Dependable and Efficient Clinical Utility of Target Capture-Based Deep Sequencing in Molecular Diagnosis of Retinitis Pigmentosa

Wang, Jing; Zhang, Victor W.; Feng, Yanming; Tian, Xia; Li, Fang Yuan; Truong, Cavatina K.; Wang, Guoli; Chiang, Pei Wen; Lewis, Richard A.; Wong, Lee Jun

doi:10.1167/iovs.14-14936

Cited by 66 publications

(53 citation statements)

References 33 publications

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“…Three advanced technologies using next-generation sequencing (NGS) are in use: targeted retinal-gene capture NGS (Simpson et al 2011; Audo et al 2012; Neveling et al 2012; O’Sullivan et al 2012; Chen et al 2013; Eisenberger et al 2013; Glockle et al 2013; Wang et al 2014), whole-exome NGS (Bowne et al 2011a; Ozgul et al 2011; Tucker et al 2011; Zeitz et al 2013; El Shamieh et al 2014; Jin et al 2014; Sergouniotis et al 2014), and whole-genome NGS (Nishiguchi et al 2013). Each has advantages and disadvantages.…”

Section: Finding Genes and Mutations Causing Adrpmentioning

confidence: 99%

Genes and Mutations Causing Autosomal Dominant Retinitis Pigmentosa

Daiger

Bowne

Sullivan

2014

Cold Spring Harb Perspect Med

109

140

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Retinitis pigmentosa (RP) has a prevalence of approximately one in 4000; 25%–30% of these cases are autosomal dominant retinitis pigmentosa (adRP). Like other forms of inherited retinal disease, adRP is exceptionally heterogeneous. Mutations in more than 25 genes are known to cause adRP, more than 1000 mutations have been reported in these genes, clinical findings are highly variable, and there is considerable overlap with other types of inherited disease. Currently, it is possible to detect disease-causing mutations in 50%–75% of adRP families in select populations. Genetic diagnosis of adRP has advantages over other forms of RP because segregation of disease in families is a useful tool for identifying and confirming potentially pathogenic variants, but there are disadvantages too. In addition to identifying the cause of disease in the remaining 25% of adRP families, a central challenge is reconciling clinical diagnosis, family history, and molecular findings in patients and families.

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Section: Finding Genes and Mutations Causing Adrpmentioning

confidence: 99%

Genes and Mutations Causing Autosomal Dominant Retinitis Pigmentosa

Daiger

Bowne

Sullivan

2014

Cold Spring Harb Perspect Med

109

140

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“…This patient had widespread rod and cone dystrophy but did not have obesity, developmental delay, speech pathology, intellectual disability, or renal defects (Fig 1B). However, after revealing the results for BBS1 mutation, the parents disclosed the previous excision of a small extra digit, consistent with polydactyly in BBS [12]. Patient 4 carries compound heterozygous novel nonsense pathogenic variants, c.2816T>A (p.L939*) and c.8776C>T (p.R2926*), in the ALMS1 gene.…”

Section: Resultsmentioning

confidence: 86%

“…Our targeted capture NGS approach has been described recently [12]. Briefly, a custom-designed DNA probe library was used to capture target exons and 20bp of the flanking intron regions of 207 ocular disease genes (S1 File).…”

Section: Methodsmentioning

confidence: 99%

“…Those regions with coverage <20X, usually GC rich or highly repetitive, were covered by PCR/Sanger sequencing. An average of 1000X per base sequence depth was achieved and 3–12 candidate variants were obtained per sample [12]. American College of Medical Genetics guidance was used for the interpretation of sequence variants [19].…”

Section: Methodsmentioning

confidence: 99%

“…Thus, tests focused on a specific group of genes for a particular clinical diagnosis may not detect variants in genes not typically associated with that condition. Despite a few reports in research settings, this phenomenon has not been evaluated systematically in clinical diagnostic laboratories that fully validate all target genes to minimize both false negatives and false positives [12]. …”

