Unravelling the genetic basis of simplex Retinitis Pigmentosa cases

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.

Genetic testing in patients with retinitis pigmentosa: Features of unsolved cases

“…Our study supports the assumption that phenotypic and demographic patient characteristics may impact clinical pre‐selection for efficient genetic testing and patient counselling . Pre‐selecting patients below 30 years‐of‐age would result in a higher diagnostic yield.…”

“…Our study supports the assumption that phenotypic and demographic patient characteristics may impact clinical preselection for efficient genetic testing and patient counselling. 25 Pre-selecting patients below 30 years-of-age would result in a higher diagnostic yield. Older patients, those with autoimmune disease in the absence of a family history of retinal disease, and patients with atypical fundus findings may be informed on the lower probability of identifying a disease-causing mutation.…”

Charcot–Marie–Tooth Disease type 4C: Novel mutations, clinical presentations, and diagnostic challenges

“…It is likely that retinitis pigmentosa was an autosomal dominant or X‐linked dominant disease because her father was also affected. Whereas proximal muscle weakness and scapular winging have been reported in rare CMT4C patients, we report an facioscapulohumeral muscular dystrophy phenotype in patient 5. Coexisting rare recessive bleeding disorders, PAI‐1 deficiency, and von Willebrand type 2M disease, are unusual associations in a patient with CMT4C.…”

“…Individual diagnosis of CMT4C patients is challenging because of considerable intrafamilial and interfamilial clinical variability. The diagnostic challenge was further compounded in sporadic CMT4C patients because of the presence of additional extremely rare inherited disorders such as SCADD, 16 retinitis pigmentosa, 17 von Willebrand type 2M, 18 and PAI-1 deficiency. 19 When considering our patients together with previous reports from the literature, it seems appropriate for CMT4C to be considered an atypical form of CMT.…”

Retrospective cohort study exploring whether an association exists between spatial distribution of cystoid spaces in cystoid macular oedema secondary to retinitis pigmentosa and response to treatment with carbonic anhydrase inhibitors

“…Retinitis pigmentosa (RP) is the most common group of IRD, causing progressive centripetal reduction of vision and associated with variants in over 80 genes to date, accounting for approximately 50%–60% of cases, with an autosomal recessive, autosomal dominant or X linked mode of inheritance 2. Secondary complications associated with RP include cataracts and RP-associated cystoid macular oedema (RP-CMO), which further contribute to reduction of visual acuity 3.…”