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Grant support

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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Garcia-Sandoval, BlancaAuthorMahillo-Fernandez, IgnacioAuthorAyuso, CarmenAuthor
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Article

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

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

Authors: 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;

Affiliations

ISCIII, Ctr Biomed Network Res Rare Dis CIBERER, Madrid, Spain. - Author

Abstract

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.

Keywords
GeneHair-cellsHearing-lossMolecular diagnosisMutation spectrumRecessive retinitis-pigmentosaRetinal dystrophiesSyndrome type-iiUsher-syndromeVisual-acuity

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal PLoS ONE due to its progression and the good impact it has achieved in recent years, according to the agency Scopus (SJR), it has become a reference in its field. In the year of publication of the work, 2018, it was in position , thus managing to position itself as a Q1 (Primer Cuartil), in the category Agricultural and Biological Sciences (Miscellaneous).

From a relative perspective, and based on the normalized impact indicator calculated from World Citations from Scopus Elsevier, it yields a value for the Field-Weighted Citation Impact from the Scopus agency: 1.34, which indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Field Citation Ratio (FCR) from Dimensions: 3.24 (source consulted: Dimensions May 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-05-14, the following number of citations:

  • WoS: 17
  • Scopus: 17
  • Europe PMC: 13
  • OpenCitations: 17
Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-05-14:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 59.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 59 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 1.5.
  • The number of mentions on the social network X (formerly Twitter): 2 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.
Leadership analysis of institutional authors

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: Last Author (AYUSO GARCIA, MARIA DEL CARMEN TOMASA).