Next-generation sequencing reveals the mutational landscape of clinically diagnosed Usher syndrome: copy number variations, phenocopies, a predominant target for translational read-through, andPEX26mutated in Heimler syndrome
Open Access
- 6 July 2017
- journal article
- research article
- Published by Wiley in Molecular Genetics & Genomic Medicine
- Vol. 5 (5), 531-552
- https://doi.org/10.1002/mgg3.312
Abstract
Combined retinal degeneration and sensorineural hearing impairment is mostly due to autosomal recessive Usher syndrome (USH1: congenital deafness, early retinitis pigmentosa (RP); USH2: progressive hearing impairment, RP). Sanger sequencing and NGS of 112 genes (Usher syndrome, nonsyndromic deafness, overlapping conditions), MLPA, and array‐CGH were conducted in 138 patients clinically diagnosed with Usher syndrome. A molecular diagnosis was achieved in 97% of both USH1 and USH2 patients, with biallelic mutations in 97% (USH1) and 90% (USH2), respectively. Quantitative readout reliably detected CNVs (confirmed by MLPA or array‐CGH), qualifying targeted NGS as one tool for detecting point mutations and CNVs. CNVs accounted for 10% of identified USH2A alleles, often in trans to seemingly monoallelic point mutations. We demonstrate PTC124‐induced read‐through of the common p.Trp3955* nonsense mutation (13% of detected USH2A alleles), a potential therapy target. Usher gene mutations were found in most patients with atypical Usher syndrome, but the diagnosis was adjusted in case of double homozygosity for mutations in OTOA and NR2E3, genes implicated in isolated deafness and RP. Two patients with additional enamel dysplasia had biallelic PEX26 mutations, for the first time linking this gene to Heimler syndrome. Targeted NGS not restricted to Usher genes proved beneficial in uncovering conditions mimicking Usher syndrome.Keywords
Funding Information
- Forschung contra Blindheit, Initiative Usher-Syndrom e.V.
- GEERS-Stiftung
This publication has 122 references indexed in Scilit:
- Spectrum of Mutations in USH2A in British Patients with Usher Syndrome Type IIExperimental Eye Research, 2001
- A recessive contiguous gene deletion causing infantile hyperinsulinism, enteropathy and deafness identifies the Usher type 1C geneNature Genetics, 2000
- Evaluation of the Myosin VIIA Gene and Visual Function in Patients with Usher Syndrome Type IExperimental Eye Research, 2000
- Identification of novel USH2A mutations: implications for the structure of USH2A proteinEuropean Journal of Human Genetics, 2000
- Missense Mutation in the USH2A Gene: Association with Recessive Retinitis Pigmentosa without Hearing LossAmerican Journal of Human Genetics, 2000
- Genomic Structure and Identification of Novel Mutations in Usherin, the Gene Responsible for Usher Syndrome Type IIaAmerican Journal of Human Genetics, 2000
- Three novel mutations and twelve polymorphisms identified in the USH2A gene in Israeli USH2 familiesHuman Mutation, 2000
- Mutation of a nuclear receptor gene, NR2E3, causes enhanced S cone syndrome, a disorder of retinal cell fateNature Genetics, 2000
- Twelve novel myosin VIIA mutations in 34 patients with Usher syndrome type I: Confirmation of genetic heterogeneityHuman Mutation, 1999
- A Mutation (2314delG) in the Usher Syndrome Type IIA Gene: High Prevalence and Phenotypic VariationAmerican Journal of Human Genetics, 1999