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CRB1 Heterozygotes with Regional Retinal Dysfunction: Implications for Genetic Testing of Leber Congenital Amaurosis

¹From the McGill Ocular Genetics Centre, Division of Ophthalmology, and the ⁵McGill Visual Physiology Laboratory, Montreal Children’s Hospital Research Institute, McGill University Health Centre, Montreal, Quebec, Canada; the ⁴Department of Ophthalmology, University of Illinois, Chicago, Illinois; the ²Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; ³Rotterdam Eye Hospital, Rotterdam, The Netherlands; and the ⁶Departments of Ophthalmology and Pathology, Columbia University, New York, New York.

PURPOSE. To test human CRB1 heterozygotes for possible clinical or functional retinal changes and to evaluate whether a patient with Leber congenital amaurosis (LCA) with CRB1 mutations not consistent with previously described CRB1 phenotypes carried a modifier allele in another LCA gene.

METHODS. Seven unrelated heterozygous carriers of CRB1 mutations underwent phenotyping by full eye examinations (indirect ophthalmoscopy and slit lamp biomicroscopy) and functional testing (standard full-field electroretinography [ERG] and multifocal ERG). For genotyping of the LCA patients and their parents, denaturing high-performance liquid chromatography (dHPLC) analyses were performed, followed by sequence analysis of CRB1, followed by sequence analysis of the AIPL1 and CRX genes to identify a putative modifier effect in a patient with an atypical CRB1 phenotype.

RESULTS. Reduced full-field ERG b-wave amplitudes were observed with scotopic –2 dB flash (140 µV; P < 0.05), normal full-field cone ERGs, and significant regional retinal dysfunction on mfERG in five of seven carriers of CRB1 mutations. A known AIPL1 mutation (p. R302L) was identified as a potential modifier allele in a patient with LCA carrying two CRB1 mutations and with a prominent maculopathy.

CONCLUSIONS. In human heterozygotes of CRB1 mutations (parents of offspring with LCA), distinctive regional retinal dysfunctions were found by multifocal ERG measurements that were consistent with the focal histologic abnormalities reported for the two CRB1 knockout mice models. This phenotypic finding may identify CRB1 carriers and point to the causal gene defect in affected LCA offspring, significantly facilitating the molecular diagnostic process. Evidence suggests a modifier allele in AIPL1 in a patient with LCA with prominent atrophic macular lesions and homozygous defects in CRB1.

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				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]