Identifying Retinal Disease Genes: How Far Have We Come, How Far Do We Have to Go?

Daiger, Stephen P.

doi:10.1002/0470092645.ch3

Cited by 48 publications

(28 citation statements)

References 16 publications

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“…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). Whereas, in recessive conditions, mutations in known genes contribute to 40-50% of cases (Riveiro-Alvarez et al, 2013).…”

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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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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“…However, it has been problematic to determine the specific mutations in HRDs because of their extensive genetic heterogeneity, which so far involves 179 known genes (www.RetNet.org), and potentially many new genes. Genetic background overlaps (e.g., LCA, RP, and CRD have overlapping genes and mutations [8][9][10] ) and clinical ambiguities of some types of HRDs further increase the difficulties to determine causative mutations because no specific panel of HRDs genes can be predicted in these circumstances.…”

Section: Discussionmentioning

confidence: 99%

Targeted Sequencing of 179 Genes Associated with Hereditary Retinal Dystrophies and 10 Candidate Genes Identifies Novel and Known Mutations in Patients with Various Retinal Diseases

Chen

Zhao

Sheng

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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A substantial number of potential new genes and new mutations associated with HRDs remain to be discovered. Identification of the novel HRDs-causing mutations in our study not only provides a better understanding of genotype-phenotype relationships in these diseases, but also demonstrates that the approach described herein is an effective method for large scale mutation detection among diverse and complicated HRDs cases.

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“…2,3 RP can be inherited in an autosomal dominant (adRP), autosomal recessive (arRP), or X-linked (XLRP) manner, with rare digenic and mitochondrial forms. 4,5 RP also is associated with several syndromic disorders, such as Bardet-Biedl and Usher syndrome. 3,5 To date, mutations in 23 genes are known to cause adRP, mutations in 36 genes cause arRP, and mutations in 3 genes cause XLRP.…”

mentioning

confidence: 99%

Mutations in the X-Linked Retinitis Pigmentosa GenesRPGRandRP2Found in 8.5% of Families with a Provisional Diagnosis of Autosomal Dominant Retinitis Pigmentosa

Churchill

Bowne

Sullivan

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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114

124

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PURPOSE. We determined the fraction of families in a wellcharacterized cohort with a provisional diagnosis of autosomal dominant retinitis pigmentosa (adRP) that have disease-causing mutations in the X-linked retinitis pigmentosa GTPase regulator (RPGR) gene or the retinitis pigmentosa 2 (RP2) gene. METHODS.Families with a provisional clinical diagnosis of adRP, and a pedigree consistent with adRP but no male-to-male transmission were selected from a cohort of 258 families, and tested for mutations in the RPGR and RP2 genes with di-deoxy sequencing. To facilitate testing of RPGR in ''adRP'' families that had no male members available for testing, the repetitive and purine-rich ORF15 of RPGR was subcloned and sequenced in heterozygous female subjects from 16 unrelated families.RESULTS. Direct sequencing of RPGR and RP2 allowed for identification of a disease-causing mutation in 21 families. Of these ''adRP'' families 19 had RPGR mutations, and two had RP2 mutations. Subcloning and sequencing of ORF15 of RPGR in female subjects identified one additional RPGR mutation. Of the 22 mutations identified, 15 have been reported previously.CONCLUSIONS. These data show that 8.5% (22 in 258) of families thought to have adRP truly have X-linked retinitis pigmentosa (XLRP). These results have substantive implications for calculation of recurrence risk, genetic counseling, and potential treatment options, and illustrate the importance of screening families with a provisional diagnosis of autosomal inheritance and no male-to-male transmission for mutations in X-linked genes. Mutations in RPGR are one of the most common causes of all forms of retinitis pigmentosa. (Invest Ophthalmol Vis Sci.

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Identifying Retinal Disease Genes: How Far Have We Come, How Far Do We Have to Go?

Cited by 48 publications

References 16 publications

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

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

Targeted Sequencing of 179 Genes Associated with Hereditary Retinal Dystrophies and 10 Candidate Genes Identifies Novel and Known Mutations in Patients with Various Retinal Diseases

Mutations in the X-Linked Retinitis Pigmentosa GenesRPGRandRP2Found in 8.5% of Families with a Provisional Diagnosis of Autosomal Dominant Retinitis Pigmentosa

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