Abstract
Macular and cone/cone-rod dystrophies (MD/CCRD) demonstrate a broad genetic and phenotypic heterogeneity, with retinal alterations solely or predominantly involving the central retina. Targeted next-generation sequencing (NGS) is an efficient diagnostic tool for identifying mutations in patient with retinitis pigmentosa, which shows similar genetic heterogeneity. To detect the genetic causes of disease in patients with MD/CCRD, we implemented a two-tier procedure consisting of Sanger sequencing and targeted NGS including genes associated with clinically overlapping conditions. Disease-causing mutations were identified in 74% of 251 consecutive MD/CCRD patients (33% of the variants were novel). Mutations in ABCA4, PRPH2 and BEST1 accounted for 57% of disease cases. Further mutations were identified in CDHR1, GUCY2D, PROM1, CRX, GUCA1A, CERKL, MT-TL1, KIF11, RP1L1, MERTK, RDH5, CDH3, C1QTNF5, CRB1, JAG1, DRAM2, POC1B, NPHP1 and RPGR. We provide detailed illustrations of rare phenotypes, including autofluorescence and optical coherence tomography imaging. Targeted NGS also identified six potential novel genotype-phenotype correlations for FAM161A, INPP5E, MERTK, FBLN5, SEMA4A and IMPDH1. Clinical reassessment of genetically unsolved patients revealed subgroups with similar retinal phenotype, indicating a common molecular disease cause in each subgroup.
Highlights
Macular and cone/cone-rod dystrophies (MD/CCRD) comprise diverse inherited retinal diseases with progressive degeneration, dysfunction and vision loss of the central retina[1]
Patients were excluded if they had the clinical diagnosis of achromatopsia, X-linked retinoschisis, and North Carolina macular dystrophy
Mutations in genes known to be involved in MD/CCRD pathogenesis
Summary
Macular and cone/cone-rod dystrophies (MD/CCRD) comprise diverse inherited retinal diseases with progressive degeneration, dysfunction and vision loss of the central retina[1]. More than 30 disease-causing genes have been reported for MD/CCRD (RetNet, https://sph.uth.edu/retnet), the genetic disease cause in a substantial number of patients is currently unknown. – have reported the performance of targeted NGS for defining the molecular basis of unselected patient cohorts with MD/CCRD2,9–11. We report results from a cohort of 251 unrelated, consecutive and clinically well characterized MD/ CCRD patients who underwent extensive molecular genetic analysis. The results provide insights into the diversity of the mutational spectrum of MD/CCRD and indicate potential novel or uncommon genotype-phenotype correlations. We reviewed the retinal phenotype of patients in whom the molecular disease cause remained unexplained and propose phenotypic subgroups which may correspond to specific yet unknown genetic disease causes
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