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

• Published in: PloS one Vol. 17; no. 12; p. e0278857
• Main Authors: Donato, Luigi, Alibrandi, Simona, Scimone, Concetta, Rinaldi, Carmela, Dascola, Angela, Calamuneri, Alessandro, D'Angelo, Rosalia, Sidoti, Antonina
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09-12-2022; Public Library of Science (PLoS)
• Subjects: Adaptation; Analysis; Bioinformatics; Biology and Life Sciences; Calcium Channels - genetics; Color vision; Cone-Rod Dystrophies - genetics; DNA Mutational Analysis; Dystrophy; Extremely low frequencies; Eye diseases; Gene sequencing; Genes; Genes, Modifier; Genomes; Genomics; Genotype & phenotype; Genotypes; Guanylate cyclase 1; Heterogeneity; Humans; Light emitting diodes; Localization; Low frequency; Medicine and Health Sciences; Mutation; Neurotransmission; Next-generation sequencing; Pax2 protein; Pedigree; Phenotype; Phenotypes; Pilot Projects; Precision medicine; Research and Analysis Methods; Retina; Retinitis Pigmentosa - genetics; Signs and symptoms; Social Sciences; Values; Italy; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0278857

Cone-rod dystrophies (CORDs) are a heterogeneous group of inherited retinopathies (IRDs) with more than 30 already known disease-causing genes. Uncertain phenotypes and extended range of intra- and interfamilial heterogenicity make still difficult to determine a precise genotype-phenotype correlation. Here, we used a next-generation sequencing approach to study a Sicilian family with a suspected form of CORD. Affected family members underwent ophthalmological examinations and a proband, blind from 50 years, underwent whole genome and exome sequencing. Variant analysis was enriched by pathway analysis and relevant variants were, then, investigated in other family members and in 100 healthy controls from Messina. CORD diagnosis with an intricate pattern of symptoms was confirmed by ophthalmological examinations. A total of about 50,000 variants were identified in both proband's genome and exome. All affected family members presented specific genotypes mainly determined by mutated GUCY2D gene, and different phenotypical traits, mainly related to focus and color perception. Thus, we looked for possible modifier genes. According to relationship with GUCY2D, predicted functional effects, eye localization, and ocular disease affinity, only 9 variants, carried by 6 genes (CACNG8, PAX2, RXRG, CCDC175, PDE4DIP and LTF), survived the filtering. These genes encode key proteins involved in cone development and survival, and retina neurotransmission. Among analyzed variants, CACNG8c.*6819A>T and the new CCDC175 c.76C>T showed extremely low frequency in the control group, suggesting a key role on disease phenotypes. Such discovery could enforce the role of modifier genes into CORD onset/progression, contributing to improve diagnostic test towards a better personalized medicine.