Johannes Birtel, Tobias Eisenberger, Martin Gliem, Philipp L. Müller, Philipp Herrmann, Christian Betz, Diana Zahnleiter, Christine Neuhaus, Steffen Lenzner, Frank G. Holz, Elisabeth Mangold, Hanno J. Bolz, Peter Charbel Issa | Scientific Reports | Vol 8 | Article # 4824 | 19 March 2018 | doi.org/10.1038/s41598-018-22096-0
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.
Introduction
Macular and cone/cone-rod dystrophies (MD/CCRD) comprise diverse inherited retinal diseases with progressive degeneration, dysfunction and vision loss of the central retina1. Characteristic symptoms include decreasing visual acuity, reading difficulties, photophobia and dyschromatopsia. Later, variable loss of rod function with reduced night vision and loss of peripheral visual field may occur1. Full-field electroretinography (ffERG) allows classifying patients into those with MD (normal ffERG), CD (only reduced photopic responses) and CRD (reduced photopic and scotopic responses).
Genotype-phenotype correlations of MD/CCRD are often complex. For instance, different mutations in one gene can cause highly diverse phenotypes, and mutations in different genes can cause very similar phenotypes. Furthermore, there is a considerable clinical overlap of CCRD with MD and RP, and the classification may change from MD to CCRD with disease progression1,2,3. Although 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.
As novel therapeutic options including gene therapy are being developed, the identification of the individual mutation has gained importance. Next-generation sequencing (NGS) has become a very efficient diagnostic tool, as exemplified in patients with RP4,5,6,7,8. However, only few studies – most of them with limited patient numbers – have reported the performance of targeted NGS for defining the molecular basis of unselected patient cohorts with MD/CCRD2,9,10,11.
Here, 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. Moreover, 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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