Inmaculada Martin-Merida1, Almudena Avila-Fernandez1, Marta Del Pozo-Valero2, Fiona Blanco-Kelly1, Olga Zurita1, Raquel Perez-Carro1, Domingo Aguilera-Garcia2, Rosa Riveiro-Alvarez1, Ana Arteche2, Maria Jose Trujillo-Tiebas1, Saoud Tahsin-Swafiri2, Elvira Rodriguez-Pinilla2, Isabel Lorda-Sanchez2, Blanca Garcia-Sandoval3, Marta Corton1, Carmen Ayuso4. 1. Department of Genetics, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital-Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain; Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain. 2. Department of Genetics, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital-Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain. 3. Department of Ophthalmology, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital-Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain. 4. Department of Genetics, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital-Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain; Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain. Electronic address: cayuso@fjd.es.
Abstract
PURPOSE: We aimed to unravel the molecular basis of sporadic retinitis pigmentosa (sRP) in the largest cohort reported to date. DESIGN: Case series. PARTICIPANTS: A cohort of 877 unrelated Spanish sporadic cases with a clinical diagnosis of retinitis pigmentosa (RP) and negative family history. METHODS: The cohort was studied by classic genotyping or targeted next-generation sequencing (NGS). Multiplex ligation-dependent probe amplification (MLPA) and array-based comparative genomic hybridization were performed to confirm copy number variations detected by NGS. Quantitative fluorescent polymerase chain reaction was assessed in sRP cases carrying de novo variants to confirm paternity. MAIN OUTCOME MEASURES: The study of the sRP cohort showed a high proportion of causal autosomal dominant (AD) and X-linked (XL) variants, most of them being de novo. RESULTS: Causative variants were identified in 38% of the patients studied, segregating recessively in 84.5% of the solved cases. Biallelic variants detected in only 6 different autosomal recessive genes explained 50% of the cases characterized. Causal AD and XL variants were found in 7.6% and 7.9% of cases, respectively. Remarkably, 20 de novo variants were confirmed after trio analysis, explaining 6% of the cases. In addition, 17% of the solved sRP cases were reclassified to a different retinopathy phenotype. CONCLUSIONS: This study highlights the clinical utility of NGS testing for sRP cases, expands the mutational spectrum, and provides accurate prevalence of mutated genes. Our findings evidence the underestimated role of de novo variants in the etiology of RP, emphasizing the importance of segregation analysis as well as comprehensive screening of genes carrying XL and AD variants in sporadic cases. Such in-depth study is essential for accurate family counseling and future enrollment in gene therapy-based treatments.
PURPOSE: We aimed to unravel the molecular basis of sporadic retinitis pigmentosa (sRP) in the largest cohort reported to date. DESIGN: Case series. PARTICIPANTS: A cohort of 877 unrelated Spanish sporadic cases with a clinical diagnosis of retinitis pigmentosa (RP) and negative family history. METHODS: The cohort was studied by classic genotyping or targeted next-generation sequencing (NGS). Multiplex ligation-dependent probe amplification (MLPA) and array-based comparative genomic hybridization were performed to confirm copy number variations detected by NGS. Quantitative fluorescent polymerase chain reaction was assessed in sRP cases carrying de novo variants to confirm paternity. MAIN OUTCOME MEASURES: The study of the sRP cohort showed a high proportion of causal autosomal dominant (AD) and X-linked (XL) variants, most of them being de novo. RESULTS: Causative variants were identified in 38% of the patients studied, segregating recessively in 84.5% of the solved cases. Biallelic variants detected in only 6 different autosomal recessive genes explained 50% of the cases characterized. Causal AD and XL variants were found in 7.6% and 7.9% of cases, respectively. Remarkably, 20 de novo variants were confirmed after trio analysis, explaining 6% of the cases. In addition, 17% of the solved sRP cases were reclassified to a different retinopathy phenotype. CONCLUSIONS: This study highlights the clinical utility of NGS testing for sRP cases, expands the mutational spectrum, and provides accurate prevalence of mutated genes. Our findings evidence the underestimated role of de novo variants in the etiology of RP, emphasizing the importance of segregation analysis as well as comprehensive screening of genes carrying XL and AD variants in sporadic cases. Such in-depth study is essential for accurate family counseling and future enrollment in gene therapy-based treatments.
Authors: Imen Habibi; Yosra Falfoul; Ahmed Turki; Asma Hassairi; Khaled El Matri; Ahmed Chebil; Daniel F Schorderet; Leila El Matri Journal: Sci Rep Date: 2020-07-08 Impact factor: 4.379
Authors: Nikolas Pontikos; Gavin Arno; Neringa Jurkute; Elena Schiff; Rola Ba-Abbad; Samantha Malka; Ainoa Gimenez; Michalis Georgiou; Genevieve Wright; Monica Armengol; Hannah Knight; Menachem Katz; Mariya Moosajee; Patrick Yu-Wai-Man; Anthony T Moore; Michel Michaelides; Andrew R Webster; Omar A Mahroo Journal: Ophthalmology Date: 2020-04-16 Impact factor: 12.079
Authors: Andrey V Marakhonov; Anna A Voskresenskaya; Maria Jose Ballesta; Fedor A Konovalov; Tatyana A Vasilyeva; Fiona Blanco-Kelly; Nadezhda A Pozdeyeva; Vitaly V Kadyshev; Vanesa López-González; Encarna Guillen; Carmen Ayuso; Rena A Zinchenko; Marta Corton Journal: Orphanet J Rare Dis Date: 2020-08-13 Impact factor: 4.123