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Mutational screening of the USH2A gene in Spanish USH patients reveals 23 novel pathogenic mutations

Gema Garcia-Garcia1, Maria J Aparisi1, Teresa Jaijo12, Regina Rodrigo1, Ana M Leon2, Almudena Avila-Fernandez23, Fiona Blanco-Kelly3, Sara Bernal24, Rafael Navarro5, Manuel Diaz-Llopis6, Montserrat Baiget24, Carmen Ayuso23, Jose M Millan127* and Elena Aller12

Author Affiliations

1 Grupo de Investigación en Enfermedades Neurosensoriales. Instituto de Investigación Sanitaria IIS-La Fe, Valencia, Spain

2 CIBER de Enfermedades Raras (CIBERER), Valencia, Spain

3 Servicio de Genética, Fundación Jiménez Díaz, Madrid, Spain

4 Servei de Genètica, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

5 Instituto de Microcirugía Ocular, Barcelona, Spain

6 Servicio de Oftalmología, Hospital Universitario La Fe, Valencia, Spain

7 Unidad de Genética y Diagnóstico Prenatal, Hospital Universitario La Fe, Valencia, Spain

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Orphanet Journal of Rare Diseases 2011, 6:65  doi:10.1186/1750-1172-6-65

Published: 17 October 2011



Usher Syndrome type II (USH2) is an autosomal recessive disorder, characterized by moderate to severe hearing impairment and retinitis pigmentosa (RP). Among the three genes implicated, mutations in the USH2A gene account for 74-90% of the USH2 cases.


To identify the genetic cause of the disease and determine the frequency of USH2A mutations in a cohort of 88 unrelated USH Spanish patients, we carried out a mutation screening of the 72 coding exons of this gene by direct sequencing. Moreover, we performed functional minigene studies for those changes that were predicted to affect splicing.


As a result, a total of 144 DNA sequence variants were identified. Based upon previous studies, allele frequencies, segregation analysis, bioinformatics' predictions and in vitro experiments, 37 variants (23 of them novel) were classified as pathogenic mutations.


This report provide a wide spectrum of USH2A mutations and clinical features, including atypical Usher syndrome phenotypes resembling Usher syndrome type I. Considering only the patients clearly diagnosed with Usher syndrome type II, and results obtained in this and previous studies, we can state that mutations in USH2A are responsible for 76.1% of USH2 disease in patients of Spanish origin.

Usher Syndrome; USH2A; Mutations; Sequence Variants