Next-generation sequencing-based molecular diagnosis of 82 retinitis pigmentosa probands from Northern Ireland

Abstract

Retinitis pigmentosa (RP) is a group of inherited retinal disorders characterized by progressive photoreceptor degeneration. An accurate molecular diagnosis is essential for disease characterization and clinical prognoses. A retinal capture panel that enriches 186 known retinal disease genes, including 55 known RP genes, was developed. Targeted next-generation sequencing was performed for a cohort of 82 unrelated RP cases from Northern Ireland, including 46 simplex cases and 36 familial cases. Disease-causing mutations were identified in 49 probands, including 28 simplex cases and 21 familial cases, achieving a solving rate of 60 %. In total, 65 pathogenic mutations were found, and 29 of these were novel. Interestingly, the molecular information of 12 probands was neither consistent with their initial inheritance pattern nor clinical diagnosis. Further clinical reassessment resulted in a refinement of the clinical diagnosis in 11 patients. This is the first study to apply next-generation sequencing-based, comprehensive molecular diagnoses to a large number of RP probands from Northern Ireland. Our study shows that molecular information can aid clinical diagnosis, potentially changing treatment options, current family counseling and management.

Molecular findings from 537 individuals with inherited retinal disease

“…These variants account or likely account for the clinical diagnosis of IRD in 51% of the 537 individuals referred for diagnostic testing, including 208 autosomal-recessive, 50 autosomal-dominant and 13 X-linked recessive cases. Other studies employing NGS have shown higher molecular diagnostic rates than reported in this study, including Eisenberger and colleagues,21 Zhao and colleagues22 and the Saudi Mendeliome group 23. We attribute differences in diagnostic success rates to a number of factors.…”

The current status of molecular diagnosis of inherited retinal dystrophies

“…In order to increase mutation detection rate, a large number of genes must be sequenced. NGS testing of several retinal dystrophy patient cohorts have been reported recently, with published mutation detection rates for nonsyndromic retinal dystrophy of 37 [13 && ], 51 [12 & ], 55 [14], 60 [15], and 70% [16], using targeted enrichment NGS panel tests.…”

Where are the missing gene defects in inherited retinal disorders? Intronic and synonymous variants contribute at least to 4% of CACNA1F ‐mediated inherited retinal disorders

“…Of note, light sensitivity may be one major symptom in patients with variants in CACNA1F , CABP4 , and CACNA2D4 in addition to phenotypic variability sometimes leading to more progressive IRD and thus the term icCSNB may be misleading (reviewed in Zeitz et al, ). More than 150 different variants in CACNA1F and only a few in CABP4 and CACNA2D4 lead to icCSNB or similar phenotypes (reviewed and summarized in 2015 in Zeitz et al, ; additional publications since then, Ba‐Abbad et al, ; Hove et al, ; X. F. Huang et al, ; L. Huang et al, ; Patel et al, ; Sun et al, ; Xu et al, ; Zhao et al, ; Q. Zhou et al, ). The pathogenic variant spectrum comprises missense, nonsense, and splice‐site variants, small insertions and deletions, gross deletions, and complex rearrangements with most of the variants representing missense or nonsense variants (HGMD_Pro; Stenson et al, ; Zeitz et al, ).…”