. (Sarina), De Geus, C.M. (Christa M.), Frints, S.G.M. (Suzanna), Vanhoutte, E.K. (Els), Dooren, M.F. (Marieke) van, Boogaard, M.H. (Marie-José Henriëtte) van den, Scheffer, H. (Hans), Nelen, M.R. (Marcel), Kremer, H. (Hannie), Hoefsloot, E.H. (Lies), Schraders, M. (Margit), Yntema, H.G., Seco, C.Z. (Celia Zazo), Wesdorp, M. (Mieke), Feenstra, I. (Ilse), Pfundt, R. (Rolph), Hehir-Kwa, J. (Jayne), Lelieveld, S.H. (Stefan H.), Castelein, S. (Steven), Gilissen, C. (Christian), Wijs, I.J. (Ilse) de, Admiraal, R.J. (Ronald), Pennings, R.J.E. (Ronald J.E.), Kunst, H.P.M. (Henricus P.M.), van de Kamp, J.M. (Jiddeke M.), Tamminga, S. (Saskia), Houweling, A.C. (Arjan), Plomp, A. (Astrid), Maas, S.M. (Saskia), de Koning Gans, P.A.M. (P. A M), Kant, S.G. (Sarina), De Geus, C.M. (Christa M.), Frints, S.G.M. (Suzanna), Vanhoutte, E.K. (Els), Dooren, M.F. (Marieke) van, Boogaard, M.H. (Marie-José Henriëtte) van den, Scheffer, H. (Hans), Nelen, M.R. (Marcel), Kremer, H. (Hannie), Hoefsloot, E.H. (Lies), Schraders, M. (Margit), and Yntema, H.G.

Abstract

Hearing impairment (HI) is genetically heterogeneous which hampers genetic counseling and molecular diagnosis. Testing of several single HI-related genes is laborious and expensive. In this study, we evaluate the diagnostic utility of whole-exome sequencing (WES) targeting a panel of HI-related genes. Two hundred index patients, mostly of Dutch origin, with presumed hereditary HI underwent WES followed by targeted analysis of an HI gene panel of 120 genes. We found causative variants underlying the HI in 67 of 200 patients (33.5%). Eight of these patients have a large homozygous deletion involving STRC, OTOA or USH2A, which could only be identified by copy number variation detection. Variants of uncertain significance were found in 10 patients (5.0%). In the remaining 123 cases, no potentially causative variants were detected (61.5%). In our patient cohort, causative variants in GJB2, USH2A, MYO15A and STRC, and in MYO6 were the leading causes for autosomal recessive and dominant HI, respectively. Segregation analysis and functional analyses of variants of uncertain significance will probably further increase the diagnostic yield of WES.

Published
2017
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5. Novel irf6 mutations detected in orofacial cleft patients by targeted massively parallel sequencing

Author

Khandelwal, K., Ishorst, N., Zhou, H., Ludwig, K.U., Venselaar, H., Gilissen, C.F., Thonissen, M., Rooij, I.A.L.M. van, Dreesen, K., Steehouwer, M., Vorst, J.M. van de, Bloemen, M., Beusekom, E. van, Roosenboom, J., Borstlap, W.A., Admiraal, R.J., Dormaar, T., Schoenaers, J., Poorten, V. Van der, Hens, G., Verdonck, A., Berge, S.J., Roeleveld, N., Vriend, G., Devriendt, K., Brunner, H.G., Mangold, E., Hoischen, A., Bokhoven, H. van, Carels, C.E.L., Khandelwal, K., Ishorst, N., Zhou, H., Ludwig, K.U., Venselaar, H., Gilissen, C.F., Thonissen, M., Rooij, I.A.L.M. van, Dreesen, K., Steehouwer, M., Vorst, J.M. van de, Bloemen, M., Beusekom, E. van, Roosenboom, J., Borstlap, W.A., Admiraal, R.J., Dormaar, T., Schoenaers, J., Poorten, V. Van der, Hens, G., Verdonck, A., Berge, S.J., Roeleveld, N., Vriend, G., Devriendt, K., Brunner, H.G., Mangold, E., Hoischen, A., Bokhoven, H. van, and Carels, C.E.L.

