Expanding the clinical and molecular heterogeneity of nonsyndromic inherited retinal dystrophies

Abstract A cohort of 172 patients diagnosed clinically with non-syndromic retinal dystrophies, from 110 families underwent full ophthalmologic examination, including retinal imaging, electrophysiology and optical coherence tomography, if feasible. Molecular analysis was performed using targeted next-generation sequencing (NGS). Variants were filtered and prioritized according to the minimum allele frequency, and finally classified according to the American College of Medical Genetics and Genomics guidelines. Multiplex Ligation-dependent Probe Amplification and array comparative genomic hibridization were performed to validate copy number variations identified by NGS. The diagnostic yield of this study was 62% of studied families. We identified 30 novel mutations and we found phenotypic intra- and interfamilial variability in families with mutations in C1QTNF5, CERKL and PROM1; biallelic mutations in PDE6B in an unilateral RP patient; 50% of the symptomatic RPGR mutated females displayed interocular asymmetry RP; the first case with possible digenism between CNGA1 and CNGB1; a ROM1 duplication in two unrelated RP families; and we reclassified 10 unrelated cases. This study highlights the clinical utility of targeted NGS for NS-IRD cases and the importance of full ophthalmologic examination, which allow us to set up new genotype-phenotype associations and expands the knowledge of this group of disorders. To identify the cause of disease is essential for improving the patient management, the accurate genetic counseling and to take advantage of gene therapy-based treatments.