Prevalence of Mutations in eyeGENE Probands With a Diagnosis of Autosomal Dominant Retinitis Pigmentosa

Sullivan, Lori S.; Bowne, Sara J.; Reeves, Melissa; Blain, Delphine; Goetz, Kerry; Ndifor, Vida; Vitez, Sally F.; Wang, Xinjing; Tumminia, Santa J.; Daiger, Stephen P.

doi:10.1167/iovs.13-12605

Cited by 61 publications

(52 citation statements)

References 43 publications

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“…We have reported 144 novel disease-causing variants as a possible cause of IRD (see online supplementary table S8). Thirteen of these variants determined as novel at the time of clinical analysis have since been described as disease causing in other studies, for example, USH2A c.11713C>T p.(Arg3905Cys)34 and PRPF31 c.1060C>T p.(Arg354Ter) 35. Many of the reported novel variants are expected to cause disruption of normal translation, including 35 nonsense variants, 6 disruptions of canonical splice sites and 31 out-of-frame coding indels.…”

Section: Discussionmentioning

confidence: 97%

Molecular findings from 537 individuals with inherited retinal disease

et al. 2016

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Background Inherited retinal diseases (IRDs) are a clinically and genetically heterogeneous set of disorders, for which diagnostic second-generation sequencing (next-generation sequencing, NGS) services have been developed worldwide. Methods We present the molecular findings of 537 individuals referred to a 105-gene diagnostic NGS test for IRDs. We assess the diagnostic yield, the spectrum of clinical referrals, the variant analysis burden and the genetic heterogeneity of IRD. We retrospectively analyse disease-causing variants, including an assessment of variant frequency in Exome Aggregation Consortium (ExAC). Results Individuals were referred from 10 clinically distinct classifications of IRD. Of the 4542 variants clinically analysed, we have reported 402 mutations as a cause or a potential cause of disease in 62 of the 105 genes surveyed. These variants account or likely account for the clinical diagnosis of IRD in 51% of the 537 referred individuals. 144 potentially disease-causing mutations were identified as novel at the time of clinical analysis, and we further demonstrate the segregation of known disease-causing variants among individuals with IRD. We show that clinically analysed variants indicated as rare in dbSNP and the Exome Variant Server remain rare in ExAC, and that genes discovered as a cause of IRD in the post-NGS era are rare causes of IRD in a population of clinically surveyed individuals. Conclusions Our findings illustrate the continued powerful utility of custom-gene panel diagnostic NGS tests for IRD in the clinic, but suggest clear future avenues for increasing diagnostic yields.

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Section: Discussionmentioning

confidence: 97%

Molecular findings from 537 individuals with inherited retinal disease

et al. 2016

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“…7,11,17,23 This variability has challenged the ability to identify the accurate disease inheritance mode in families with affected female patients. [24][25][26] In the early stages of genetic counseling of an RP pedigree, the presence of affected female subjects should raise suspicion of both an autosomal-dominant and an X-linked inheritance mode. In fact, typical RP fundus features, such as bonespicular or nummular intraretinal pigmentation, optic disc pallor, and vascular attenuation, were common in this cohort, expectedly more so in heterozygotes from RP pedigrees (49%, 44%, and 56%, respectively; Table) than in those from COD/ CORD pedigrees (18%, 18%, and 18%, respectively).…”

Section: Discussionmentioning

confidence: 99%

The Spectrum of Structural and Functional Abnormalities in Female Carriers of Pathogenic Variants in theRPGRGene

