Non-Truncating Homozygous Deletion in CACNA2D4 Mimicking Oligocone Trichromacy

Abstract

Purpose: To detail phenotypic characteristics of an unusual case of CACNA2D4-related retinopathy

Methods: A 13-year-old affected male underwent detailed ophthalmological evaluation, fundus autofluorescence (FAF) testing, spectral-domain optical coherence tomography (SD-OCT) and ISCEV standard full-field electroretinography (ERG). Retinal images within 6° eccentricity of the fovea were captured using adaptive-optics enhanced scanning laser ophthalmoscopy (AOSLO; PSI, Andovar, MA). The coding sequence of CNGA3, CNGB3, GNAT2, PDE6C and CACNA2D4 were sequenced for pathogenic mutations. A previously suggested association of bipolar disorder (BPD) to copy number variations in CACNA2D4 was also explored in the family. Reverse transcription polymerase chain reaction (RT-PCR) analysis was performed from cDNA extracted from lymphoblast cell lines of the proband and mother.

Results: The proband had symptoms of photophobia since infancy. His best-corrected distance visual acuity was 20/25 and 20/30 in the right and left eyes respectively; color vision was normal. Retina showed a dull foveal reflex. The FAF of the posterior pole was near normal. The SD-OCT showed normal central retinal thickness; all retinal layers were continuous at the macula. ERG showed normal scotopic responses and mildly reduced photopic responses. AOSLO images showed normal cone-photoreceptor mosaic with regular hexagonal packing. A 35.7 kb homozygous deletion of exons 17 - 26 of CACNA2D4 was identified in the proband, and it segregated with the retinal phenotype. The deletion in CACNA2D4 in a heterozygous state did not segregate with BPD (n=5) in the extended family (n=10). RT-PCR suggested a shorter CACNA2D4 transcript extending until the last exon.

Conclusions: The clinical phenotype and ERG results are consistent with oligocone trichromacy, a form of generalized cone photoreceptor dysfunction syndrome with preserved color vision. However, genetic testing revealed a homozygous deletion in CACNA2D4, a gene previously associated with selective inner retinal dysfunction of both rod and cone bipolar cells. Contiguous packing of cone mosaic in regions adjacent to the fovea may support an inner retinal locus of abnormality in the cone system. The reason for normal rod ON-bipolar function in the proband is unclear. This case demonstrates the considerable extent of overlap between two contrasting disease phenotypes and highlights the benefits of careful phenotyping.

Keywords: 539 genetics • 696 retinal degenerations: hereditary • 509 electroretinography: clinical