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.

Mutations in known disease genes account for the majority of autosomal recessive retinal dystrophies

“…There are currently 261 genes listed with established links to RDs (http://www.sph.uth.tmc.edu/RetNet/). Several studies have shown a rather high diagnostic yield (50%‐79%) of multigene panels in patients with RD . However, those cohorts were not selected on the basis of a particular mode of inheritance.…”

A novel, homozygous nonsense variant of the CDHR1 gene in a Chinese family causes autosomal recessive retinal dystrophy by NGS‐based genetic diagnosis

“…In literatures, different autosomal recessive phenotypes have been associated with the CDHR1 gene mutations, ranging from RP to CRD although the relationship between phenotypes and gene mutations are variable . The proband in our study, with a loss of more than one‐thirds of CDHR1 by a homozygous and nonsense variant p.Y547*, has been noticed the simultaneous onset of dark adaptation difficulties, trouble with color vision, and light sensitivity at age of 24; ERG in different waves showed markedly reduced rod‐and‐cone responses; FP/FPP showed macular dysdrophy (MD).…”

“…Clinically, this patient presented MD/CRD. Thus, combined with our study, patients with CDHR1 truncated protein by nonsense, splicing variants or deletions with frameshift, other than missense variants, might cause more severely phenotypes, such as MD/CRD, and/or earlier disease onset …”

“…The pathogenic CDHR1 mutation was first identified in 2010, and only a few mutations have been reported since then . Very recently, six CDHR1 mutations were also identified in Germany for macular and cone/cone‐rod dystrophies or retinal dystrophy . These small amounts of mutations suggest that the mutations in the CDHR1 gene are a rare case of arCRD (autosomal recessive cone‐rod dystrophy) in Western countries .…”

“…Here, we applied targeted next‐generation sequencing (TGS) technology, the most available ‎and promising method available, to identify a novel, homologous mutation of CDHR1 gene in a Chinese family with autosomal recessive retinal dystrophy, extending the gene's mutation spectrum.…”