Abstract

Contains fulltext : 191986.pdf (publisher's version ) (Closed access)

Published
2017

6. Novel irf6 mutations detected in orofacial cleft patients by targeted massively parallel sequencing

Author

Khandelwal, K., Ishorst, N., Zhou, H., Ludwig, K.U., Venselaar, H., Gilissen, C.F., Thonissen, M., Rooij, I.A.L.M. van, Dreesen, K., Steehouwer, M., Vorst, J.M. van de, Bloemen, M., Beusekom, E. van, Roosenboom, J., Borstlap, W.A., Admiraal, R.J., Dormaar, T., Schoenaers, J., Poorten, V. Van der, Hens, G., Verdonck, A., Berge, S.J., Roeleveld, N., Vriend, G., Devriendt, K., Brunner, H.G., Mangold, E., Hoischen, A., Bokhoven, H. van, Carels, C.E.L., Khandelwal, K., Ishorst, N., Zhou, H., Ludwig, K.U., Venselaar, H., Gilissen, C.F., Thonissen, M., Rooij, I.A.L.M. van, Dreesen, K., Steehouwer, M., Vorst, J.M. van de, Bloemen, M., Beusekom, E. van, Roosenboom, J., Borstlap, W.A., Admiraal, R.J., Dormaar, T., Schoenaers, J., Poorten, V. Van der, Hens, G., Verdonck, A., Berge, S.J., Roeleveld, N., Vriend, G., Devriendt, K., Brunner, H.G., Mangold, E., Hoischen, A., Bokhoven, H. van, and Carels, C.E.L.

Abstract

Contains fulltext : 191986.pdf (Publisher’s version ) (Open Access)

Published
2017

7. AGORA, a data- and biobank for birth defects and childhood cancer

Author

Rooij, I.A.L.M. van, Zanden, L.F.M. van der, Bongers, E.M., Renkema, K.Y., Wijers, C.H., Thonissen, M., Dokter, E.M., Marcelis, C.L., Blaauw, I. de, Wijnen, M.H.W.A., Hoogerbrugge, P.M., Bökkerink, J.P., Schreuder, M.F., Koster-Kamphuis, L., Cornelissen, E.A., Kapusta, L., Heijst, A.F.J. van, Liem, K.D., Gier, R.P. de, Kuijpers-Jagtman, A.M., Admiraal, R.J., Berge, S.J., Biezen, J.J. van der, Verdonck, A., Poorten, V. Van der, Hens, G., Roosenboom, J., Lilien, M.R., Jong, T.P. de, Broens, P., Wijnen, R., Brooks, A., Franke, B., Brunner, H.G., Carels, C.E., Knoers, N.V.A.M., Feitz, W.F., Roeleveld, N., Rooij, I.A.L.M. van, Zanden, L.F.M. van der, Bongers, E.M., Renkema, K.Y., Wijers, C.H., Thonissen, M., Dokter, E.M., Marcelis, C.L., Blaauw, I. de, Wijnen, M.H.W.A., Hoogerbrugge, P.M., Bökkerink, J.P., Schreuder, M.F., Koster-Kamphuis, L., Cornelissen, E.A., Kapusta, L., Heijst, A.F.J. van, Liem, K.D., Gier, R.P. de, Kuijpers-Jagtman, A.M., Admiraal, R.J., Berge, S.J., Biezen, J.J. van der, Verdonck, A., Poorten, V. Van der, Hens, G., Roosenboom, J., Lilien, M.R., Jong, T.P. de, Broens, P., Wijnen, R., Brooks, A., Franke, B., Brunner, H.G., Carels, C.E., Knoers, N.V.A.M., Feitz, W.F., and Roeleveld, N.

