Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy

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.

Figure 1

Mutational spectrum (A) Spectrum of variants identified in 251 patients affected by macular and cone/cone-rod dystrophies. (B) Functional categorization of variants identified in our study. (C) Inheritance based on the genetic findings. Percentages refer to patients with mutations in the considered causative gene, pathway or mode of inheritance.

Figure 2

Uncommonly observed but characteristic genotype-phenotype correlations. Retinal phenotype associated with mutations in CRB1 [#117] (A), KIF11 [#179] (B), JAG1 [#184] (C), DRAM2 [#119] (D), POC1B [#120] (E), NPHP1 [#115] (F), RPGR [#189] (G). Fundus color image (first column), fundus AF with 488 nm excitation light (second column), and horizontal spectral-domain OCT (third and fourth column) are shown. Patient numbers refer to Supplementary Table 1. Only one eye is shown due to high symmetry between eyes.

Figure 3

Potential novel genotype-phenotype correlations. Potential novel genotype-phenotype correlations in FAM161A [#122] (A), INPP5E [#121] (B), MERTK [#113] (C), FBLN5 [#187] (D), SEMA4A [#188] (E) and IMPDH1 [#186] (F). Fundus color image (first column), fundus AF with 488 nm excitation light (second column), and horizontal spectral-domain OCT (third and fourth column) are shown. Patient numbers refer to Supplementary Table 1. Only one eye is shown due to high symmetry between eyes.