Section: Introductionmentioning

confidence: 99%

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Retinal Diseases Caused by Mutations in Genes Not Specifically Associated with the Clinical Diagnosis

Wang

Feng

et al. 2016

PLoS ONE

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PurposeWhen seeking a confirmed molecular diagnosis in the research setting, patients with one descriptive diagnosis of retinal disease could carry pathogenic variants in genes not specifically associated with that description. However, this event has not been evaluated systematically in clinical diagnostic laboratories that validate fully all target genes to minimize false negatives/positives.MethodsWe performed targeted next-generation sequencing analysis on 207 ocular disease-related genes for 42 patients whose DNA had been tested negative for disease-specific panels of genes known to be associated with retinitis pigmentosa, Leber congenital amaurosis, or exudative vitreoretinopathy.ResultsPathogenic variants, including single nucleotide variations and copy number variations, were identified in 9 patients, including 6 with variants in syndromic retinal disease genes and 3 whose molecular diagnosis could not be distinguished easily from their submitted clinical diagnosis, accounting for 21% (9/42) of the unsolved cases.ConclusionOur study underscores the clinical and genetic heterogeneity of retinal disorders and provides valuable reference to estimate the fraction of clinical samples whose retinal disorders could be explained by genes not specifically associated with the corresponding clinical diagnosis. Our data suggest that sequencing a larger set of retinal disorder related genes can increase the molecular diagnostic yield, especially for clinically hard-to-distinguish cases.

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Clinical and molecular findings in a cohort of 152 Brazilian severe early onset inherited retinal dystrophy patients

Sallum

Motta

Arno

et al. 2020

American J of Med Genetics Pt C

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Leber congenital amaurosis (LCA) and early-onset retinal dystrophy (EORD) are severe inherited retinal dystrophy that can cause deep blindness childhood. They represent 5% of all retinal dystrophies in the world population and about 10% in Brazil. Clinical findings and molecular basis of syndromic and nonsyndromic LCA/EORD in a Brazilian sample (152 patients/137 families) were studied. In this population, 15 genes were found to be related to the phenotype, 38 new variants were detected and four new complex alleles were discovered. Among 123 variants found, the most common were CEP290: c.2991+1655A>G, CRB1: p.Cys948Tyr, and RPGRIP1: exon10-18 deletion. K E Y W O R D S causal genes, childhood blindness, early-onset retinal dystrophy (EORD), genotypephenotype, Leber congenital amaurosis (LCA), pathogenic variants 1 | INTRODUCTION Leber congenital amaurosis (LCA) is the most severe and earliest onset inherited retinal dystrophy. Affected individuals usually present, in the first year of life with severe visual impairment, nystagmus and occasionally a systemic manifestation (Francis, 2006). Phenotypic variability in fundus abnormality, refractive errors, photophobia or lightseeking behavior, nyctalopia, nystagmus, low visual acuity, and Franceschetti's oculo-digital sign, are also commonly observed in these patients (Chung & Traboulsi, 2009; den Hollander, Roepman, Koenekoop, & Cremers, 2008). Early-onset retinal dystrophy (EORD) can be considered as belonging to the same LCA spectrum but a milder form, where signs and symptoms appear after the first year of life up to 5-7 years-old (Weleber, Francis, Trzupek, & Beattie, 2004), but still a disease that severely compromises vision. Clinically, LCA and EORD are similar and may represent a continuum; the distinction between them is an extinguished or markedly diminished ERG response before the first year of life for individuals with

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Dependable and Efficient Clinical Utility of Target Capture-Based Deep Sequencing in Molecular Diagnosis of Retinitis Pigmentosa

Cited by 66 publications

References 33 publications

Genes and Mutations Causing Autosomal Dominant Retinitis Pigmentosa

Genes and Mutations Causing Autosomal Dominant Retinitis Pigmentosa

Retinal Diseases Caused by Mutations in Genes Not Specifically Associated with the Clinical Diagnosis

Clinical and molecular findings in a cohort of 152 Brazilian severe early onset inherited retinal dystrophy patients

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