<i>RP1</i> Dominant p.Ser740* Pathogenic Variant in 20 Knowingly Unrelated Families Affected by Rod–Cone Dystrophy: Potential Founder Effect in Western Sicily
<i>Background and Objectives</i>. Retinitis pigmentosa (RP) is the most common inherited rod–cone dystrophy (RCD), resulting in nyctalopia, progressive visual field, and visual acuity decay in the late stages. The autosomal dominant form (ADRP) accounts for about 20% of RPs. Among the ov...
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MDPI AG
2024-02-01
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| Series: | Medicina |
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| author | Fabiana D’Esposito Viviana Randazzo Maria Igea Vega Gabriella Esposito Paolo Enrico Maltese Salvatore Torregrossa Paola Scibetta Florinda Listì Caterina Gagliano Lucia Scalia Antonino Pioppo Antonio Marino Marco Piergentili Emanuele Malvone Tiziana Fioretti Angela Vitrano Maria Piccione Teresio Avitabile Francesco Salvatore Matteo Bertelli Ciro Costagliola Maria Francesca Cordeiro Aurelio Maggio Elena D’Alcamo |
| author_facet | Fabiana D’Esposito Viviana Randazzo Maria Igea Vega Gabriella Esposito Paolo Enrico Maltese Salvatore Torregrossa Paola Scibetta Florinda Listì Caterina Gagliano Lucia Scalia Antonino Pioppo Antonio Marino Marco Piergentili Emanuele Malvone Tiziana Fioretti Angela Vitrano Maria Piccione Teresio Avitabile Francesco Salvatore Matteo Bertelli Ciro Costagliola Maria Francesca Cordeiro Aurelio Maggio Elena D’Alcamo |
| author_sort | Fabiana D’Esposito |
| collection | DOAJ |
| description | <i>Background and Objectives</i>. Retinitis pigmentosa (RP) is the most common inherited rod–cone dystrophy (RCD), resulting in nyctalopia, progressive visual field, and visual acuity decay in the late stages. The autosomal dominant form (ADRP) accounts for about 20% of RPs. Among the over 30 genes found to date related to ADRP, <i>RP1</i> pathogenic variants have been identified in 5–10% of cases. In a cohort of RCD patients from the Palermo province on the island of Sicily, we identified a prevalent nonsense variant in <i>RP1</i>, which was associated with ADRP. The objective of our study was to analyse the clinical and molecular data of this patient cohort and to evaluate the potential presence of a founder effect. <i>Materials and Methods</i>. From 2005 to January 2023, 84 probands originating from Western Sicily (Italy) with a diagnosis of RCD or RP and their relatives underwent deep phenotyping, which was performed in various Italian clinical institutions. Molecular characterisation of patients and familial segregation of pathogenic variants were carried out in different laboratories using Sanger and/or next-generation sequencing (NGS). <i>Results.</i> Among 84 probands with RCD/RP, we found 28 heterozygotes for the <i>RP1</i> variant c.2219C>G, p.Ser740* ((NM_006269.2)*, which was therefore significantly prevalent in this patient cohort. After a careful interview process, we ascertained that some of these patients shared the same pedigree. Therefore, we were ultimately able to define 20 independent family groups with no traceable consanguinity. Lastly, analysis of clinical data showed, in our patients, that the p.Ser740* nonsense variant was often associated with a late-onset and relatively mild phenotype. <i>Conclusions</i>. The high prevalence of the p.Ser740* variant in ADRP patients from Western Sicily suggests the presence of a founder effect, which has useful implications for the molecular diagnosis of RCD in patients coming from this Italian region. This variant can be primarily searched for in RP-affected subjects displaying compatible modes of transmission and phenotypes, with an advantage in terms of the required costs and time for analysis. Moreover, given its high prevalence, the <i>RP1</i> 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. |