Talib

Schooneveld

Cauwenbergh

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. The purpose of this study was to investigate the phenotype and long-term clinical course of female carriers of RPGR mutations.METHODS. This was a retrospective cohort study of 125 heterozygous RPGR mutation carriers from 49 families.RESULTS. Eighty-three heterozygotes were from retinitis pigmentosa (RP) pedigrees, 37 were from cone-/cone-rod dystrophy (COD/CORD) pedigrees, and 5 heterozygotes were from pedigrees with mixed RP/CORD or unknown diagnosis. Mutations were located in exon 1-14 and in ORF15 in 42 of 125 (34%) and 83 of 125 (66%) subjects, respectively. The mean age at the first examination was 34.4 years (range, 2.1 to 86.0 years). The median follow-up time in heterozygotes with longitudinal data (n ¼ 62) was 12.2 years (range, 1.1 to 52.2 years). Retinal pigmentary changes were present in 73 (58%) individuals. Visual symptoms were reported in 51 (40%) cases. Subjects with both symptoms and pigmentary fundus changes were older than the other heterozygotes (P ¼ 0.01) and had thinner foveal outer retinas (P ¼ 0.006). Complete expression of the RP or CORD phenotype was observed in 29 (23%) heterozygotes, although usually in milder forms than in affected male relatives. Best-corrected visual acuity (BCVA) was <20/40 and <20/400 in at least one eye in 45 of 116 (39%) and 11 of 116 (9%) heterozygotes, respectively. Myopia was observed in 74 of 101 (73%) subjects and was associated with lower BCVA (P ¼ 0.006). Increasing age was associated with lower BCVA (P ¼ 0.002) and decreasing visual field size (P ¼ 0.012; I4e isopter).CONCLUSIONS. RPGR mutations lead to a phenotypic spectrum in female carriers, with myopia as a significantly aggravating factor. Complete disease expression is observed in some individuals, who may benefit from future (gene) therapeutic options.

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“…In another study of patients with recessive Stargardt disease, the causative mutation detection rate using similar methods was 44% (Briggs et al, 2001). In a study of patients with autosomal dominant RP, the disease-causing mutation was found in 52% of probands with complete sequencing of 12 genes (Sullivan et al, 2013). Mutations in known genes are estimated to contribute to IRD pathology in about 50% of dominant cases (Daiger, 2004).…”

Section: Discussionmentioning

confidence: 99%

A Report on Molecular Diagnostic Testing for Inherited Retinal Dystrophies by Targeted Genetic Analyses

Ramkumar

Gudiseva

Kishaba

et al. 2017

Genetic Testing and Molecular Biomarkers

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Aim: To test the utility of targeted sequencing as a method of clinical molecular testing in patients diagnosed with inherited retinal degeneration (IRD). Methods: After genetic counseling, peripheral blood was drawn from 188 probands and 36 carriers of IRD. Single gene testing was performed on each patient in a Clinical Laboratory Improvement Amendment (CLIA) certified laboratory. DNA was isolated, and all exons in the gene of interest were analyzed along with 20 base pairs of flanking intronic sequence. Genetic testing was most often performed on ABCA4, CTRP5, ELOV4, BEST1, CRB1, and PRPH2. Pathogenicity of novel sequence changes was predicted by PolyPhen2 and sorting intolerant from tolerant (SIFT). Results: Of the 225 genetic tests performed, 150 were for recessive IRD, and 75 were for dominant IRD. A positive molecular diagnosis was made in 70 (59%) of probands with recessive IRD and 19 (26%) probands with dominant IRD. Analysis confirmed 12 (34%) of individuals as carriers of familial mutations associated with IRD. Thirty-two novel variants were identified; among these, 17 sequence changes in four genes were predicted to be possibly or probably damaging including: ABCA4 (14), BEST1 (2), PRPH2 (1), and TIMP3 (1). Conclusions: Targeted analysis of clinically suspected genes in 225 subjects resulted in a positive molecular diagnosis in 26% of patients with dominant IRD and 59% of patients with recessive IRD. Novel damaging mutations were identified in four genes. Single gene screening is not an ideal method for diagnostic testing given the phenotypic and genetic heterogeneity among IRD cases. High-throughput sequencing of all genes associated with retinal degeneration may be more efficient for molecular diagnosis.

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Prevalence of Mutations in eyeGENE Probands With a Diagnosis of Autosomal Dominant Retinitis Pigmentosa

Cited by 61 publications

References 43 publications

Molecular findings from 537 individuals with inherited retinal disease

Molecular findings from 537 individuals with inherited retinal disease

The Spectrum of Structural and Functional Abnormalities in Female Carriers of Pathogenic Variants in theRPGRGene

A Report on Molecular Diagnostic Testing for Inherited Retinal Dystrophies by Targeted Genetic Analyses

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