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A novel overview of the human retinal transcriptome may contribute missing heritability in IRD patients

Researchers at the Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy, has reported the results of 5,054 gene transcripts analysed from 218 IRD (inherited retinal degenerations) genes.  435 of the transcripts were estimated to account for at least 5% of the expression of the corresponding gene.  Researchers concluded that the “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”.  On reviewing their data, published in the journal BMC Genomics [Ruiz‑Ceja et al., 2023, 24:206], researchers believed that the data is the most comprehensive and extended meta-analysis of IRD genes carried out on certain data (transcriptome) in the human retina.

Research within IRDs are one of the leading causes of visual loss in children and young adults and mutations in over 281 genes lead to retinal dysfunction, degeneration and sight loss.  At present, an estimated two-thirds of analysed cases of IRDs have identified a genetic cause, while the remaining third of cases are not yet resolved.  This “missing heritability” of these cases may be due to the presence undetected mutations by genomic NGS-based procedures (next-generation sequencing), or novel IRD genes, or unknown functional elements, including those undetected cases arising from transcriptome analysis, analysis from the set of all RNA transcripts, including coding and non-coding, in an individual or a population of cells in the retina.  Alternative splicing, whereby a single gene can code multiple proteins or different RNA transcripts, can arise from exon skipping, exon elongation, novel exons, and intron retention. Researchers have suggested there are ~9% of IRD-causing mutations can affect splicing, with cases of cone-rod dystrophy, Usher syndrome (USH), retinitis pigmentosa (RP), and Leber Congenital Amaurosis (LCA).  These type of alternative splicing cases could be under-estimated from as yet undiagnosed IRD patients, and therefore new research could uncover these elements from transcriptomic analysis thereby reduce the current “missing heritability”.

Following the Italian TIGEM results reported, the 218 IRD genes identified 5,054 transcripts, 3,367 (67%) of which were not previously reported and the putative expression levels on 435 of the transcripts predicted to account for at least 5% of the expression of the corresponding gene.  According to the study, the researchers said that, “to the best of our knowledge, this is the most comprehensive and extended meta-analysis of IRD genes carried out on RNA-Seq data [transcriptome analysis] in the human retina. Our work yielded a reliable quantification of IRD transcript expression in this tissue, including the identification of novel ones. The generated resource can improve our understanding of the organization of the transcriptional units of IRD genes and, ultimately, of the molecular mechanisms underlying inherited retinal diseases”.