Novel recessive cone-rod dystrophy caused by POC1B mutation

Importance: A new form of cone-rod dystrophy (CORD) is described and the gene responsible for the disease is identified.

Objective: To clinically evaluate 4 patients and 5 control relatives, perform disease gene mapping, and identify the gene defect responsible for CORD.

Design, setting, and participants: Prospective observational case series of 13 members of a consanguineous family and 113 unrelated control individuals.

Interventions: Clinical investigations included eye examination with color fundus and autofluorescent imaging, spectral-domain optical coherence tomography, and electrophysiologic measurements. Linkage mapping was performed using single-nucleotide polymorphism genotype data. Candidate genes were analyzed for mutations via Sanger Sequencing.

Main outcomes and measures: Clinical diagnosis of CORD, disease gene mapping, and mutation identification.

Results: The onset of CORD occurred in early childhood. The clinical phenotype was typical CORD with photophobia, decreased central vision, and dyschromatopsia. In all patients, a disrupted inner segment/outer segment line and the external limiting membrane were noted as a single blurry line at the central fovea, and the cone outer segment tip line was absent. In the midperipheral retina, the rod inner segment/outer segment line was disrupted and blurry, and the rod outer segment tip line was absent. Cone response was nonrecordable in all patients, whereas rod response was nonrecordable in the eldest patient and subnormal in the Others. The Arden Index was abnormal in the youngest patient and flat in the Others. The disease gene mapped to a less than 2-megabase recessive locus at 12q21.33 with a logarithm of odds score of 3.92. At the locus, we identified a homozygous missense POC1B p.R106P mutation that was predicted as damaging by online tools.

Conclusions and relevance: POC1B is a novel gene for a new disease typical of CORD except that patients did not report night blindness. The clinical course was slowly progressive. Screening for POC1B mutation could benefit families afflicted with CORD.