Comprehensive Molecular Screening in Chinese Usher Syndrome Patients

Abstract

PURPOSE. Usher syndrome (USH) refers to a group of autosomal recessive disorders causing deafness and blindness. The objectives of this study were to determine the mutation spectrum in a cohort of Chinese patients with USH and to describe the clinical features of the patients with mutations. METHODS.A total of 119 probands who were clinically diagnosed with USH were recruited for genetic analysis. All probands underwent ophthalmic examinations. A combination of molecular screening methods, including targeted next-generation sequencing, Sanger-DNA sequencing, and multiplex ligation probe amplification assay, was used to detect mutations. RESULTS.We found biallelic mutations in 92 probands (77.3%), monoallelic mutations in 5 patients (4.2%), and 1 hemizygous mutation in 1 patient (0.8%), resulting in an overall mutation detection rate of 78.2%. Overall, 132 distinct disease-causing mutations involving seven USH (ABHD12, CDH23, GPR98, MYO7A, PCDH15, USH1C, and USH2A) genes; 5 other retinal degeneration genes (CHM, CNGA1, EYS, PDE6B, and TULP1); and 1 nonsyndromic hearing loss gene (MYO15A) were identified, and 78 were novel. Mutations of MYOA7 were responsible for 60% of USH1 families, followed by PCDH15 (20%) and USH1C (10%). Mutations of USH2A accounted for 67.7% of USH2 families, and mutation c.8559-2A>G was the most frequent one, accounting for 19.1% of the identified USH2A alleles. CONCLUSIONS.Our results confirm that the mutation spectrum for each USH gene in Chinese patients differs from those of other populations. The formation of the mutation profile for the Chinese population will enable a precise genetic diagnosis for USH patients in the future.

Identification of 13 novel USH2A mutations in Chinese retinitis pigmentosa and Usher syndrome patients by targeted next-generation sequencing

“…In our study, the patients with this mutation showed similar characteristics. In RP F3, the splice-site mutation c.8559-2A>G has been described in Japanese [19,20] and Chinese [10,14] USH II patients; however, this mutation is a frequent founder variant in Japanese USH II patients [20] and the most common mutation in Chinese USH II patients [10]. We have previously reported the presence of this mutation in combination with c.9570+1 G>A, another splice-site variant, in a USH II family [14].…”

“…The two new splice-site mutations c.8682−1 G>T and c.22+3 A>G were each predicted to introduce an ectopic splice site. The previously reported splice-site mutation c.8559-2 A>G was detected in proband F3-II-2 [10,14,20]. An online splice-site prediction software program indicated that this variant would abolish the splice acceptor site in exon 43, resulting in the skipping of this exon.…”

“…Targeted-exome sequencing (TES) based on next-generation sequencing (NGS) is a powerful, robust, precise, and cost-effective method for detecting genetic mutations in large genomic regions. However, only a small number of studies have been published on the USH2A mutation spectrum in Chinese RP and USH patients [10][11][12][13][14][15][16][17]. The genetic characteristics of Chinese USH patients differ from those of the other populations.…”

“…The genetic characteristics of Chinese USH patients differ from those of the other populations. For example, the mutation c.8559-2A > G in USH2A accounts for 19.1% in a Chinese USH II cohort [10], and 26% of all Western Japanese USH patients, but was never observed in Europeans. Furthermore, the full extent of genotype-phenotype correlations between USH2A mutations and RP and USH II symptoms in the Chinese population has not been elucidated.…”

In silico analysis of a novel causative mutation in Cadherin23 gene identified in an Omani family with hearing loss

“…It is found in 1 to 6% in the general population. However, in the Finnish and Ashkenazi Jews populations, it rises to about 40% [7][8][9][10]. So far, 13 genes have been identified to be involved in USH development (https://sph.uth.edu/ Retnet/sum-dis.htm).…”