Abstract

Contains fulltext : 167851.pdf (publisher's version ) (Closed access), BACKGROUND: Research regarding the etiology of birth defects and childhood cancer is essential to develop preventive measures, but often requires large study populations. Therefore, we established the AGORA data- and biobank in the Netherlands. In this study, we describe its rationale, design, and ongoing data collection. METHODS: Children diagnosed with and/or treated for a structural birth defect or childhood cancer and their parents are invited to participate in the AGORA data- and biobank. Controls are recruited through random sampling from municipal registries. The parents receive questionnaires about demographics, family and pregnancy history, health status, prescribed medication, lifestyle, and occupational exposures before and during the index pregnancy. In addition, blood or saliva is collected from children and parents, while medical records are reviewed for diagnostic information. RESULTS: So far, we have collected data from over 6,860 families (3,747 birth defects, 905 childhood cancers, and 2,208 controls). The types of birth defects vary widely and comprise malformations of the digestive, respiratory, and urogenital tracts as well as facial, cardiovascular, kidney, skeletal, and central nervous system anomalies. The most frequently occurring childhood cancer types are acute lymphatic leukemia, Hodgkin and non-Hodgkin lymphoma, Wilms' tumor, and brain and spinal cord tumors. Our genetic and/or epidemiologic studies have been focused on hypospadias, anorectal malformations, congenital anomalies of the kidney and urinary tract (CAKUT), and orofacial clefts. CONCLUSION: The large AGORA data- and biobank offers great opportunities for investigating genetic and nongenetic risk factors for disorders in children and is open to collaborative initiatives. Birth Defects Research (Part A) 106:675-684, 2016. (c) 2016 Wiley Periodicals, Inc.

Published
2016

8. Novel and recurrent CIB2 variants, associated with nonsyndromic deafness, do not affect calcium buffering and localization in hair cells

Author

Seco, C.Z., Giese, A.P., Shafique, S., Schraders, M., Oonk, A.M., Grossheim, M., Oostrik, J., Strom, T., Hegde, R., WIjk, E. van, Frolenkov, G.I., Azam, M., Yntema, H.G., Free, R.H., Riazuddin, S., Verheij, J.B., Admiraal, R.J., Qamar, R., Ahmed, Z.M., Kremer, H., Seco, C.Z., Giese, A.P., Shafique, S., Schraders, M., Oonk, A.M., Grossheim, M., Oostrik, J., Strom, T., Hegde, R., WIjk, E. van, Frolenkov, G.I., Azam, M., Yntema, H.G., Free, R.H., Riazuddin, S., Verheij, J.B., Admiraal, R.J., Qamar, R., Ahmed, Z.M., and Kremer, H.

Abstract

Contains fulltext : 167996.pdf (publisher's version ) (Closed access), Variants in CIB2 can underlie either Usher syndrome type I (USH1J) or nonsyndromic hearing impairment (NSHI) (DFNB48). Here, a novel homozygous missense variant c.196C>T and compound heterozygous variants, c.[97C>T];[196C>T], were found, respectively, in two unrelated families of Dutch origin. Besides, the previously reported c.272 T>C functional missense variant in CIB2 was identified in two families of Pakistani origin. The missense variants are demonstrated not to affect subcellular localization of CIB2 in vestibular hair cells in ex vivo expression experiments. Furthermore, these variants do not affect the ATP-induced calcium responses in COS-7 cells. However, based on the residues affected, the variants are suggested to alter alphaIIbeta integrin binding. HI was nonsyndromic in all four families. However, deafness segregating with the c.272T>C variant in one Pakistani family is remarkably less severe than that in all other families with this mutation. Our results contribute to the insight in genotype-phenotype correlations of CIB2 mutations.

