Spectrum of NPHP6 (CEP290) Mutations in Leber Congenital Amaurosis and Delineation of the Associated Phenotype

Abstract

Purpose:: Mutations in the NPHP6 (CEP290) gene were recently shown to account for Joubert syndrome and Senior-Loken syndrome as well as Leber congenital amaurosis (LCA). All reported patients affected with LCA carried an intronic mutation resulting in an aberrantly spliced transcript and low levels of wild-type transcript that was believed to explain the absence of cerebellar and renal involvement in LCA patients. The aim of the present study was to give the survey of NPHP6 mutations in our series.

Methods:: 192 unrelated LCA cases were screened for mutations by DHPLC and direct sequencing using specific primers designed to flank each of the 53 NPHP6 coding exons and the frequent c.2991+1655A>G mutation located in intron 26. The natural history of the disease and ophthalmologic data were reviewed for all patients harbouring NPHP6 mutations

Results:: NPHP6 mutations were identified in 38/192 LCA families of our series. All families were of European descent and one frequent founder mutation was identified in the North region of France. All mutations but two were either non-sense, frameshift or splice-site changes. The common NPHP6 (CEP290) intronic mutation accounted for 33/76 of all disease alleles in our series. Twelve unrelated LCA cases did not carry this common intronic mutation, ten of which, at least, harboured two mutations expected to truncate the protein. Whatever their NPHP6 genotype, all patients but three had a visual acuity <1/20, salt and pepper aspect of the retina with macular degeneration in the first decade progressing to a typical aspect of RP at the end of the second decade onwards, a severe hyperopia (+6D or more) and a slight photoaversion.

Conclusions:: We confirm the high frequency of NPHP6 (CEP290) mutations in LCA (19.8%) as well as that of the c.2991+1655A>G mutation (43% of disease alleles). We also suggest that a significant fraction of LCA families segregate two NPHP6 null alleles questioning the relevance of the assumption according to which the retinal-restricted phenotype in LCA patient could be due to a residual NPHP6 (CEP290) activity. Indeed, Joubert syndrome was excluded by cerebral MRI in all patients presenting with developmental delay. Finally, we show that all patients of our series are affected with the cone-rod subtype of the disease whatever their NPHP6 genotype.

Keywords: candidate gene analysis • retinal degenerations: hereditary • genetics