Exome Sequencing Reveals Novel and Recurrent Mutations with Clinical Significance in Inherited Retinal Dystrophies

<div><p>This study aimed to identify the underlying molecular genetic cause in four Spanish families clinically diagnosed of Retinitis Pigmentosa (RP), comprising one autosomal dominant RP (adRP), two autosomal recessive RP (arRP) and one with two possible modes of inheritance: arRP or X-Linked RP (XLRP). We performed whole exome sequencing (WES) using NimbleGen SeqCap EZ Exome V3 sample preparation kit and SOLID 5500xl platform. All variants passing filter criteria were validated by Sanger sequencing to confirm familial segregation and the absence in local control population. This strategy allowed the detection of: (i) one novel heterozygous splice-site deletion in <i>RHO</i>, c.937-2_944del, (ii) one rare homozygous mutation in <i>C2orf71</i>, c.1795T>C; p.Cys599Arg, not previously associated with the disease, (iii) two heterozygous null mutations in <i>ABCA4,</i> c.2041C>T; p.R681* and c.6088C>T; p.R2030*, and (iv) one mutation, c.2405-2406delAG; p.Glu802Glyfs*31 in the ORF15 of <i>RPGR</i>. The molecular findings for <i>RHO</i> and <i>C2orf71</i> confirmed the initial diagnosis of adRP and arRP, respectively, while patients with the two <i>ABCA4</i> mutations, both previously associated with Stargardt disease, presented symptoms of RP with early macular involvement. Finally, the X-Linked inheritance was confirmed for the family with the <i>RPGR</i> mutation. This latter finding allowed the inclusion of carrier sisters in our preimplantational genetic diagnosis program.</p>