Published
2016

9. AGORA, a data- and biobank for birth defects and childhood cancer

Author

Rooij, I.A.L.M. van, Zanden, L.F.M. van der, Bongers, E.M., Renkema, K.Y., Wijers, C.H., Thonissen, M., Dokter, E.M., Marcelis, C.L., Blaauw, I. de, Wijnen, M.H.W.A., Hoogerbrugge, P.M., Bökkerink, J.P., Schreuder, M.F., Koster-Kamphuis, L., Cornelissen, E.A., Kapusta, L., Heijst, A.F.J. van, Liem, K.D., Gier, R.P. de, Kuijpers-Jagtman, A.M., Admiraal, R.J., Berge, S.J., Biezen, J.J. van der, Verdonck, A., Poorten, V. Van der, Hens, G., Roosenboom, J., Lilien, M.R., Jong, T.P. de, Broens, P., Wijnen, R., Brooks, A., Franke, B., Brunner, H.G., Carels, C.E., Knoers, N.V.A.M., Feitz, W.F., Roeleveld, N., Rooij, I.A.L.M. van, Zanden, L.F.M. van der, Bongers, E.M., Renkema, K.Y., Wijers, C.H., Thonissen, M., Dokter, E.M., Marcelis, C.L., Blaauw, I. de, Wijnen, M.H.W.A., Hoogerbrugge, P.M., Bökkerink, J.P., Schreuder, M.F., Koster-Kamphuis, L., Cornelissen, E.A., Kapusta, L., Heijst, A.F.J. van, Liem, K.D., Gier, R.P. de, Kuijpers-Jagtman, A.M., Admiraal, R.J., Berge, S.J., Biezen, J.J. van der, Verdonck, A., Poorten, V. Van der, Hens, G., Roosenboom, J., Lilien, M.R., Jong, T.P. de, Broens, P., Wijnen, R., Brooks, A., Franke, B., Brunner, H.G., Carels, C.E., Knoers, N.V.A.M., Feitz, W.F., and Roeleveld, N.

Abstract

Contains fulltext : 167851.pdf (publisher's version ) (Closed access), BACKGROUND: Research regarding the etiology of birth defects and childhood cancer is essential to develop preventive measures, but often requires large study populations. Therefore, we established the AGORA data- and biobank in the Netherlands. In this study, we describe its rationale, design, and ongoing data collection. METHODS: Children diagnosed with and/or treated for a structural birth defect or childhood cancer and their parents are invited to participate in the AGORA data- and biobank. Controls are recruited through random sampling from municipal registries. The parents receive questionnaires about demographics, family and pregnancy history, health status, prescribed medication, lifestyle, and occupational exposures before and during the index pregnancy. In addition, blood or saliva is collected from children and parents, while medical records are reviewed for diagnostic information. RESULTS: So far, we have collected data from over 6,860 families (3,747 birth defects, 905 childhood cancers, and 2,208 controls). The types of birth defects vary widely and comprise malformations of the digestive, respiratory, and urogenital tracts as well as facial, cardiovascular, kidney, skeletal, and central nervous system anomalies. The most frequently occurring childhood cancer types are acute lymphatic leukemia, Hodgkin and non-Hodgkin lymphoma, Wilms' tumor, and brain and spinal cord tumors. Our genetic and/or epidemiologic studies have been focused on hypospadias, anorectal malformations, congenital anomalies of the kidney and urinary tract (CAKUT), and orofacial clefts. CONCLUSION: The large AGORA data- and biobank offers great opportunities for investigating genetic and nongenetic risk factors for disorders in children and is open to collaborative initiatives. Birth Defects Research (Part A) 106:675-684, 2016. (c) 2016 Wiley Periodicals, Inc.

Published
2016

10. Novel and recurrent CIB2 variants, associated with nonsyndromic deafness, do not affect calcium buffering and localization in hair cells

Author

Seco, C.Z., Giese, A.P., Shafique, S., Schraders, M., Oonk, A.M., Grossheim, M., Oostrik, J., Strom, T., Hegde, R., WIjk, E. van, Frolenkov, G.I., Azam, M., Yntema, H.G., Free, R.H., Riazuddin, S., Verheij, J.B., Admiraal, R.J., Qamar, R., Ahmed, Z.M., Kremer, H., Seco, C.Z., Giese, A.P., Shafique, S., Schraders, M., Oonk, A.M., Grossheim, M., Oostrik, J., Strom, T., Hegde, R., WIjk, E. van, Frolenkov, G.I., Azam, M., Yntema, H.G., Free, R.H., Riazuddin, S., Verheij, J.B., Admiraal, R.J., Qamar, R., Ahmed, Z.M., and Kremer, H.

