Inmaculada Martin-Merida1,2, Domingo Aguilera-Garcia1, Jose P Fernandez-San1,2, Fiona Blanco-Kelly1,2, Olga Zurita1,2, Berta Almoguera1,3, Blanca Garcia-Sandoval4, Almudena Avila-Fernandez1,2, Ana Arteche1, Pablo Minguez1, Miguel Carballo5, Marta Corton1,2, Carmen Ayuso1,2. 1. Department of Genetics, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital-Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain. 2. Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain. 3. Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States. 4. Department of Ophthalmology, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital-Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain. 5. Molecular Genetics Unit, Hospital de Terrassa, Terrassa, Barcelona, Spain.
Abstract
Purpose: To provide a comprehensive overview of the molecular basis of autosomal dominant retinitis pigmentosa (adRP) in Spanish families. Thus, we established the molecular characterization rate, gene prevalence, and mutational spectrum in the largest European cohort reported to date. Methods: A total of 258 unrelated Spanish families with a clinical diagnosis of RP and suspected autosomal dominant inheritance were included. Clinical diagnosis was based on complete ophthalmologic examination and family history. Retrospective and prospective analysis of Spanish adRP families was carried out using a combined strategy consisting of classic genetic techniques and next-generation sequencing (NGS) for single-nucleotide variants and copy number variation (CNV) screening. Results: Overall, 60% of our families were genetically solved. Interestingly, 3.1% of the cohort carried pathogenic CNVs. Disease-causing variants were found in an autosomal dominant gene in 55% of the families; however, X-linked and autosomal recessive forms were also identified in 3% and 2%, respectively. Four genes (RHO, PRPF31, RP1, and PRPH2) explained up to 62% of the solved families. Missense changes were most frequently found in adRP-associated genes; however, CNVs represented a relevant disease cause in PRPF31- and CRX-associated forms. Conclusions: Implementation of NGS technologies in the adRP study clearly increased the diagnostic yield compared with classic approaches. Our study outcome expands the spectrum of disease-causing variants, provides accurate data on mutation gene prevalence, and highlights the implication of CNVs as important contributors to adRP etiology.
Purpose: To provide a comprehensive overview of the molecular basis of autosomal dominant retinitis pigmentosa (adRP) in Spanish families. Thus, we established the molecular characterization rate, gene prevalence, and mutational spectrum in the largest European cohort reported to date. Methods: A total of 258 unrelated Spanish families with a clinical diagnosis of RP and suspected autosomal dominant inheritance were included. Clinical diagnosis was based on complete ophthalmologic examination and family history. Retrospective and prospective analysis of Spanish adRP families was carried out using a combined strategy consisting of classic genetic techniques and next-generation sequencing (NGS) for single-nucleotide variants and copy number variation (CNV) screening. Results: Overall, 60% of our families were genetically solved. Interestingly, 3.1% of the cohort carried pathogenic CNVs. Disease-causing variants were found in an autosomal dominant gene in 55% of the families; however, X-linked and autosomal recessive forms were also identified in 3% and 2%, respectively. Four genes (RHO, PRPF31, RP1, and PRPH2) explained up to 62% of the solved families. Missense changes were most frequently found in adRP-associated genes; however, CNVs represented a relevant disease cause in PRPF31- and CRX-associated forms. Conclusions: Implementation of NGS technologies in the adRP study clearly increased the diagnostic yield compared with classic approaches. Our study outcome expands the spectrum of disease-causing variants, provides accurate data on mutation gene prevalence, and highlights the implication of CNVs as important contributors to adRP etiology.
Authors: Manon H C A Peeters; Mubeen Khan; Anoek A M B Rooijakkers; Timo Mulders; Lonneke Haer-Wigman; Camiel J F Boon; Caroline C W Klaver; L Ingeborgh van den Born; Carel B Hoyng; Frans P M Cremers; Anneke I den Hollander; Claire-Marie Dhaenens; Rob W J Collin Journal: Hum Mutat Date: 2021-09-20 Impact factor: 4.700
Authors: Gema García-García; Iker Sanchez-Navarro; Elena Aller; Teresa Jaijo; Carla Fuster-Garcia; Ana Rodríguez-Munoz; Elena Vallejo; Juan José Tellería; Selma Vázquez; Sergi Beltrán; Sophia Derdak; Olga Zurita; Cristina Villaverde-Montero; Almudena Avila-Fernández; Marta Corton; Fiona Blanco-Kelly; Hakon Hakonarson; José M Millán; Carmen Ayuso Journal: Mol Vis Date: 2020-03-18 Impact factor: 2.367
Authors: Marta Del Pozo-Valero; Rosa Riveiro-Alvarez; Inmaculada Martin-Merida; Fiona Blanco-Kelly; Saoud Swafiri; Isabel Lorda-Sanchez; Maria José Trujillo-Tiebas; Ester Carreño; Belen Jimenez-Rolando; Blanca Garcia-Sandoval; Marta Corton; Almudena Avila-Fernandez; Carmen Ayuso Journal: Invest Ophthalmol Vis Sci Date: 2022-02-01 Impact factor: 4.799