Top

BMC Medical Genetics

Published in:

Open Access 01-12-2015 | Research article

Targeted exome sequencing reveals novel USH2A mutations in Chinese patients with simplex Usher syndrome

Authors: Hai-Rong Shu, Huai Bi, Yang-Chun Pan, Hang-Yu Xu, Jian-Xin Song, Jie Hu

Published in: BMC Medical Genetics | Issue 1/2015

Abstract

Background

Usher syndrome (USH) is an autosomal recessive disorder characterized by hearing impairment and vision dysfunction due to retinitis pigmentosa. Phenotypic and genetic heterogeneities of this disease make it impractical to obtain a genetic diagnosis by conventional Sanger sequencing.

Methods

In this study, we applied a next-generation sequencing approach to detect genetic abnormalities in patients with USH. Two unrelated Chinese families were recruited, consisting of two USH afflicted patients and four unaffected relatives. We selected 199 genes related to inherited retinal diseases as targets for deep exome sequencing. Through systematic data analysis using an established bioinformatics pipeline, all variants that passed filter criteria were validated by Sanger sequencing and co-segregation analysis.

Results

A homozygous frameshift mutation (c.4382delA, p.T1462Lfs*2) was revealed in exon20 of gene USH2A in the F1 family. Two compound heterozygous mutations, IVS47 + 1G > A and c.13156A > T (p.I4386F), located in intron 48 and exon 63 respectively, of USH2A, were identified as causative mutations for the F2 family. Of note, the missense mutation c.13156A > T has not been reported so far.

Conclusion

In conclusion, targeted exome sequencing precisely and rapidly identified the genetic defects in two Chinese USH families and this technique can be applied as a routine examination for these disorders with significant clinical and genetic heterogeneity.

Boughman JA, Vernon M, Shaver KA. Usher syndrome: definition and estimate of prevalence from two high-risk populations. J Chronic Dis. 1983;36(8):595–603.CrossRefPubMed

Besnard T, Vache C, Baux D, Larrieu L, Abadie C, Blanchet C, et al. Non-USH2A mutations in USH2 patients. Hum Mutat. 2012;33(3):504–10.CrossRefPubMed

Bonnet C, El-Amraoui A. Usher syndrome (sensorineural deafness and retinitis pigmentosa): pathogenesis, molecular diagnosis and therapeutic approaches. Curr Opin Neurol. 2012;25(1):42–9.CrossRefPubMed

Petit C. Usher syndrome: from genetics to pathogenesis. Annu Rev Genomics Hum Genet. 2001;2:271–97.CrossRefPubMed

Nakanishi H, Ohtsubo M, Iwasaki S, Hotta Y, Usami S, Mizuta K, et al. Novel USH2A mutations in Japanese Usher syndrome type 2 patients: marked differences in the mutation spectrum between the Japanese and other populations. J Hum Genet. 2011;56(7):484–90.CrossRefPubMed

Nakanishi H, Ohtsubo M, Iwasaki S, Hotta Y, Mizuta K, Mineta H, et al. Identification of 11 novel mutations in USH2A among Japanese patients with Usher syndrome type 2. Clin Genet. 2009;76(4):383–91.CrossRefPubMed

Bras J, Guerreiro R, Hardy J. Use of next-generation sequencing and other whole-genome strategies to dissect neurological disease. Nat Rev Neurosci. 2012;13(7):453–64.CrossRefPubMed

Huang XF, Xiang P, Chen J, Xing DJ, Huang N, Min Q, et al. Targeted exome sequencing identified novel USH2A mutations in Usher syndrome families. PLoS One. 2013;8(5), e63832.CrossRefPubMedPubMedCentral

Cox MP, Peterson DA, Biggs PJ. SolexaQA: At-a-glance quality assessment of Illumina second-generation sequencing data. BMC Bioinformatics. 2010;11:485.CrossRefPubMedPubMedCentral

10.

Li H, Durbin R. Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics (Oxford, England). 2010;26(5):589–95.CrossRef

11.

DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C, et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011;43(5):491–8.CrossRefPubMedPubMedCentral

12.

Jin ZB, Mandai M, Yokota T, Higuchi K, Ohmori K, Ohtsuki F, et al. Identifying pathogenic genetic background of simplex or multiplex retinitis pigmentosa patients: a large scale mutation screening study. J Med Genet. 2008;45(7):465–72.CrossRefPubMed

13.

Dreyer B, Brox V, Tranebjaerg L, Rosenberg T, Sadeghi AM, Moller C, et al. Spectrum of USH2A mutations in Scandinavian patients with Usher syndrome type II. Hum Mutat. 2008;29(3):451.CrossRefPubMed

14.

van Wijk E, Pennings RJ, te Brinke H, Claassen A, Yntema HG, Hoefsloot LH, et al. Identification of 51 novel exons of the Usher syndrome type 2A (USH2A) gene that encode multiple conserved functional domains and that are mutated in patients with Usher syndrome type II. Am J Hum Genet. 2004;74(4):738–44.CrossRefPubMedPubMedCentral

Title: Targeted exome sequencing reveals novel USH2A mutations in Chinese patients with simplex Usher syndrome
Authors: Hai-Rong Shu
Huai Bi
Yang-Chun Pan
Hang-Yu Xu
Jian-Xin Song
Jie Hu
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: BMC Medical Genetics / Issue 1/2015
Electronic ISSN: 1471-2350
DOI: https://doi.org/10.1186/s12881-015-0223-9

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Targeted exome sequencing reveals novel USH2A mutations in Chinese patients with simplex Usher syndrome

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2015

The importance of distinguishing between the odds ratio and the incidence rate ratio in GWAS

Insight into response to mTOR inhibition when PKD1 and TSC2 are mutated

A role for VAX2 in correct retinal function revealed by a novel genomic deletion at 2p13.3 causing distal Renal Tubular Acidosis: case report

Sex-specific genetic effects in physical activity: results from a quantitative genetic analysis

Validation of a high resolution NGS method for detecting spinal muscular atrophy carriers among phase 3 participants in the 1000 Genomes Project

Medium-chain acyl-CoA dehydrogenase deficiency associated with a novel splice mutation in the ACADM gene missed by newborn screening