The impact of modifier genes on cone-rod dystrophy heterogeneity: An explorative familial pilot study and a hypothesis on neurotransmission impairment

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Summary

This familial pilot study identifies modifier genes (CACNG8, PAX2, RXRG, CCDC175, PDE4DIP, LTF) that contribute to phenotypic heterogeneity in cone-rod dystrophy beyond the primary GUCY2D mutation, with implications for personalized diagnostic approaches. The findings suggest retinal neurotransmission pathways play a key role in disease progression, which is relevant context for understanding photoreceptor-based visual impairments that affect light perception and color vision.

Key Findings

Approximately 50,000 variants were identified in the proband's genome and exome; 9 variants across 6 genes survived filtering based on functional relevance to cone development, survival, and retinal neurotransmission.
Variants CACNG8 c.*6819A>T and novel CCDC175 c.76C>T showed extremely low frequency in 100 healthy controls from Messina, suggesting a key modifier role in cone-rod dystrophy phenotype expression.
All affected family members shared mutations in GUCY2D as the primary disease-causing gene, but exhibited differing phenotypic traits related to focus and color perception, attributed to modifier gene variation.