Definition of the transcriptional units of inherited retinal disease genes by meta-analysis of human retinal transcriptome data

BACKGROUND: Inherited retinal diseases (IRD) are genetically heterogeneous disorders that cause the dysfunction or loss of photoreceptor cells and ultimately lead to blindness. To date, next-generation sequencing procedures fail to detect pathogenic sequence variants in coding regions of known IRD disease genes in about 30–40% of patients. One of the possible explanations for this missing heritability is the presence of yet unidentified transcripts of known IRD genes. Here, we aimed to define the transcript composition of IRD genes in the human retina by a meta-analysis of publicly available RNA-seq datasets using an ad-hoc designed pipeline. RESULTS: We analysed 218 IRD genes and identified 5,054 transcripts, 3,367 of which were not previously reported. We assessed their putative expression levels and focused our attention on 435 transcripts predicted to account for at least 5% of the expression of the corresponding gene. We looked at the possible impact of the newly identified transcripts at the protein level and experimentally validated a subset of them. CONCLUSIONS: This study provides an unprecedented, detailed overview of the complexity of the human retinal transcriptome that can be instrumental in contributing to the resolution of some cases of missing heritability in IRD patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12864-023-09300-w.