Advanced search
1 file | 474.63 KB

Microarray-based mutation detection and phenotypic characterization of patients with Leber congenital amaurosis

Author
Organization
Abstract
PURPOSE. To test the efficiency of a microarray chip as a diagnostic toot 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.
Keywords
SEVERE RETINAL DYSTROPHY, CHIP, VISION, ALLELES, STARGARDT-DISEASE, RPE65, DEGENERATION, RETINITIS-PIGMENTOSA, TRANSPORTER GENE ABCR, HOMOLOG-1 CRB1 GENE

Downloads

  • (...).pdf
    • full text
    • |
    • UGent only
    • |
    • PDF
    • |
    • 474.63 KB

Citation

Please use this url to cite or link to this publication:

Chicago
Yzer, Suzanne, Bart Leroy, Elfride De Baere, Thomy J de Ravel, Marijke N Zonneveld, Krysta Voesenek, Ulrich Kellner, et al. 2006. “Microarray-based Mutation Detection and Phenotypic Characterization of Patients with Leber Congenital Amaurosis.” Investigative Ophthalmology & Visual Science 47 (3): 1167–1176.
APA
Yzer, S., Leroy, B., De Baere, E., de Ravel, T. J., Zonneveld, M. N., Voesenek, K., Kellner, U., et al. (2006). Microarray-based mutation detection and phenotypic characterization of patients with Leber congenital amaurosis. INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 47(3), 1167–1176.
Vancouver
1.
Yzer S, Leroy B, De Baere E, de Ravel TJ, Zonneveld MN, Voesenek K, et al. Microarray-based mutation detection and phenotypic characterization of patients with Leber congenital amaurosis. INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE. 2006;47(3):1167–76.
MLA
Yzer, Suzanne, Bart Leroy, Elfride De Baere, et al. “Microarray-based Mutation Detection and Phenotypic Characterization of Patients with Leber Congenital Amaurosis.” INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE 47.3 (2006): 1167–1176. Print.
@article{351364,
  abstract     = {PURPOSE. To test the efficiency of a microarray chip as a diagnostic toot 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.},
  author       = {Yzer, Suzanne and Leroy, Bart and De Baere, Elfride and de Ravel, Thomy J and Zonneveld, Marijke N and Voesenek, Krysta and Kellner, Ulrich and Martinez Ciriano, Jose P and de Faber, Jan-Tjeerd HN and Rohrschneider, Klaus and Roepman, Ronald and den Hollander, Anneke I and Cruysberg, Johannes R and Meire, Fran\c{c}oise and Casteels, Ingele and van Moll-Ramirez, Norka G and Allikmets, Rando and van den Born, L Ingeborgh and Cremers, Frans PM},
  issn         = {0146-0404},
  journal      = {INVESTIGATIVE OPHTHALMOLOGY \& VISUAL SCIENCE},
  keyword      = {SEVERE RETINAL DYSTROPHY,CHIP,VISION,ALLELES,STARGARDT-DISEASE,RPE65,DEGENERATION,RETINITIS-PIGMENTOSA,TRANSPORTER GENE ABCR,HOMOLOG-1 CRB1 GENE},
  language     = {eng},
  number       = {3},
  pages        = {1167--1176},
  title        = {Microarray-based mutation detection and phenotypic characterization of patients with Leber congenital amaurosis},
  url          = {http://dx.doi.org/10.1167/iovs.05-0848},
  volume       = {47},
  year         = {2006},
}

Altmetric
View in Altmetric
Web of Science
Times cited: