Navigating the current landscape of clinical genetic testing for inherited retinal dystrophies

Lee, Kristy; Garg, Seema

doi:10.1038/gim.2015.15

Cited by 57 publications

(44 citation statements)

References 61 publications

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“…The overall lower detection rate of mutations in our recessive IRD cohort could be due to screening only some of the many genes associated with this condition (Table 1), the significant overlap in the phenotype, and the genetic heterogeneity of recessive IRDs. Furthermore, failure to detect certain mutation types due to methodology limitations may also contribute to the low detection rate (Amano et al, 2009;Lee and Garg, 2015). Clinically significant intronic mutations have been described in patients with IRDs (den Hollander et al, 2006;Braun et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Genetic testing has the potential to accurately diagnose and predict disease occurrence in early and late-onset IRD Tajiguli et al, 2016;Weisschuh et al, 2016). Finding the genetic basis of IRDs is the first step of recruitment into gene mutation-based clinical trials (Wiggs and Pierce, 2013;Chiang and Trzupek, 2015;Lee and Garg, 2015;Nash et al, 2015). Sensitive and specific genetic tests are currently available at moderate cost for dozens of inherited eye diseases to genotype patients (Chiang and Trzupek, 2015;Consugar et al, 2015;Lee and Garg, 2015).…”

mentioning

confidence: 99%

“…Finding the genetic basis of IRDs is the first step of recruitment into gene mutation-based clinical trials (Wiggs and Pierce, 2013;Chiang and Trzupek, 2015;Lee and Garg, 2015;Nash et al, 2015). Sensitive and specific genetic tests are currently available at moderate cost for dozens of inherited eye diseases to genotype patients (Chiang and Trzupek, 2015;Consugar et al, 2015;Lee and Garg, 2015). Compared with whole exome or genome sequencing with challenging data analysis, targeted genetic testing may improve cost efficiency and decrease turnaround time (Stone, 2003).…”

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confidence: 99%

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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%

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confidence: 99%

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confidence: 99%

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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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“…Next-generation sequencing (NGS) is a cost-effective approach for the genetic diagnosis of retinal diseases 16,17 . Several studies have focused on specific retinal ciliopathies, such as Bardet-Biedl syndrome (BBS) 18 and Joubert syndrome 7,19–21 , with a wide range of reported mutation detection rates depending on the number of targeted genes, NGS platform, and use of pre-screened or “naive” cases.…”

Section: Introductionmentioning

confidence: 99%

Combining targeted panel-based resequencing and copy-number variation analysis for the diagnosis of inherited syndromic retinopathies and associated ciliopathies

Sánchez‐Navarro

Silva

Blanco‐Kelly

et al. 2018

Sci Rep

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Inherited syndromic retinopathies are a highly heterogeneous group of diseases that involve retinal anomalies and systemic manifestations. They include retinal ciliopathies, other well-defined clinical syndromes presenting with retinal alterations and cases of non-specific multisystemic diseases. The heterogeneity of these conditions makes molecular and clinical characterization of patients challenging in daily clinical practice. We explored the capacity of targeted resequencing and copy-number variation analysis to improve diagnosis of a heterogeneous cohort of 47 patients mainly comprising atypical cases that did not clearly fit a specific clinical diagnosis. Thirty-three likely pathogenic variants were identified in 18 genes (ABCC6, ALMS1, BBS1, BBS2, BBS12, CEP41, CEP290, IFT172, IFT27, MKKS, MYO7A, OTX2, PDZD7, PEX1, RPGRIP1, USH2A, VPS13B, and WDPCP). Molecular findings and additional clinical reassessments made it possible to accurately characterize 14 probands (30% of the total). Notably, clinical refinement of complex phenotypes was achieved in 4 cases, including 2 de novo OTX2-related syndromes, a novel phenotypic association for the ciliary CEP41 gene, and the co-existence of biallelic USH2A variants and a Koolen-de-Vries syndrome–related 17q21.31 microdeletion. We demonstrate that combining next-generation sequencing and CNV analysis is a comprehensive and useful approach to unravel the extensive phenotypic and genotypic complexity of inherited syndromic retinopathies.

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“…Our case highlights how an evolving phenotype complicates accurate clinical diagnosis and the ability to provide counselling to a patient and their family; and it lends support to the argument for broad molecular DNA testing to complement ophthalmic testing. 7 Given increasing treatment options for rare diseases, a diagnosis made at an earlier rather than later disease stage could become vision-saving.…”

Section: Introductionmentioning

confidence: 99%

SPATA7: Evolving phenotype from cone-rod dystrophy to retinitis pigmentosa

Matsui

McGuigan

Gruzensky

et al. 2016

Ophthalmic Genetics

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Background SPATA7 mutations have been associated with different autosomal recessive retinal degeneration phenotypes. Long-term follow-up has not been described in detail. Materials and methods A Hispanic patient with SPATA7 mutations was evaluated serially over a 12-year period with kinetic and static chromatic perimetry, optical coherence tomography (OCT) and fundus autofluorescence (AF) imaging. Electroretinography (ERG) was performed at the initial visit. Results The patient was homozygous for a mutation in SPATA7 (p.V458fs). At age 9, the ERG showed an abnormally reduced but preserved rod b-wave but no detectable cone signals. There were two islands of vision: a midperipheral island with greater cone than rod dysfunction and a central island with normal cone but no rod function. Serial measures of rod and cone vision and co-localized retinal structure showed that the midperipheral island slowly became undetectable. By age 21, only the central island and its cone function remained, but it had become more abnormal in structure and function. Conclusion The disease resulting from SPATA7 mutations in this patient initially presented as a cone-rod dystrophy (CRD), but changed over time into a phenotype more reminiscent of late-stage retinitis pigmentosa (RP). The differential diagnosis for both CRD and RP should include this rare molecular cause of autosomal retinal degeneration. An evolving phenotype complicates not only clinical diagnosis and patient counselling but also future strategies aimed at treating specific retinal regions.

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Navigating the current landscape of clinical genetic testing for inherited retinal dystrophies

Cited by 57 publications

References 61 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

Combining targeted panel-based resequencing and copy-number variation analysis for the diagnosis of inherited syndromic retinopathies and associated ciliopathies

SPATA7: Evolving phenotype from cone-rod dystrophy to retinitis pigmentosa

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