| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1From the The Rotterdam Eye Hospital, Rotterdam, The Netherlands; the 2Departments of Human Genetics and 9Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; the 4Department of Ophthalmology and the 5Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium; the 6Center for Human Genetics and the 10Department of Ophthalmology, Leuven University Hospitals, Leuven, Belgium; 7RetinaScience, Bonn, Germany; the 8Department of Ophthalmology, University of Heidelberg, Heidelberg, Germany; 11Sensis, Grave, The Netherlands; and the 12Department of Ophthalmology and Pathology, Columbia University, New York, New York.
PURPOSE. To test the efficiency of a microarray chip as a diagnostic tool in a cohort of northwestern European patients with Leber congenital amaurosis (LCA) and to perform a genotype–phenotype analysis in patients in whom pathologic mutations were identified.
METHODS. DNAs from 58 patients with LCA were analyzed using a microarray chip containing previously identified disease-associated sequence variants in six LCA genes. Mutations identified by chip analysis were confirmed by sequence analysis. On identification of one mutation, all protein coding exons of the relevant genes were sequenced. In addition, sequence analysis of the RDH12 gene was performed in 22 patients. Patients with mutations were phenotyped.
RESULTS. Pathogenic mutations were identified in 19 of the 58 patients with LCA (32.8%). Four novel sequence variants were identified. Mutations were most frequently found in CRB1 (15.5%), followed by GUCY2D (10.3%). The p.R768W mutation was found in 8 of 10 GUCY2D alleles, suggesting that it is a founder mutation in the northwest of Europe. In early childhood, patients with AIPL1 or GUCY2D mutations show normal fundi. Those with AIPL1-associated LCA progress to an RP-like fundus before the age of 8, whereas patients with GUCY2D-associated LCA still have relatively normal fundi in their mid-20s. Patients with CRB1 mutations present with distinct fundus abnormalities at birth and consistently show characteristics of RP12. Pathogenic GUCY2D mutations result in the most severe form of LCA.
CONCLUSIONS. Microarray-based mutation detection allowed the identification of 32% of LCA sequence variants and represents an efficient first-pass screening tool. Mutations in CRB1, and to a lesser extent, in GUCY2D, underlie most LCA cases in this cohort. The present study establishes a genotype-phenotype correlation for AIPL1, CRB1, and GUCY2D.
This article has been cited by other articles:
|
|
 |
|
  R. H. Henderson, N. Waseem, R. Searle, J. van der Spuy, I. Russell-Eggitt, S. S. Bhattacharya, D. A. Thompson, G. E. Holder, M. E. Cheetham, A. R. Webster, et al. An Assessment of the Apex Microarray Technology in Genotyping Patients with Leber Congenital Amaurosis and Early-Onset Severe Retinal Dystrophy Invest. Ophthalmol. Vis. Sci., December 1, 2007; 48(12): 5684 - 5689. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. I. den Hollander, I. Lopez, S. Yzer, M. N. Zonneveld, I. M. Janssen, T. M. Strom, J. Y. Hehir-Kwa, J. A. Veltman, M. L. Arends, T. Meitinger, et al. Identification of Novel Mutations in Patients with Leber Congenital Amaurosis and Juvenile RP by Genome-wide Homozygosity Mapping with SNP Microarrays Invest. Ophthalmol. Vis. Sci., December 1, 2007; 48(12): 5690 - 5698. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Simonelli, C. Ziviello, F. Testa, S. Rossi, E. Fazzi, P. E. Bianchi, M. Fossarello, S. Signorini, C. Bertone, S. Galantuomo, et al. Clinical and Molecular Genetics of Leber's Congenital Amaurosis: A Multicenter Study of Italian Patients Invest. Ophthalmol. Vis. Sci., September 1, 2007; 48(9): 4284 - 4290. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Schuster, A. R. Janecke, R. Wilke, E. Schmid, D. A. Thompson, G. Utermann, B. Wissinger, E. Zrenner, and A. Gal The Phenotype of Early-Onset Retinal Degeneration in Persons with RDH12 Mutations Invest. Ophthalmol. Vis. Sci., April 1, 2007; 48(4): 1824 - 1831. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. P. Daiger, S. J. Bowne, and L. S. Sullivan Perspective on Genes and Mutations Causing Retinitis Pigmentosa Arch Ophthalmol, February 1, 2007; 125(2): 151 - 158. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Blain and B. P. Brooks Molecular Diagnosis and Genetic Counseling in Ophthalmology Arch Ophthalmol, February 1, 2007; 125(2): 196 - 203. [Full Text] [PDF]
|
|
|
|
 |
|
 F. P M Cremers, W. J Kimberling, M. Kulm, A. P de Brouwer, E. van Wijk, H. te Brinke, C. W R J Cremers, L. H Hoefsloot, S. Banfi, F. Simonelli, et al. Development of a genotyping microarray for Usher syndrome J. Med. Genet., February 1, 2007; 44(2): 153 - 160. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Maeda, T. Maeda, Y. Imanishi, W. Sun, B. Jastrzebska, D. A. Hatala, H. J. Winkens, K. P. Hofmann, J. J. Janssen, W. Baehr, et al. Retinol Dehydrogenase (RDH12) Protects Photoreceptors from Light-induced Degeneration in Mice J. Biol. Chem., December 8, 2006; 281(49): 37697 - 37704. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Richard, R. Roepman, W. M. Aartsen, A. G.S.H. van Rossum, A. I. den Hollander, E. Knust, J. Wijnholds, and F. P.M. Cremers Towards understanding CRUMBS function in retinal dystrophies Hum. Mol. Genet., October 15, 2006; 15(suppl_2): R235 - R243. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Yzer, G. A. Fishman, J. Racine, S. Al-Zuhaibi, H. Chakor, A. Dorfman, J. Szlyk, P. Lachapelle, L. I. van den Born, R. Allikmets, et al. CRB1 Heterozygotes with Regional Retinal Dysfunction: Implications for Genetic Testing of Leber Congenital Amaurosis. Invest. Ophthalmol. Vis. Sci., September 1, 2006; 47(9): 3736 - 3744. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
