Long-read sequencing uncovers novel pathogenic duplications in the PRPH2 gene in patients with macular dystrophy

Clinical variability and incomplete penetrance characterize retinal dystrophies associated with PRPH2 gene variants. Here, we utilized adaptive nanopore long-read sequencing (LRS) to solve a genetic diagnosis for dominantly inherited macular dystrophies in two families.

Patient 1 (P1) and her daughter, Patient 2 (P2) were clinically evaluated using multimodal imaging and electrophysiological testing at Helsinki University Hospital, Finland, and Patient 3 (P3) from a different family, at Loma Linda University, USA. The patients were subjected to retinal dystrophy gene panels and the suspected duplications were characterized with nanopore LRS.

P1 presented with butterfly-shaped pattern dystrophy (BPD) and P2 with vitelliform macular dystrophy. P3 showed BPD in the right eye and late-stage BPD in the left. Gene panels suggested that the patients shared the same heterozygous 482 bp PRPH2 exon 2 duplication. LRS revealed the duplications to be almost 4kb in size with breakpoints (BP) in intronic Alu-elements. In P1 and P2, the 3'BP resides within a novel Alu-element. The duplication has not been reported earlier and is missing from the gnomAD database.

This study presents novel PRPH2 exon 2 duplications associated with macular dystrophies.