Abstract

Contains fulltext : 167996.pdf (publisher's version ) (Closed access), Variants in CIB2 can underlie either Usher syndrome type I (USH1J) or nonsyndromic hearing impairment (NSHI) (DFNB48). Here, a novel homozygous missense variant c.196C>T and compound heterozygous variants, c.[97C>T];[196C>T], were found, respectively, in two unrelated families of Dutch origin. Besides, the previously reported c.272 T>C functional missense variant in CIB2 was identified in two families of Pakistani origin. The missense variants are demonstrated not to affect subcellular localization of CIB2 in vestibular hair cells in ex vivo expression experiments. Furthermore, these variants do not affect the ATP-induced calcium responses in COS-7 cells. However, based on the residues affected, the variants are suggested to alter alphaIIbeta integrin binding. HI was nonsyndromic in all four families. However, deafness segregating with the c.272T>C variant in one Pakistani family is remarkably less severe than that in all other families with this mutation. Our results contribute to the insight in genotype-phenotype correlations of CIB2 mutations.

Published
2016

11. AGORA, a data- and biobank for birth defects and childhood cancer

Author

Rooij, I.A.L.M. van, Zanden, L.F.M. van der, Bongers, E.M., Renkema, K.Y., Wijers, C.H., Thonissen, M., Dokter, E.M., Marcelis, C.L., Blaauw, I. de, Wijnen, M.H.W.A., Hoogerbrugge, P.M., Bökkerink, J.P., Schreuder, M.F., Koster-Kamphuis, L., Cornelissen, E.A., Kapusta, L., Heijst, A.F.J. van, Liem, K.D., Gier, R.P. de, Kuijpers-Jagtman, A.M., Admiraal, R.J., Berge, S.J., Biezen, J.J. van der, Verdonck, A., Poorten, V. Van der, Hens, G., Roosenboom, J., Lilien, M.R., Jong, T.P. de, Broens, P., Wijnen, R., Brooks, A., Franke, B., Brunner, H.G., Carels, C.E., Knoers, N.V.A.M., Feitz, W.F., Roeleveld, N., Rooij, I.A.L.M. van, Zanden, L.F.M. van der, Bongers, E.M., Renkema, K.Y., Wijers, C.H., Thonissen, M., Dokter, E.M., Marcelis, C.L., Blaauw, I. de, Wijnen, M.H.W.A., Hoogerbrugge, P.M., Bökkerink, J.P., Schreuder, M.F., Koster-Kamphuis, L., Cornelissen, E.A., Kapusta, L., Heijst, A.F.J. van, Liem, K.D., Gier, R.P. de, Kuijpers-Jagtman, A.M., Admiraal, R.J., Berge, S.J., Biezen, J.J. van der, Verdonck, A., Poorten, V. Van der, Hens, G., Roosenboom, J., Lilien, M.R., Jong, T.P. de, Broens, P., Wijnen, R., Brooks, A., Franke, B., Brunner, H.G., Carels, C.E., Knoers, N.V.A.M., Feitz, W.F., and Roeleveld, N.

Abstract

Contains fulltext : 167851.pdf (Publisher’s version ) (Open Access), BACKGROUND: Research regarding the etiology of birth defects and childhood cancer is essential to develop preventive measures, but often requires large study populations. Therefore, we established the AGORA data- and biobank in the Netherlands. In this study, we describe its rationale, design, and ongoing data collection. METHODS: Children diagnosed with and/or treated for a structural birth defect or childhood cancer and their parents are invited to participate in the AGORA data- and biobank. Controls are recruited through random sampling from municipal registries. The parents receive questionnaires about demographics, family and pregnancy history, health status, prescribed medication, lifestyle, and occupational exposures before and during the index pregnancy. In addition, blood or saliva is collected from children and parents, while medical records are reviewed for diagnostic information. RESULTS: So far, we have collected data from over 6,860 families (3,747 birth defects, 905 childhood cancers, and 2,208 controls). The types of birth defects vary widely and comprise malformations of the digestive, respiratory, and urogenital tracts as well as facial, cardiovascular, kidney, skeletal, and central nervous system anomalies. The most frequently occurring childhood cancer types are acute lymphatic leukemia, Hodgkin and non-Hodgkin lymphoma, Wilms' tumor, and brain and spinal cord tumors. Our genetic and/or epidemiologic studies have been focused on hypospadias, anorectal malformations, congenital anomalies of the kidney and urinary tract (CAKUT), and orofacial clefts. CONCLUSION: The large AGORA data- and biobank offers great opportunities for investigating genetic and nongenetic risk factors for disorders in children and is open to collaborative initiatives. Birth Defects Research (Part A) 106:675-684, 2016. (c) 2016 Wiley Periodicals, Inc.

