Clinical aspects of Usher syndrome and the USH2A gene in a cohort of 433 patients.
OBJECTIVE
A new statistical approach is needed to describe the clinical differences between type I and type II Usher syndrome and between the 2 most frequent mutations in the USH2A gene.


OBJECTIVE
To describe the primary phenotypic characteristics and differences between type I and type II Usher syndrome and to establish a phenotype-genotype correlation for the 2 most frequent mutations in the USH2A gene.


METHODS
Cross-sectional study at a genetics department, in which clinical evaluations were performed for 433 patients (297 unrelated families) who were classified as having type I, II, III, atypical, or unclassified Usher syndrome according to their clinical history, pedigree data, results from ophthalmological studies, and audiological, neurophysiological, and vestibular test results. Molecular studies were performed for 304 patients (256 unrelated families). The Mann-Whitney U test or the χ2 test was used for calculating the differences between mean values for the analyzed parameters.


METHODS
Age at diagnosis; age at onset of night blindness, visual field loss, visual acuity loss, and cataracts; and severity and age at diagnosis of hearing loss.


RESULTS
The comparison between patients with type I Usher syndrome and those with type II Usher syndrome revealed P < .001 for most items analyzed. The most frequent mutations in the USH2A gene were the p.Glu767Serfs*21 and p.Cys759Phe mutations, with an allelic frequency of 23.2% (63 of 272 alleles) and 8.1% (22 of 272 alleles), respectively. The phenotypic analysis for patients carrying p.Cys759Phe showed P < .001 for most items analyzed when compared with patients carrying p.Glu767Serfs*21 and when compared with patients carrying other mutations in the USH2A gene. None of the p.Cys759Phe patients exhibited a severe hearing loss phenotype, and more than 60% had only mild hearing loss. Most patients carrying the p.Glu767Serfs*21 mutation (72.1%) were moderately deaf.


CONCLUSIONS
Our study presents the clinical differences between type I and type II Usher syndrome and between the 2 most frequent mutations in the USH2A gene. Detailed genotype-phenotype correlations, as presented in our study, allow for a better correlation of clinical signs with a known genotype and can improve the clinical management, genetic counseling, and risk assessment of patients with Usher syndrome because an estimated prognosis of their disease can be made.
Servicio de Genética, Instituto de Investigación-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain2Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain.
Fiona
F
Blanco-Kelly
Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain3Grupo de Investigación en Enfermedades Neurosensoriales, Instituto de Investigación Sanitaria-La Fe, Valencia, Spain.
Teresa
T
Jaijo
Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain3Grupo de Investigación en Enfermedades Neurosensoriales, Instituto de Investigación Sanitaria-La Fe, Valencia, Spain.
Elena
E
Aller
Servicio de Genética, Instituto de Investigación-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain2Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain.
Almudena
A
Avila-Fernandez
Department of Ophthalmology, Instituto de Investigación-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain.
María Isabel
MI
López-Molina
Servicio de Genética, Instituto de Investigación-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain.
Ascensión
A
Giménez
Department of Ophthalmology, Instituto de Investigación-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain.
Blanca
B
García-Sandoval
Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain3Grupo de Investigación en Enfermedades Neurosensoriales, Instituto de Investigación Sanitaria-La Fe, Valencia, Spain5Unidad de Genética y Diagnóstico Prenatal, Hospital Universi.
José M
JM
Millán
Servicio de Genética, Instituto de Investigación-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain2Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain.
Carmen
C
Ayuso
D000293:Adolescent; D000328:Adult; D001299:Audiometry; D003430:Cross-Sectional Studies; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D004596:Electroretinography; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D009887:Ophthalmoscopy; D010375:Pedigree; D010641:Phenotype; D012189:Retrospective Studies; D052245:Usher Syndromes / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
D016326:Extracellular Matrix Proteins; C112735:USH2A protein, human; D004247:DNA