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Lucia Guidugli, Miika Mehine, Sari Tuupanen, Kati Kämpjärvi, Kirsty Wells, Johanna Känsäkoski, Miko Valori, Inka Saarinen, Mikko Muona, Eeva-Marja Kaarina Sankila, Samuel Myllykangas, Juha Koskenvuo, Tero-Pekka Alastalo; Characterization of copy number variants (CNVs) identified by genetic testing of inherited retinal disorders. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2944.
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Retinal dystrophies (RD) include a heterogeneous group of disorders that damage the photoreceptors in the retina and cause visual impairment. Prompt and comprehensive genetic diagnosis of these disorders can assist in risk assessment measures, management of symptoms, and selection of the appropriate targeted treatment. To provide a comprehensive diagnosis, the genetic testing strategy needs to take into account sequence alterations as well as copy number variants (CNVs). The purpose of this study was to evaluate the rates and characteristics of CNVs in a cohort of 2754 patients tested using a comprehensive RD panel.
DNA from patients was sequenced by targeted OS-Seq using the Illumina NextSeq500 sequencing platform or the IDT xGEN Exome Research Panel using the Illumina NovaSeq platform.
CNVs in a total of 47 genes matching the patient’s phenotype were reported as a primary finding in 128 out of 2754 (4.6%) cases. Of these, 91 (71.1%) were partial gene deletions, 17 (13.3%) whole gene deletions, four (3.1%) one exon deletions, and one (0.8%) was a partial exon deletion. In addition, ten (7.8%) partial gene duplications, three (2.3%) whole gene duplications, one (0.8%) whole gene gain (CN>3), and one (0.8%) partial gene gain (CN>3) were identified (Figure 1). The majority of CNVs (113, 88.3%) were either likely pathogenic or pathogenic while 15 (11.7%) were variants of uncertain significance. Of the likely pathogenic and pathogenic CNVs, 94 (73.4%) were diagnostic: 66 (70.2%) in autosomal recessive genes, 17 (18.1%) in autosomal dominant genes, and 11 (11.7%) in X-linked genes. The USH2A, EYS and PRPF31 genes were enriched in CNVs compared to other genes. Notably, CNVs were identified also in genes in which CNVs are not commonly reported, e.g. ABCA4 and RPE65.
Overall, these results highlight the importance of a comprehensive genetic testing approach for the diagnosis of retinal dystrophies. We have identified CNVs ranging from one exon deletions to whole gene deletions in multiple genes. In addition, we have detected a relatively high percentage of copy number duplications that warrant further investigation.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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