Abstract
Purpose To delineate the clinical and genetic characteristics of Chinese patients with RPGRIP1-associated Leber congenital amaurosis 6 (LCA6). Methods After screening 352 unrelated families with clinically diagnosed RP, five LCA6 patients with RPGRIP1 variations from unrelated Chinese families were identified. Full ophthalmology examinations, including decimal best-corrected visual acuity (BCVA), fundus photography, fundus autofluorescence imaging, spectral-domain optical coherence tomography (SD-OCT), full-field electroretinography (ffERG), multifocal electroretinography (mfERG), perimetry, and flash visual evoked potential (FVEP), were performed. Target next-generation sequencing (NGS) and Sanger sequencing were performed for the five patients to identify and to validate candidate disease-causing variants. Results Five patients were molecularly diagnosed as the LCA6 associated with RPGRIP1 variation, with typical clinical characteristics including congenital night blindness, nystagmus, and visual defect, at an early age. Interestingly, LCA6 exhibited extensive clinical heterogeneity and the changes in the morphology and function were not completely consistent in the five LCA6 patients. Case 1 showed extensive inferior-nasal retinal atrophy with a corresponding area of hypofluorescence in fundus autofluorescence, and the fundus photograph was nearly normal in cases 2 and 3. The ERG results displayed a moderately reduced rod-system response in cases 1 and 2 and a significant reduced rod-system response in case 3. Both case 4 and case 5 showed mottled pigmentation in fundi and an unrecordable rod and cone-system response in ERG. Moreover, we identified eight compound variants and one homozygous variant in the five patients with RPGRIP1. Conclusions This is the largest report focused on the clinical electrophysiological features of patients with associated LCA6 caused by the variation in the RPGRIP1 gene in the Chinese population with an enriched phenotypic and genotypic background of LCA6 to improve future gene therapies.
Highlights
Leber congenital amaurosis (LCA, MIM 204000) is a group of severe and early onset inherited retinal disorders (IRDs) with a worldwide prevalence of 1/33000 [1]∼1/81000 [2] and contributes to approximately 10%∼20% of blind children in school [1]
Leber congenital amaurosis 6 (LCA6) patients present with a stable and nonprogressive disease course after the initial rapid decline in visual function, and the morphology of photoreceptors in the central retina can persist for a long time. us, LCA6 associated with retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1) gene variants are expected to be treated by a gene replacement strategy [5, 6]; despite the latest advances in gene therapy on LCA2 (RPE65) [7] and LCA10 (CEP290) [8], there is no available clinically applicable treatment for LCA6 at present
RPGRIP1 has been reported to be associated with conerod dystrophy 13 (CROD 13), in which the phenotype of patients seemed to have been characterized by a rapid loss of vision in the second decade of life, but further details were not provided [13]. e clinical distinction between LCA and CORD is not clear, and there are large overlaps in the phenotype
Summary
Leber congenital amaurosis (LCA, MIM 204000) is a group of severe and early onset inherited retinal disorders (IRDs) with a worldwide prevalence of 1/33000 [1]∼1/81000 [2] and contributes to approximately 10%∼20% of blind children in school [1]. Journal of Ophthalmology (CRX, IMPDH1, OTX2, AIPL1, CABP4, CCT2, CEP290, CLUAP1, CRB1, DTHD1, GDF6, GUCY2D, IFT140, IQCB1, KCNJ13, LCA5, LRAT, NMNAT1, PRPH2, RD3, RDH12, RPE65, RPGRIP1, SPATA7, and TULP1) with autosomal recessive or dominant inheritance have been identified to be related to LCA (https://sph.uth.edu/Retnet/, accessed July 14, 2021). Leber congenital amaurosis 6 (LCA6, MIM 613826) is caused by variations in the RPGRIP1 gene encoding retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1), which participates in ciliary transport processes. LCA6 patients present with a stable and nonprogressive disease course after the initial rapid decline in visual function, and the morphology of photoreceptors in the central retina can persist for a long time. us, LCA6 associated with RPGRIP1 gene variants are expected to be treated by a gene replacement strategy [5, 6]; despite the latest advances in gene therapy on LCA2 (RPE65) [7] and LCA10 (CEP290) [8], there is no available clinically applicable treatment for LCA6 at present
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