Original Article Clinical and genetic studies in Spanish patients with Usher syndrome type II: description of new mutations and evidence for a lack of genotype–phenotype correlation Bernal S, Meda` C, Solans T, Ayuso C, Garcia-Sandoval B, Valverde D, Del Rio E, Baiget M. Clinical and genetic studies in Spanish patients with Usher syndrome type II: description of new mutations and evidence for a lack of genotype–phenotype correlation. Clin Genet 2005: 68: 204–214. # Blackwell Munksgaard, 2005 Patients with Usher syndrome type II (USH2) show moderate-to-severe hearing loss (HL), retinitis pigmentosa and normal vestibular function. The progression of HL remains controversial. To evaluate whether a phenotype–genotype correlation exists regarding the issue of progres- sion of HL, only USH2 patients with a defined genotype were selected. Ophthalmologic, vestibular and audiometric examination along with a mutation analysis of the USH2A gene (exons 1–21) was performed in twenty-eight Spanish USH2 patients. Ten different pathogenic muta- tions and 17 sequence variants not associated with the disease were found. Six of the 10 mutations are novel. Disease alleles were identified in 13 of the 28 families tested. Eight of these 13 families had a mutation found in both alleles. In the other five families, only one mutation was identified. The phenotypic data provide evidence for the existence of phenotypic differences between patients with the same genotype. These differences were observed at both the interfamilial and intrafamilial levels. S Bernal a , C Meda ` b , T Solans c , C Ayuso d , B Garcia-Sandoval e , D Valverde f , E Del Rio a and M Baiget a a Servei de Gene ` tica, b Servei d’Otorrinolaringologia, c Servei d’Oftalmologia del Hospital de la Santa Creu i Sant Pau, Barcelona, d Servicio de Gene ´ tica, e Servicio de Oftalmologia de la Fundacio ´n Jime ´nez Dı ´az, Madrid, and f Facultad de Ciencias, Universidad de Vigo, Vigo, Spain Key words: hearing loss – Usher syn- drome type II – USH2A gene mutations Corresponding author: M. Baiget, Servei de Gene ` tica. Hospital de la Santa Creu i Sant Pau, Pare Claret 167, 08025 Barcelona, Spain. Tel.: þ34 93 2919194; fax: þ34 93 3919494; e-mail: mbaiget@hsp.santpau.es Received 30 March 2005, revised and accepted for publication 17 May 2005 Usher syndrome comprises a group of autosomal recessive disorders characterized by sensorineural hearing impairment and retinitis pigmentosa (RP). Despite the fact that Usher patients suffer progressive RP, three clinical types have been described on the basis of the severity and pro- gression of hearing loss (HL) and the presence or absence of vestibular impairment. Usher syn- drome type I (USH1) is characterized by pro- found HL and vestibular areflexia from birth, whereas Usher syndrome type II (USH2) presents from moderate-to-severe HL with down-sloping pure-tone audiograms and normal vestibular function. Usher syndrome type III (USH3) exhibits progressive hearing impairment and variation in vestibular responses between patients (1, 2). A number of genetic subtypes have been iden- tified for the three clinical types of Usher syn- drome. To date, 11 loci (USH1A–USH1G, USH2A–USH2C and USH3) are known, and the corresponding genes have been identified for eight of these (USH1B/MYO7A, USH1C/USH1C, USH1D/CDH23, USH1F/PCDH15, USH1G/ SANS, USH2A/USH2A, USH2C/VLGR1 and USH3/USH3) (hereditary HL homepage: http:// dnalab-http://www.uia.ac.be/dnalab/hhh/). USH2 is the most common form of Usher syn- drome and may account for more than 50% of all Usher subjects. Moreover, USH2A could be responsible for as many as 74–83% of the USH2 cases (3–5). In 1998, a defect of the gene encoding a novel protein, Usherin, was found to account for the Clin Genet 2005: 68: 204–214 Copyright # Blackwell Munksgaard 2005 Printed in Singapore. All rights reserved CLINICAL GENETICS doi: 10.1111/j.1399-0004.2005.00481.x 204