Unravelling the genetic basis of simplex Retinitis Pigmentosa cases

Nereida Bravo-Gil, María González-Del Pozo, Marta Martín-Sánchez, Cristina Méndez-Vidal, Enrique Rodríguez-de la Rúa, Salud Borrego, Guillermo Antiñolo, Nereida Bravo-Gil, María González-Del Pozo, Marta Martín-Sánchez, Cristina Méndez-Vidal, Enrique Rodríguez-de la Rúa, Salud Borrego, Guillermo Antiñolo

Abstract

Retinitis Pigmentosa (RP) is the most common form of inherited retinal dystrophy (IRD) characterized ultimately by photoreceptors degeneration. Exhibiting great clinical and genetic heterogeneity, RP can be inherited as an autosomal dominant (ad), autosomal recessive (ar) and X-linked (xl) disorder. Although the relative prevalence of each form varies somewhat between populations, a major proportion (41% in Spain) of patients represent simplex cases (sRP) in which the mode of inheritance is unknown. Molecular genetic diagnostic is crucial, but also challenging, for sRP patients because any of the 81 RP genes identified to date may be causative. Herein, we report the use of a customized targeted gene panel consisting of 68 IRD genes for the molecular characterization of 106 sRP cases. The diagnostic rate was 62.26% (66 of 106) with a proportion of clinical refinements of 30.3%, demonstrating the high efficiency of this genomic approach even for clinically ambiguous cases. The high number of patients diagnosed here has allowed us to study in detail the genetic basis of the sRP. The solved sRP cohort is composed of 62.1% of arRP cases, 24.2% of adRP and 13.6% of xlRP, which implies consequences for counselling of patients and families.

Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1. Prevalence analyses of solved cases.
Figure 1. Prevalence analyses of solved cases.
(A) Proportion of each type of mutation. (B) Principal detected modes of inheritance. (C) Recurrence of all mutated retinal genes. (D) Distribution of different types of mutations for each of the identified mutated gene.
Figure 2. Genotype-phenotype correlations.
Figure 2. Genotype-phenotype correlations.
(A) Overlapping phenotypes among different forms of non syndromic IRD: RP (Retinitis Pigmentosa), CHM (Choroideremia), CD/CRD (Cone dystrophy/Cone-rod dystrophy), STGD (Stargardt disease) and LCA (Leber congenital amaurosis). Gene positions show the associated phenotype/s and the first reported symptom of cases in which they are involved (NB: Night blindness; RVF: Reduced visual field; DVA: Decreased visual acuity). Asterisks indicate genes represented more than once in the figure due to the high heterogeneity. (B) Distribution of types of mutations behind the different phenotypes caused by the same gene. (C) Mean age of onset of each of the identified genes. Vertical lines show the age of onset of cases not included in the average to be considerably different from the rest. Of note, the gene RHO was identified in only two cases with very different clinical features hence the calculated average may not be representative. Moreover, this representation do not include clinical and genetic data of family #65 since the large deletion affects several genes and it is not possible to determine the involvement of each of them. Light blue marks early-onset cases while a juvenile onset is stated with medium blue and a late-onset with dark blue. (D) Distribution of early-, juvenile- and late-onset IRD for the different modes of inheritance.

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