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Intrafamilial variability of phenotype in CACNA2D4-associated retinal dysfunction: more or less
Vasily Smirnov1,2, Claire-Marie Dhaenens3, Vincent Canel4
1CHU Lille, Service d'Exploration de la Vision et de Neuro-Ophtalmologie, Hôpital Salengro, 59037, Lille, France. vasily.smirnov@chu-lille.fr.
Documenta Ophthalmologica. Advances in Ophthalmology
|August 29, 2025
Summary
CACNA2D4 gene defects cause rare retinal dysfunction. Siblings showed variable symptoms and electroretinography (ffERG) results, despite sharing the same genetic variant, highlighting intrafamily variability.
Area of Science:
- Ophthalmology
- Genetics
- Neuroscience
Background:
- Retinal dysfunction linked to CACNA2D4 gene mutations affects photoreceptor to bipolar cell signaling.
- This rare disorder's intrafamily variability is not well understood.
Purpose of the Study:
- To investigate the clinical and electrophysiological variability of CACNA2D4-associated retinal dysfunction in siblings.
- To characterize the phenotype associated with a specific CACNA2D4 variant.
Main Methods:
- Comprehensive ophthalmic examinations, including multimodal fundus imaging and full-field electroretinography (ffERG).
- Next Generation Sequencing (NGS) panel for genetic testing.
- Clinical and electrophysiological assessments over a 17-year follow-up period.
Main Results:
- Two siblings with the CACNA2D4 variant c.2406C>A, p.(Tyr802*) presented with reduced visual acuity and photosensitivity.
- ffERG revealed specific patterns for CACNA2D4 dysfunction but with differing response amplitudes between siblings.
- A preserved x-wave and reduced b/a ratio were noted, with stable vision in one sibling over 17 years.
Conclusions:
- Intrafamilial clinical and electrophysiological variability is a key feature of CACNA2D4-associated retinal dysfunction.
- Genetic defects in CACNA2D4 can manifest differently even within the same family.
