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This project was financially supported by the Center for Biomedical Network Research on Rare Diseases (CIBERER), FIS (PI16/00425 and PI16/00539) from Institute of Health Carlos III (ISCIII, Spanish Ministry of the Economy, Industry and Competitiveness), the European Regional Development Fund (ERDF), the Ramon Areces Foundation, the IIS-Fundacion Jimenez Diaz-UAM Genome Medicine Chair, the Spanish National Organization of the Blind (ONCE) and the Spanish Fighting Blindness Foundation (FUNDALUCE). RP-C were sponsored by the Conchita Rabago Foundation, and LG-M and IM-M by the Rio Hortega Programs (CM16/00126 and CM14/00079, respectively) from ISCIII. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Unravelling the pathogenic role and genotype-phenotype correlation of the USH2A p.(Cys759Phe) variant among Spanish families

Publicado en:PLoS ONE. 13 (6): e0199048- - 2018-06-01 13(6), DOI: 10.1371/journal.pone.0199048

Autores: Perez-Carro, Raquel; Blanco-Kelly, Fiona; Galbis-Martinez, Lilian; Garcia-Garcia, Gema; Aller, Elena; Garcia-Sandoval, Blanca; Minguez, Pablo; Corton, Marta; Mahillo-Fernandez, Ignacio; Martin-Merida, Inmaculada; Avila-Fernandez, Almudena; Millan, Jose M.; Ayuso, Carmen;

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Introduction Mutations in USH2A cause both isolated Retinitis Pigmentosa (RP) and Usher syndrome (that implies RP and hearing impairment). One of the most frequent variants identified in this gene and among these patients is the p.(Cys759Phe) change. However, the pathogenic role of this allele has been questioned since it was found in homozygosity in two healthy siblings of a Spanish family. To assess the causative role of USH2A p.(Cys759Phe) in autosomal recessive RP (ARRP) and Usher syndrome type II (USH2) and to establish possible genotype-phenotype correlations associated with p.(Cys759Phe), we performed a comprehensive genetic and clinical study in patients suffering from any of the two above-mentioned diseases and carrying at least one p.(Cys759Phe) allele. Materials and methods Diagnosis was set according to previously reported protocols. Genetic analyses were performed by using classical molecular and Next-Generation Sequencing approaches. Probands of 57 unrelated families were molecularly studied and 63 patients belonging to these families were phenotypically evaluated. Results Molecular analysis characterized 100% of the cases, identifying: 11 homozygous patients for USH2A p.(Cys759Phe), 42 compound heterozygous patients (12 of them with another missense USH2A pathogenic variant and 30 with a truncating USH2A variant), and 4 patients carrying the p.(Cys759Phe) allele and a pathogenic variant in another RP gene (PROM1, CNGB1 or RP1). No additional causative variants were identified in symptomatic homozygous patients. Statistical analysis of clinical differences between zygosity states yielded differences (p <= 0.05) in age at diagnosis of RP and hypoacusis, and progression of visual field loss. Homozygosity of p.(Cys759Phe) and compound heterozygosity with another USH2A missense variant is associated with ARRP or ARRP plus late onset hypoacusis (OR = 20.62, CI = 95%, p = 0.041). Conclusions The present study supports the role of USH2A p.(Cys759Phe) in ARRP and USH2 pathogenesis, and demonstrates the clinical differences between different zygosity states. Phenotype-genotype correlations may guide the genetic characterization based upon specific clinical signs and may advise on the clinical management and prognosis based upon a specific genotype.

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