Genotype–phenotype Correlation in a German Family With a Novel 816delCACinsAA CRX Mutation

Abstract

Abstract: : Purpose:Mutations in CRX can be associated with Cone Rod Dystrophy (CRD), autosomal dominant Retinitis Pigmentosa (ADRP) and autosomal dominant Leber’s Congenital Amaurosis (a.d.LCA). Here we describe the phenotype in a German 2 generation family with a novel 816delCACinsAA CRX mutation. Methods:DNA was extracted from peripheral blood and amplified with exon flanking primers for CRX. Amplimers were screened by SSCP and directly sequenced when necessary. To confirm the sequencing results amplimers of exon 3 were subcloned into pDRIVE and sequenced. Segregation analysis was performed in 4 members of this family by Styl digestion. In addition to clinical examination including visual fields, 2–colour–threshold perimetry, full field ERG according to the ISCEV standard, fundus photography, and fundus autofluorescence (AF) were performed. Results:A novel 816delCACinsAA CRX mutation was identified in all 4 patients. In childhood, visual acuity (VA) was variable (range 0. 1. – 0. 8) and deteriorated in all, refraction was hypermetropic in. VFs were clearly constricted, showed only temporal residual VF islands or were not measurable. Some residual rod answers in the ERG were detected only in the 2 younger patients. In the absence of a measurable ERG, 2 CT perimetry revealed a CRD . Funduscopy showed severe chorioretinal atrophy and sparse hyperpigmented spots in the mother, distinct macular and spotted hypopigmented midperiphery changes in the oldest 36 y and the 31 y old siblings, and only minimal macular and mild midperiphery changes in the 33 y old. AF was severely disturbed in areas of atrophy but otherwise well preserved. Conclusions:816delCACinsAA – is a complex mutation that predicts the loss of 27 C–terminal amino acids and a substitution by 44 novel amino acids. This way the OTX tail and the WSP–motif are lost. The three affected siblings in this study had central vision loss due to rod and cone disease in the macula. The reduced VA and color vision implicate a cone disease, while the spotted hypopigmented midperiphery changes in the region of highest rod density implicate predominant rod involvement. The phenotype showed variable severity and progression. 2CT–perimetry allowed the classification as CRD even in the absence of a measurable ERG. Partially preserved AF would indicate viable photoreceptor cells. A review of previously reported CRX cases will be presented.

Keywords: retinal degenerations: hereditary • retinal development • retina