| first_indexed | 2024-03-07T22:21:53Z |
| format | Article |
| id | doaj.art-83b2da28abdc4e8788f1ab43b53ceb6c |
| institution | Directory Open Access Journal |
| issn | 1010-660X 1648-9144 |
| language | English |
| last_indexed | 2024-03-07T22:21:53Z |
| publishDate | 2024-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Medicina |
| spelling | doaj.art-83b2da28abdc4e8788f1ab43b53ceb6c2024-02-23T15:26:33ZengMDPI AGMedicina1010-660X1648-91442024-02-0160225410.3390/medicina60020254<i>RP1</i> Dominant p.Ser740* Pathogenic Variant in 20 Knowingly Unrelated Families Affected by Rod–Cone Dystrophy: Potential Founder Effect in Western SicilyFabiana D’Esposito0Viviana Randazzo1Maria Igea Vega2Gabriella Esposito3Paolo Enrico Maltese4Salvatore Torregrossa5Paola Scibetta6Florinda Listì7Caterina Gagliano8Lucia Scalia9Antonino Pioppo10Antonio Marino11Marco Piergentili12Emanuele Malvone13Tiziana Fioretti14Angela Vitrano15Maria Piccione16Teresio Avitabile17Francesco Salvatore18Matteo Bertelli19Ciro Costagliola20Maria Francesca Cordeiro21Aurelio Maggio22Elena D’Alcamo23Imperial College Ophthalmic Research Group (ICORG) Unit, Imperial College, London SW7 2AZ, UKEye Clinic, AOOR Villa Sofia-Cervello, 90100 Palermo, ItalyDepartment of Genetics, Oncohaematology and Rare Diseases, AOOR Villa Sofia-Cervello, 90100 Palermo, ItalyDepartment of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, 80100 Naples, ItalyMAGI’S Lab s.r.l., 38068 Rovereto, ItalyEye Clinic, AOOR Villa Sofia-Cervello, 90100 Palermo, ItalyEye Clinic, AOOR Villa Sofia-Cervello, 90100 Palermo, ItalyDepartment of Genetics, Oncohaematology and Rare Diseases, AOOR Villa Sofia-Cervello, 90100 Palermo, ItalyDepartment of Medicine and Surgery, School of Medicine, Kore University of Enna, 94100 Enna, ItalyEye Clinic, Catania University, Policlinico “Rodolico”-San Marco, 95100 Catania, ItalyEye Clinic, ARNAS Civico, 90100 Palermo, ItalyDepartment of Ophthalmology, Garibaldi Hospital, 95100 Catania, ItalyDepartment of Ophthalmology, Careggi Teaching Hospital, 50100 Florence, ItalyEye Clinic, Department of Neurosciences, Reproductive Sciences and Dentistry, University of Naples Federico II, 80100 Naples, ItalyCEINGE-Advanced Biotechnologies Franco Salvatore, 80100 Naples, ItalyDepartment of Genetics, Oncohaematology and Rare Diseases, AOOR Villa Sofia-Cervello, 90100 Palermo, ItalyDepartment of Genetics, Oncohaematology and Rare Diseases, AOOR Villa Sofia-Cervello, 90100 Palermo, ItalyEye Clinic, Catania University, Policlinico “Rodolico”-San Marco, 95100 Catania, ItalyDepartment of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, 80100 Naples, ItalyMAGI Euregio, 39100 Bolzano, ItalyEye Clinic, Department of Neurosciences, Reproductive Sciences and Dentistry, University of Naples Federico II, 80100 Naples, ItalyImperial College Ophthalmic Research Group (ICORG) Unit, Imperial College, London SW7 2AZ, UKDepartment of Genetics, Oncohaematology and Rare Diseases, AOOR Villa Sofia-Cervello, 90100 Palermo, ItalyDepartment of Genetics, Oncohaematology and Rare Diseases, AOOR Villa Sofia-Cervello, 90100 Palermo, Italy<i>Background and Objectives</i>. Retinitis pigmentosa (RP) is the most common inherited rod–cone dystrophy (RCD), resulting in nyctalopia, progressive visual field, and visual acuity decay in the late stages. The autosomal dominant form (ADRP) accounts for about 20% of RPs. Among the over 30 genes found to date related to ADRP, <i>RP1</i> pathogenic variants have been identified in 5–10% of cases. In a cohort of RCD patients from the Palermo province on the island of Sicily, we identified a prevalent nonsense variant in <i>RP1</i>, which was associated with ADRP. The objective of our study was to analyse the clinical and molecular data of this patient cohort and to evaluate the potential presence of a founder effect. <i>Materials and Methods</i>. From 2005 to January 2023, 84 probands originating from Western Sicily (Italy) with a diagnosis of RCD or RP and their relatives underwent deep phenotyping, which was performed in various Italian clinical institutions. Molecular characterisation of patients and familial segregation of pathogenic variants were carried out in different laboratories using Sanger and/or next-generation sequencing (NGS). <i>Results.