Identification of a novel MYO7A mutation in Usher syndrome type 1.

Ling Cheng,Li Zhang,Hongsong Yu,Sisi Pu,Yan Jiang,Juan He,Xin Li

doi:10.18632/oncotarget.23408

Ling Cheng, Li Zhang + Show 5 more

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https://doi.org/10.18632/oncotarget.23408

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Usher syndrome (USH) is an autosomal recessive disease characterized by deafness and retinitis pigmentosa. In view of the high phenotypic and genetic heterogeneity in USH, performing genetic screening with traditional methods is impractical. In the present study, we carried out targeted next-generation sequencing (NGS) to uncover the underlying gene in an USH family (2 USH patients and 15 unaffected relatives). One hundred and thirty-five genes associated with inherited retinal degeneration were selected for deep exome sequencing. Subsequently, variant analysis, Sanger validation and segregation tests were utilized to identify the disease-causing mutations in this family. All affected individuals had a classic USH type I (USH1) phenotype which included deafness, vestibular dysfunction and retinitis pigmentosa. Targeted NGS and Sanger sequencing validation suggested that USH1 patients carried an unreported splice site mutation, c.5168+1G>A, as a compound heterozygous mutation with c.6070C>T (p.R2024X) in the MYO7A gene. A functional study revealed decreased expression of the MYO7A gene in the individuals carrying heterozygous mutations. In conclusion, targeted next-generation sequencing provided a comprehensive and efficient diagnosis for USH1. This study revealed the genetic defects in the MYO7A gene and expanded the spectrum of clinical phenotypes associated with USH1 mutations.

Highlights

Usher syndrome (USH) is recognized as the most common form of hereditary deaf-blindness [1]
This study revealed the genetic defects in the MYO7A gene and expanded the spectrum of clinical phenotypes associated with USH1 mutations
We identified a novel MYO7A splicing site mutation (c.5168+1G>A) in a Chinese USH1 family, and found that the compound heterozygous mutations c.6070C>T (p.R2024X) and c.5168+1G>A in the MYO7A gene could lead to USH1

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Introduction

Usher syndrome (USH) is recognized as the most common form of hereditary deaf-blindness [1]. USH is an autosomal recessive disease that is characterized by clinical and genetic heterogeneity. The frequency of USH has been reported to range from 3.8 to 6.2/100 000 in different countries, such as Spain, Denmark and the United States [2,3,4]. The prevalence of USH in China has not been reported. The classification of USH is mainly based on the severity and progression of hearing loss (HL), the status of vestibular function and age at onset of retinitis pigmentosa (RP). Patients with USH1 typically have profound and congenital HL, which is further accompanied by vestibular areflexia and progressive RP of prepubertal onset. Patients with USH2 present with moderate-to-severe HL with downsloping pure tone audiograms, normal vestibular function, www.impactjournals.com/oncotarget and RP in adolescence. USH3 is very rare and variable in presentation. It may resemble USH1 or USH2, and vestibular dysfunction may be present [5]

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