Published
2016

12. Novel and recurrent CIB2 variants, associated with nonsyndromic deafness, do not affect calcium buffering and localization in hair cells

Author

Seco, C.Z., Giese, A.P., Shafique, S., Schraders, M., Oonk, A.M., Grossheim, M., Oostrik, J., Strom, T., Hegde, R., WIjk, E. van, Frolenkov, G.I., Azam, M., Yntema, H.G., Free, R.H., Riazuddin, S., Verheij, J.B., Admiraal, R.J., Qamar, R., Ahmed, Z.M., Kremer, H., Seco, C.Z., Giese, A.P., Shafique, S., Schraders, M., Oonk, A.M., Grossheim, M., Oostrik, J., Strom, T., Hegde, R., WIjk, E. van, Frolenkov, G.I., Azam, M., Yntema, H.G., Free, R.H., Riazuddin, S., Verheij, J.B., Admiraal, R.J., Qamar, R., Ahmed, Z.M., and Kremer, H.

Abstract

Contains fulltext : 167996.pdf (publisher's version ) (Closed access), Variants in CIB2 can underlie either Usher syndrome type I (USH1J) or nonsyndromic hearing impairment (NSHI) (DFNB48). Here, a novel homozygous missense variant c.196C>T and compound heterozygous variants, c.[97C>T];[196C>T], were found, respectively, in two unrelated families of Dutch origin. Besides, the previously reported c.272 T>C functional missense variant in CIB2 was identified in two families of Pakistani origin. The missense variants are demonstrated not to affect subcellular localization of CIB2 in vestibular hair cells in ex vivo expression experiments. Furthermore, these variants do not affect the ATP-induced calcium responses in COS-7 cells. However, based on the residues affected, the variants are suggested to alter alphaIIbeta integrin binding. HI was nonsyndromic in all four families. However, deafness segregating with the c.272T>C variant in one Pakistani family is remarkably less severe than that in all other families with this mutation. Our results contribute to the insight in genotype-phenotype correlations of CIB2 mutations.

Published
2016

13. Allelic mutations of KITLG, encoding KIT ligand, cause asymmetric and unilateral hearing loss and Waardenburg syndrome type 2

Author

Zazo Seco, C. (Celia), Serrão De Castro, L. (Luciana), Nierop, J.W.I. van, Morín, M. (Matías), Jhangiani, S.N. (Shalini N.), Verver, E.J.J. (Eva J. J.), Schraders, M. (Margit), Maiwald, N. (Nadine), Wesdorp, M. (Mieke), Venselaar, H. (Hanka), Spruijt, L. (Liesbeth), Oostrik, J. (Jaap), Schoots, J. (Jeroen), Reeuwijk, J. (Jeroen) van, Lelieveld, S.H. (Stefan H.), Huygen, P.L.M. (Patrick), Insenser, M. (María), Admiraal, R.J. (Ronald), Pennings, R.J.E. (Ronald J.E.), Hoefsloot, E.H. (Lies), Arias-Vásquez, A. (Alejandro), Ligt, J. (Joep) de, Yntema, H.G., Jansen, J.H. (Joop H.), Muzny, D. (Donna), Huls, G. (Gerwin), Rossum, M.M. (Michelle) van, Lupski, J.R. (James R.), Moreno-Pelayo, M.A. (Miguel Angel), Kunst, H.P.M. (Henricus P.M.), Kremer, H. (Hannie), Zazo Seco, C. (Celia), Serrão De Castro, L. (Luciana), Nierop, J.W.I. van, Morín, M. (Matías), Jhangiani, S.N. (Shalini N.), Verver, E.J.J. (Eva J. J.), Schraders, M. (Margit), Maiwald, N. (Nadine), Wesdorp, M. (Mieke), Venselaar, H. (Hanka), Spruijt, L. (Liesbeth), Oostrik, J. (Jaap), Schoots, J. (Jeroen), Reeuwijk, J. (Jeroen) van, Lelieveld, S.H. (Stefan H.), Huygen, P.L.M. (Patrick), Insenser, M. (María), Admiraal, R.J. (Ronald), Pennings, R.J.E. (Ronald J.E.), Hoefsloot, E.H. (Lies), Arias-Vásquez, A. (Alejandro), Ligt, J. (Joep) de, Yntema, H.G., Jansen, J.H. (Joop H.), Muzny, D. (Donna), Huls, G. (Gerwin), Rossum, M.M. (Michelle) van, Lupski, J.R. (James R.), Moreno-Pelayo, M.A. (Miguel Angel), Kunst, H.P.M. (Henricus P.M.), and Kremer, H. (Hannie)