</i> Among 84 probands with RCD/RP, we found 28 heterozygotes for the <i>RP1</i> variant c.2219C>G, p.Ser740* ((NM_006269.2)*, which was therefore significantly prevalent in this patient cohort. After a careful interview process, we ascertained that some of these patients shared the same pedigree. Therefore, we were ultimately able to define 20 independent family groups with no traceable consanguinity. Lastly, analysis of clinical data showed, in our patients, that the p.Ser740* nonsense variant was often associated with a late-onset and relatively mild phenotype. <i>Conclusions</i>. The high prevalence of the p.Ser740* variant in ADRP patients from Western Sicily suggests the presence of a founder effect, which has useful implications for the molecular diagnosis of RCD in patients coming from this Italian region. This variant can be primarily searched for in RP-affected subjects displaying compatible modes of transmission and phenotypes, with an advantage in terms of the required costs and time for analysis. Moreover, given its high prevalence, the <i>RP1</i> 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.https://www.mdpi.com/1648-9144/60/2/254rod–cone dystrophyretinitis pigmentosa<i>RP1</i> genefounder effectinherited retinal dystrophiesfounder mutation |
| spellingShingle | Fabiana D’Esposito Viviana Randazzo Maria Igea Vega Gabriella Esposito Paolo Enrico Maltese Salvatore Torregrossa Paola Scibetta Florinda Listì Caterina Gagliano Lucia Scalia Antonino Pioppo Antonio Marino Marco Piergentili Emanuele Malvone Tiziana Fioretti Angela Vitrano Maria Piccione Teresio Avitabile Francesco Salvatore Matteo Bertelli Ciro Costagliola Maria Francesca Cordeiro Aurelio Maggio Elena D’Alcamo <i>RP1</i> Dominant p.Ser740* Pathogenic Variant in 20 Knowingly Unrelated Families Affected by Rod–Cone Dystrophy: Potential Founder Effect in Western Sicily Medicina rod–cone dystrophy retinitis pigmentosa <i>RP1</i> gene founder effect inherited retinal dystrophies founder mutation |
| title | <i>RP1</i> Dominant p.Ser740* Pathogenic Variant in 20 Knowingly Unrelated Families Affected by Rod–Cone Dystrophy: Potential Founder Effect in Western Sicily |
| title_full | <i>RP1</i> Dominant p.Ser740* Pathogenic Variant in 20 Knowingly Unrelated Families Affected by Rod–Cone Dystrophy: Potential Founder Effect in Western Sicily |
| title_fullStr | <i>RP1</i> Dominant p.Ser740* Pathogenic Variant in 20 Knowingly Unrelated Families Affected by Rod–Cone Dystrophy: Potential Founder Effect in Western Sicily |
| title_full_unstemmed | <i>RP1</i> Dominant p.Ser740* Pathogenic Variant in 20 Knowingly Unrelated Families Affected by Rod–Cone Dystrophy: Potential Founder Effect in Western Sicily |
| title_short | <i>RP1</i> Dominant p.Ser740* Pathogenic Variant in 20 Knowingly Unrelated Families Affected by Rod–Cone Dystrophy: Potential Founder Effect in Western Sicily |
| title_sort | i rp1 i dominant p ser740 pathogenic variant in 20 knowingly unrelated families affected by rod cone dystrophy potential founder effect in western sicily |
| topic | rod–cone dystrophy retinitis pigmentosa <i>RP1</i> gene founder effect inherited retinal dystrophies founder mutation |
| url | https://www.mdpi.com/1648-9144/60/2/254 |
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