Copy-number variation contributes 9% of pathogenicity in the inherited retinal degenerations

Zampaglione, Erin; Kinde, Benyam; Place, Emily; Navarro-Gómez, Daniel; Maher, Matthew; Jamshidi, Farzad; Nassiri, Sherwin; Mazzone, J Alex; Finn, Caitlin; Schlegel, Dana; Comander, Jason; Pierce, Eric A.; Bujakowska, Kinga

doi:10.1038/s41436-020-0759-8

Cited by 74 publications

(75 citation statements)

References 39 publications

(64 reference statements)

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“…This also prevented from knowing whether the two ABCA4 gene mutations in the patient from family 2 were in the same allele or not; as a result, we can only hypothesize that this as a blended phenotype. Besides, we did not include the study of copy number variation, which sometimes contributes significantly to pathogenicity in IRDs [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

PRPH2-Related Retinal Diseases: Broadening the Clinical Spectrum and Describing a New Mutation

Coco‐Martín

Sánchez-Tocino

Desco

et al. 2020

Genes

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Over 175 pathogenic mutations in the Peripherin-2 (PRPH2) gene are linked to various retinal diseases. We report the phenotype and genotype of eight families (24 patients) with retinal diseases associated with seven distinct PRPH2 gene mutations. We identified a new mutation, c.824_828+3delinsCATTTGGGCTCCTCATTTGG, in a patient with adult-onset vitelliform macular dystrophy (AVMD). One family with the p.Arg46Ter mutation presented with the already described AVMD phenotype, but another family presented with the same mutation and two heterozygous pathogenic mutations (p.Leu2027Phe and p.Gly1977Ser) in the ATP Binding Cassette Subfamily A Member 4 (ABCA4) gene that cause extensive chorioretinal atrophy (ECA), which could be a blended phenotype. The p.Lys154del PRPH2 gene mutation associated with the p.Arg2030Glu mutation in the ABCA4 gene was found in a patient with multifocal pattern dystrophy simulating fundus flavimaculatus (PDsFF), for whom we considered ABCA4 as a possible modifying gene. The mutation p.Gly167Ser was already known to cause pattern dystrophy, but we also found ECA, PDsFF, and autosomal-dominant retinitis pigmentosa (ADRP) as possible phenotypes. Finally, we identified the mutation p.Arg195Leu in a large family with common ancestry, which previously was described to cause central areolar choroidal dystrophy (CACD), but we also found ADRP and observed that it caused ECA more frequently than CACD in this family.

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Section: Discussionmentioning

confidence: 99%

PRPH2-Related Retinal Diseases: Broadening the Clinical Spectrum and Describing a New Mutation

Coco‐Martín

Sánchez-Tocino

Desco

et al. 2020

Genes

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“…A total of 24 CNVs were found in the cohort of 677 individuals (3.5%) and of these four were in MERTK ; only EYS with seven CNVs had more deletions/duplications than MERTK [ 16 ]. Others have performed CNV analysis using NGS data and found substantially higher yields of causal CNVs [ 13 , 15 ]. However, their numbers are based on unsolved cases.…”

Section: Discussionmentioning

confidence: 99%

“…Copy number variations (CNV) has become an important contributor to the cause of retinal dystrophies [ 13 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Bi-Allelic Pathogenic Variations in MERTK Including Deletions Are Associated with an Early Onset Progressive Form of Retinitis Pigmentosa

Jespersgaard

Bertelsen

Arif

et al. 2020

Genes

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Bi-allelic pathogenic variants in MERTK cause retinitis pigmentosa (RP). Since deletions of more than one exon have been reported repeatedly for MERTK, CNV (copy number variation) analysis of next-generation sequencing (NGS) data has proven important in molecular genetic diagnostics of MERTK. CNV analysis was performed on NGS data of 677 individuals with inherited retinal diseases (IRD) and confirmed by quantitative RT-PCR analysis. Clinical evaluation was based on retrospective records. Clinical re-examination included visual field examination, dark adaption, scotopic and photopic full-field electroretinograms (ffERG), multifocal ERG (mfERG) and optic coherence tomography (OCT). Fourteen variants were detected in MERTK in six individuals, three of which were deletions of more than one exon. Clinical examinations of five out of six individuals revealed a severe phenotype with early-onset generalized retinal dystrophy with night blindness and progressive visual field loss; however, one individual had a milder phenotype. Three individuals had hearing impairments. We show that deletions represent a substantial part of the causative variants in MERTK and emphasize that CNV analysis should be included in the molecular genetic diagnostics of IRDs.

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“…In particular, the study of CNV on whole-exome sequencing (WES) is much more popular 1 and affordable 2 than the study on whole-genome sequencing (WGS). The study of CNVs on WES provides insights into human genome diversity and predisposition to diseases, 3 such as autism, 4 schizophrenia, 5 type-2 diabetes, 6 congenital heart disease (CHD), 7 non-syndromic hearing loss 8 , 9 and inherited retinal degenerations, 10 among others. Nevertheless, issues with the accuracy and complexity of captured CNVs as well as their interpretation still exist.…”

Section: Introductionmentioning

confidence: 99%

inCNV: An Integrated Analysis Tool for Copy Number Variation on Whole Exome Sequencing

Chanwigoon

Piwluang

Wichadakul

2020

Evol Bioinform Online

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The detection of copy number variations (CNVs) on whole-exome sequencing (WES) represents a cost-effective technique for the study of genetic variants. This approach, however, has encountered an obstacle with high false-positive rates due to biases from exome sequencing capture kits and GC contents. Although plenty of CNV detection tools have been developed, they do not perform well with all types of CNVs. In addition, most tools lack features of genetic annotation, CNV visualization, and flexible installation, requiring users to put much effort into CNV interpretation. Here, we present “inCNV,” a web-based application that can accept multiple CNV-tool results, then integrate and prioritize them with user-friendly interfaces. This application helps users analyze the importance of called CNVs by generating CNV annotations from Ensembl, Database of Genomic Variants (DGV), ClinVar, and Online Mendelian Inheritance in Man (OMIM). Moreover, users can select and export CNVs of interest including their flanking sequences for primer design and experimental verification. We demonstrated how inCNV could help users filter and narrow down the called CNVs to a potentially novel CNV, a common CNV within a group of samples of the same disease, or a de novo CNV of a sample within the same family. Besides, we have provided in CNV as a docker image for ease of installation ( https://github.com/saowwapark/inCNV ).

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Copy-number variation contributes 9% of pathogenicity in the inherited retinal degenerations

Cited by 74 publications

References 39 publications

PRPH2-Related Retinal Diseases: Broadening the Clinical Spectrum and Describing a New Mutation

PRPH2-Related Retinal Diseases: Broadening the Clinical Spectrum and Describing a New Mutation

Bi-Allelic Pathogenic Variations in MERTK Including Deletions Are Associated with an Early Onset Progressive Form of Retinitis Pigmentosa

inCNV: An Integrated Analysis Tool for Copy Number Variation on Whole Exome Sequencing

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