How to Set Up Genetic Counselling for Inherited Macular Dystrophies: Focus on Genetic Characterization

Raimondi, Raffaele; D’Esposito, Fabiana; Sorrentino, Tania; Tsoutsanis, Panagiotis; Rosa, Francesco Paolo De; Stradiotto, Elisa; Barone, Gianmaria; Rizzato, Angelica; Allegrini, Davide; Costagliola, Ciro; Romano, Mario R.

doi:10.3390/ijms24119722

Cited by 2 publications

(1 citation statement)

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“…Inherited retinal dystrophies still represent an important cause of visual impairment and blindness, with a great effort of the scientific community towards the characterization of pathogenic mechanisms and ultimately therapeutic strategies. Given the high genetic and phenotypic heterogeneity, molecular diagnosis is crucial for the correct definition of each patient condition, for familial genetic counselling, for better understanding pathogenic mechanisms and for creating datasets of patients, based on the phenotype-related genetic defect, rather than exclusively on the phenotype itself, especially in the perspective of developing potential innovative therapies [24].…”

Section: Discussionmentioning

confidence: 99%

RP1 Dominant p.Ser740* Pathogenic Variant In 20 Knowingly Unrelated Families Affected by Rod-Cone Dystrophy: Founder Effect in Western Sicily

D’Esposito,

Randazzo,

Vega

et al. 2023

Preprint

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BACKGROUND AND OBJECTIVES. Rod-Cone Dystrophies (RCDs) are genetically determined retinal dystrophies, resulting in nyctalopia, visual field progressive reduction and visual acuity decay in the late stages. Retinitis Pigmentosa (RP) is the most described type. All modes of transmission can be identified in RP, with the autosomal dominant form (ADRP) accounting for about 20% of cases. To date, over 30 genes have been related to ADRP, with RP1 gene estimated to be involved in 5-10% of cases. In a cohort of patients affected by RCD and sharing the same geographic origin from Palermo province in Western Sicily, we identified a prevalent causative variant in the RP1 gene (NM_006269.2; c.2219C>G, p.Ser740*). Objective of our study was to analyse clinical and molecular data of this population and define the entity and the meaning of this finding. MATERIALS AND METHODS. Eighty-four patients with a diagnosis of RCD or RP underwent deep phenotyping, pedigree definition and molecular characterization, mostly by Next Generation Sequencing (NGS). All potentially pathogenic variants have been confirmed through direct sequencing and familial segregation. Statistical evaluation of resulting data has been performed. RESULTS. In 28 probands we identified a pathogenic variant (p.Ser740*) in the RP1 gene that resulted significantly prevalent. Some patients, after careful interviewing, were found to share the same pedigree; we ultimately defined 20 family groups with no traceable consanguinity. CONCLUSIONS. The high prevalence of the p.Ser740* variant in RP patients from Western Sicily unveils the presence of a founder effect, which has implications for the molecular diagnosis of RCD in patients coming from this Italian region. This variant can be primarily searched in RP affected subjects displaying compatible mode of transmission and phenotype, with an advantage in terms of costs and analysis time. Moreover, given its high prevalence, RP1 p.Ser740* variant could represent a potential candidate for the development of therapeutic strategies based on gene editing or translational read-through therapy for suppression of nonsense variants.

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Section: Discussionmentioning

confidence: 99%