Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Fabiana D’Esposito
* ORCID logo ,
Viviana Randazzo
,
Maria Igea Vega
,
Caterina Gagliano
ORCID logo ,
Gabriella Esposito
ORCID logo ,
Paolo Enrico Maltese
ORCID logo ,
Salvatore Torregrossa
,
Paola Scibetta
,
Florinda Listì
,
Lucia Scalia
,
Antonino Pioppo
,
Antonio Marino
,
Marco Piergentili
,
Emanuele Malvone
,
Tiziana Fioretti
,
Angela Vitrano
,
Maria Piccione
,
Teresio Avitabile
,
Francesco Salvatore
ORCID logo ,
Matteo Bertelli
ORCID logo ,
Ciro Costagliola
,
Maria Francesca Cordeiro
,
Aurelio Maggio
,
Elena D'Alcamo
Version 1 : Received: 26 September 2023 / Approved: 27 September 2023 / Online: 27 September 2023 (11:06:58 CEST)

A peer-reviewed article of this Preprint also exists.

D’Esposito, F.; Randazzo, V.; Vega, M.I.; Esposito, G.; Maltese, P.E.; Torregrossa, S.; Scibetta, P.; Listì, F.; Gagliano, C.; Scalia, L.; et al. RP1 Dominant p.Ser740* Pathogenic Variant in 20 Knowingly Unrelated Families Affected by Rod–Cone Dystrophy: Potential Founder Effect in Western Sicily. Medicina 2024, 60, 254. https://doi.org/10.3390/medicina60020254 D’Esposito, F.; Randazzo, V.; Vega, M.I.; Esposito, G.; Maltese, P.E.; Torregrossa, S.; Scibetta, P.; Listì, F.; Gagliano, C.; Scalia, L.; et al. RP1 Dominant p.Ser740* Pathogenic Variant in 20 Knowingly Unrelated Families Affected by Rod–Cone Dystrophy: Potential Founder Effect in Western Sicily. Medicina 2024, 60, 254. https://doi.org/10.3390/medicina60020254

Abstract

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.

Keywords

rod-cone dystrophy; retinitis pigmentosa; RP1 gene; founder effect; inherited retinal dystrophies; founder mutation

Subject

Medicine and Pharmacology, Ophthalmology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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