Comprehensive Molecular Diagnosis of a Large Cohort of Japanese Retinitis Pigmentosa and Usher Syndrome Patients by Next-Generation Sequencing

Oishi, Maho; Oishi, Akio; Gotoh, Noriko; Ogino, Ken; Higasa, Koichiro; Iida, Kei; Makiyama, Yukiko; Morooka, Shigenori; Matsuda, Fumihiko; Yoshimura, Nagahisa

doi:10.1167/iovs.14-15458

Cited by 149 publications

(127 citation statements)

References 32 publications

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“…36,[39][40][41][42][43][44][45][46] Electroretinography is consistent with a severe generalized rod-cone dysfunction, typical for RP, and may have an electronegative pattern. 47 Only two cases of recessive retinal dystrophies due to NRL mutations have been reported to date (Table).…”

Section: Discussionmentioning

confidence: 99%

Homozygosity for a Recessive Loss-of-Function Mutation of the NRL Gene Is Associated With a Variant of Enhanced S-Cone Syndrome

Newman

Blumen

Braverman

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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Citation: Newman H, Blumen SC, Braverman I, et al. Homozygosity for a recessive loss-of-function mutation of the NRL gene is associated with a variant of enhanced S-cone syndrome. Invest Ophthalmol Vis Sci. 2016;57:5361-5371. DOI:10.1167/ iovs.16-19505 PURPOSE. To investigate the genetic basis for severe visual complaints by Bukharan Jewish patients with oculopharyngeal muscular dystrophy (OPMD). METHODS.Polymerase chain reaction amplification and direct sequencing were used to test for NRL, PABPN1, and NR2E3 mutations. Complete ophthalmic examination included bestcorrected visual acuity, biomicroscopic examination, optical coherence tomography, and fundus autofluorescence. Detailed electroretinography (ERG) testing was conducted including expanded International Society for Clinical Electrophysiology of Vision protocol for light-adapted and dark-adapted conditions, measurements of S-cone function, and ON-OFF light-adapted ERG.RESULTS. The index patients were homozygotes for both a dominant mutation of the PABPN1 gene, (GCN)13, and a recessive mutation of the NRL gene, p.R31X, on chromosome 14q11.1, leading to early-onset OPMD accompanied by night blindness and reduced visual acuity. No mutations were found in the NR2E3 gene. Both patients were of Bukharan Jewish origin, but from unrelated families. Electroretinography responses of both patients were dominated by short-wavelength-sensitive mechanisms, with no detectable rod function, similar to the ERG responses of individuals with enhanced S-cone syndrome (ESCS) due to NR2E3 mutations. Heterozygotes for the PABPN1 and NRL mutations demonstrated normal fundi and ERG responses.CONCLUSIONS. Homozygosity for the recessive NRL mutation described here appears to be associated with a distinct retinal phenotype, demonstrating ERG characteristics similar to those of ESCS patients. This report expands the spectrum of NRL recessive mutations, as well as the genetic spectrum of ESCS, and indicates a new syndrome of OPMD with an ESCS-like phenotype.

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Section: Discussionmentioning

confidence: 99%

Homozygosity for a Recessive Loss-of-Function Mutation of the NRL Gene Is Associated With a Variant of Enhanced S-Cone Syndrome

Newman

Blumen

Braverman

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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“…5 All patients underwent comprehensive ophthalmological examinations, including measurement of the best-corrected visual acuity (BCVA) using a decimal visual acuity chart (Landolt chart), indirect ophthalmoscopy, slit-lamp biomicroscopy, SD-OCT (Spectralis HRA+OCT, Heidelberg Engineering, Heidelberg, Germany); mean deviation (MD) value at baseline calculated using a Humphrey field analyzer (HFA; 10-2 SITA Standard Program; Carl Zeiss Meditec, Jena, Germany) and 30 Hz flicker electroretinography (ERG) were also performed. ERG results were recorded according to the International Society for Clinical Electrophysiology of Vision standard protocol recommended in 2008 using LS-C (Mayo Co., Nagoya, Japan) and Neuropack MEB-2204 systems (Nihon Kohden, Tokyo, Japan).…”

Section: Subjectsmentioning

confidence: 99%

“…4 EYS is an important and common cause of RP in the Japanese, Spanish, British, Chinese, Israelis, and Palestinians. [5][6][7][8][9] Furthermore, a report has described that EYS-associated RP patients share a relatively uniform phenotype with near-normal central visual function up to their 20s. 10 We have previously reported that severity of RP patients with EYS mutations was relatively moderate among RP patients with various mutations.…”

Section: Introductionmentioning

confidence: 99%

Inner segment ellipsoid band length is a prognostic factor in retinitis pigmentosa associated with EYS mutations: 5-year observation of retinal structure

Miyata

Ogino

Gotoh

et al. 2016

Eye

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Purpose To evaluate whether the length of the inner segment ellipsoid (ISe) band can be used as a prognostic factor for disease course in retinitis pigmentosa (RP) patients with EYS mutations by observation over a period of 5 years. Methods Twelve RP patients with EYS mutations were studied. The horizontal and vertical ISe length of the right eye was manually measured at five time points annually, using spectral domain optical coherence tomography. A regression line through the five points from baseline to the final measurement was drawn and the ratio of the length (%) at each point to the baseline length was calculated; the slope was defined as the rate of ISe shortening (%/year). The correlation between the rate of ISe shortening and age, visual acuity, and mean deviation (MD) value were evaluated. The intraclass correlation coefficient (ICC) for the measurements was calculated. Results The mean rate of ISe shortening was − 4.65 ± 2.89% per year and the decline was statistically significant. The rate of shortening was significantly negatively correlated with the baseline length (P = 0.046, r = 0.58), but not with the baseline age, visual acuity, and MD value. The ICC (2, 1) was 0.999. Conclusions ISe of all RP patients with EYS mutations shortened during the 5 years of annual observation. The measurement of the length of ISe is a simple and convenient method with high repeatability, and the length is a sensitive prognostic factor for the rate of ISe shortening in RP patients with EYS mutations.

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“…25 Several studies have proven TES as a highefficiency method of molecular diagnosis of USH, with a detection rate of around 70%. 10,[26][27][28][29] Targeted NGS can detect both point mutations and large genomic DNA rearrangements; its ability to detect CNVs is related to the coverage depth of TES. 10,26 In one Spanish study, six different CNVs of USH2A, CDH23, PCDH15, and GPR98 were detected by their own capture panel TES, with a mean coverage of 1334x.…”

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confidence: 99%

Comprehensive Molecular Screening in Chinese Usher Syndrome Patients

Sun

Ren

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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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.

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Comprehensive Molecular Diagnosis of a Large Cohort of Japanese Retinitis Pigmentosa and Usher Syndrome Patients by Next-Generation Sequencing

Abstract: By screening a large cohort of patients, this study catalogued the genetic variations involved in RP and Usher syndrome in a Japanese population and highlighted the different distribution of causative genes among populations.

Cited by 149 publications

References 32 publications

Homozygosity for a Recessive Loss-of-Function Mutation of the NRL Gene Is Associated With a Variant of Enhanced S-Cone Syndrome

Homozygosity for a Recessive Loss-of-Function Mutation of the NRL Gene Is Associated With a Variant of Enhanced S-Cone Syndrome

Inner segment ellipsoid band length is a prognostic factor in retinitis pigmentosa associated with EYS mutations: 5-year observation of retinal structure

Comprehensive Molecular Screening in Chinese Usher Syndrome Patients

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