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Rod cone dystrophy (RCD), also known as retinitis pigmentosa, is an inherited condition leading to vision loss, affecting 1/3500 people.  Over 270 genes are known to be implicated in the inherited retinal degenerations (IRDs), yet genetic diagnosis for ~30% IRD of patients remains elusive despite advances in sequencing technologies. The goal of this study was to determine the genetic causality in a family with Rod-cone dystrophy (RCD).   Family members were given a full ophthalmic exam at the Retinal Service at MEE and consented to genetic testing.  Whole exome sequencing (WES) was performed and variants of interest were Sanger validated.  Functional assays were conducted in zebrafish along with splicing assays in relevant cell lines to determine the impact on retinal function.  WES identified variants in two potential candidate genes that segregated with disease: GNL3 (G Protein Nucleolar 3) c.1187+3A&gt;C and c.1568-8C&gt;A; and PDE4DIP (Phosphodiester 4D Interacting Protein) c.3868G&gt;A (p.Glu1290Lys) and c.4603G&gt;A (p.Ala1535Thr).  Both genes were promising candidates based on their retinal involvement (development and interactions with IRD-associated proteins), however the functional assays did not validate either gene.  Subsequent WES reanalysis with an updated bioinformatics pipeline and widened search parameters led to the detection of a 94bp duplication in PRPF31 (pre-mRNA Processing Factor 31) c.73_266dup (p.Asp56GlyfsTer33) as the causal variant.  Our study demonstrates the importance of thorough functional characterization of new disease candidate genes, and the value of reanalyzing NGS sequence data, which in our case led to identification of a hidden pathogenic variant in a known IRD gene.

A Hidden Structural Variation in a Known IRD Gene: A Cautionary Tale of Two New Disease Candidate Genes