Clinical Aspects of Usher Syndrome and theUSH2AGene in a Cohort of 433 Patients

Abstract

IMPORTANCE 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. OBJECTIVES 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. DESIGN, SETTING, AND PARTICIPANTS 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 χ 2 test was used for calculating the differences between mean values for the analyzed parameters. MAIN OUTCOMES AND MEASURES 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 AND RELEVANCE 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.

Identification of the genetic determinants responsible for retinal degeneration in families of Mexican descent

“…Mex RD1 had compound heterozygous mutations; a novel nonsense variant c.10820A>C (p.His3607Pro) and a previously reported mutation c. 11864G>A (p.Trp3955*) (25). A previously reported homozygous USH2A mutation c. 2276G>T (p.Cys759Phe) was observed in the Mex RD101 pedigree (Table 1)(26, 27). Neither of the two affected siblings of Mex RD1 (Fig 1B) had sensorineural hearing loss.…”

Genome-Wide Detection of Copy Number Variations in Unsolved Inherited Retinal Disease

“…Notably, mutations in USH2A could lead to Usher syndrome or RP. 21 In this study, patient F1:II:2 was clinically diagnosed to suffer from RP. Our data also provide novel genotype-phenotype correlations in cases of IRDs.…”

Severe or Profound Sensorineural Hearing Loss Caused by Novel <i>USH2A</i> Variants in Korea: Potential Genotype-Phenotype Correlation

“…Diverse audiological phenotypes from mild to profound hearing loss have been reported in USH2A variants [18,19,31], although most patients exhibited a moderate degree of hearing loss. By reporting two novel variants of USH2A, our findings provide novel insights regarding the expansion of audiological spectrum from moderate to severe SNHL to more than severe SNHL in Koreans, supporting the diverse auditory phenotype of USH2.…”

“…However, it has recently been suggested that there is evidence of genotype-phenotype correlation for some known USH2A variants. In detail, based on a large cohort study evaluating patients diagnosed with USH, most carriers of p.Glu767Serfs*21 variant showed moderate deafness, whereas patients with p. Cys759Phe variant exhibited only mild hearing loss [31]. Furthermore, a recent study suggested that an alternative allele may contribute to the variation in auditory manifestation [18].…”