Genotypic and phenotypic characteristics of patients with USH2A variants

Objective To analyze the genotype and phenotype of patients with hearing loss and USH2A gene variants, in order to deliver precise genetic counseling. Methods USH2A variations were screened out from 547 patients with sensorineural hearing loss collected by genetic testing from 2015 to 2018 in Institute of Otolaryngology, Chinese PLA General Hospital. The pedigrees of patients with USH2A gene variant were drawn and their characteristics were analyzed. The pathogenicity of mutations were identified. Standard otology examination and audiological examination were carried out to analyze the degree of hearing loss and the type of hearing curve in patients with USH2A variants. The relationship between the age of onset and the degree of hearing loss was analyzed in patients with different USH2A gene mutations. Results We screened out 10 patients with USH2A gene variants from 547 patients with sensorineural hearing loss who underwent genetic testing, with a positive rate of 1.8%. The median age of hearing loss onset was 6 year-old （range, 7 months to 13 years）. One case had mild hearing loss, 1 case had moderate hearing loss, 6 cases had moderate to severe hearing loss, 1 case had severe hearing loss, and 1 case had profound hearing loss. The hearing loss in some patients had further progressed with age. According to audiogram shape, patients were divided into 3 groups, mild ski-slope loss type （2 cases）, flat loss type （3 cases）, steep drop in low frequency （125-500 Hz or 125-1 000 Hz） and flat loss in high frequency （500 -8 000 Hz） type （5 cases）. There were 20 different USH2A variant sites in these patients, of which 10 were never reported. The variations included 3 splice site variant: c.5572+1G>A, c.14969-2A>G, c.15297+1G>A; 3 frameshift variants: c.5548delT, c.6292₆296ATAAG>TA, c.7863delA; 4 missense variant: c.T3364G, c.11279G>C, c.13876C>G, c.14225C>T. Of the other 10 reported variants, 6 pathogenic ones were c.99₁00insT, c.187C>T, c.2797C>T, c.8559-2A>G, c.11156G>A, c.15104₁5105del. Two patients carried USH2A c.99₁00insT, accounting for 20% of the total variants, and the remaining variants were all detected in different patients. Of the 22 USH2A variant sites, 3 were located in exon 2. Conclusion We find 10 novel USH2A variants in 10 patients with hearing loss. In this cohort, c.99₁00insT is more common, and the hearing loss are more likely to be moderate to severe. Half patients are classified as low frequency steep drop and medium to high frequency flat type by audiogram shape. These findings provide clinical evidences for early diagnosis, early intervention and precise genetic counseling of USH2A.