Abstract

Linkage analysis combined with whole-exome sequencing in a large family with congenital and stable non-syndromic unilateral and asymmetric hearing loss (NS-UHL/AHL) revealed a heterozygous truncating mutation, c.286-303delinsT (p.Ser96Ter), in KITLG. This mutation co-segregated with NS-UHL/AHL as a dominant trait with reduced penetrance. By screening a panel of probands with NS-UHL/AHL, we found an additional mutation, c.200-202del (p.His67-Cys68delinsArg). In vitro studies revealed that the p.His67-Cys68delinsArg transmembrane isoform of KITLG is not detectable at the cell membrane, supporting pathogenicity. KITLG encodes a ligand for the KIT receptor. Also, KITLG-KIT signaling and MITF are suggested to mutually interact in melanocyte development. Because mutations in MITF are causative of Waardenburg syndrome type 2 (WS2), we screened KITLG in suspected WS2-affected probands. A heterozygous missense mutation, c.310C>G (p.Leu104Val), that segregated with WS2 was identified in a small family. In vitro studies revealed that the p.Leu104Val transmembrane isoform of KITLG is located at the cell membrane, as is wild-type KITLG. However, in culture media of transfected cells, the p.Leu104Val soluble isoform of KITLG was reduced, and no soluble p.His67-Cys68delinsArg and p.Ser96Ter KITLG could be detected. These data suggest that mutations in KITLG associated with NS-UHL/AHL have a loss-of-function effect. We speculate that the mechanism of the mutation underlying WS2 and leading to membrane incorporation and reduced secretion of KITLG occurs via a dominant-negative or gain-of-function effect. Our study unveils different phenotypes associated with KITLG, previously associated with pigmentation abnormalities, and will thereby improve the genetic counseling given to individuals with KITLG variants.

Published
2015
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17. Disruption of Teashirt Zinc Finger Homeobox 1 Is Associated with Congenital Aural Atresia in Humans.

Author

Feenstra, I., Vissers, L.E.L.M., Pennings, R.J.E., Nillesen, W.M., Pfundt, R., Kunst, H.P., Admiraal, R.J., Veltman, J.A., Ravenswaaij-Arts, C.M.A. van, Brunner, H.G., Cremers, C.W.R.J., Feenstra, I., Vissers, L.E.L.M., Pennings, R.J.E., Nillesen, W.M., Pfundt, R., Kunst, H.P., Admiraal, R.J., Veltman, J.A., Ravenswaaij-Arts, C.M.A. van, Brunner, H.G., and Cremers, C.W.R.J.

Abstract

Item does not contain fulltext

Published
2011

18. Disruption of Teashirt Zinc Finger Homeobox 1 Is Associated with Congenital Aural Atresia in Humans.

Author

Feenstra, I., Vissers, L.E.L.M., Pennings, R.J.E., Nillesen, W.M., Pfundt, R., Kunst, H.P., Admiraal, R.J., Veltman, J.A., Ravenswaaij-Arts, C.M.A. van, Brunner, H.G., Cremers, C.W.R.J., Feenstra, I., Vissers, L.E.L.M., Pennings, R.J.E., Nillesen, W.M., Pfundt, R., Kunst, H.P., Admiraal, R.J., Veltman, J.A., Ravenswaaij-Arts, C.M.A. van, Brunner, H.G., and Cremers, C.W.R.J.

Abstract

Item does not contain fulltext

Published
2011

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