The LOVD3 platform: efficient genome-wide sharing of genetic variants

Fokkema, Ivo F.A.C.; Kroon, Mark; Hernandez, J.; Asscheman, Daan; Lugtenburg, Ivar; Hoogenboom, Jerry; Dunnen, Johan T. den

doi:10.1038/s41431-021-00959-x

Cited by 90 publications

(56 citation statements)

References 12 publications

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“…Both the LOVD and ClinVar database are curated gene variant databases, also known as locus-specific databases (LSDB), that store information on the variants of the human genome and their phenotypic consequences [ 39 ]. LOVD was founded 15 years ago, ClinVar in 2012.…”

Section: Discussionmentioning

confidence: 99%

In Silico Analysis of Pathogenic CRB1 Single Nucleotide Variants and Their Amenability to Base Editing as a Potential Lead for Therapeutic Intervention

Bellingrath

McClements

Kaukonen

et al. 2021

Genes

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Mutations in the Crumbs homolog 1 (CRB1) gene cause both autosomal recessive retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA). Since three separate CRB1 isoforms are expressed at meaningful levels in the human retina, base editing shows promise as a therapeutic approach. This retrospective analysis aims to summarise the reported pathogenic CRB1 variants and investigate their amenability to treatment with currently available DNA base editors. Pathogenic single nucleotide variants (SNVs) were extracted from the Leiden open-source variation database (LOVD) and ClinVar database and coded by mutational consequence. They were then analyzed for their amenability to currently available DNA base editors and available PAM sites from a selection of different Cas proteins. Of a total of 1115 unique CRB1 variants, 69% were classified as pathogenic SNVs. Of these, 62% were amenable to currently available DNA BEs. Adenine base editors (ABEs) alone have the potential of targeting 34% of pathogenic SNVs; 19% were amenable to a CBE while GBEs could target an additional 9%. Of the pathogenic SNVs targetable with a DNA BE, 87% had a PAM site for a Cas protein. Of the 33 most frequently reported pathogenic SNVs, 70% were targetable with a base editor. The most common pathogenic variant was c.2843G>A, p.Cys948Arg, which is targetable with an ABE. Since 62% of pathogenic CRB1 SNVs are amenable to correction with a base editor and 87% of these mutations had a suitable PAM site, gene editing represents a promising therapeutic avenue for CRB1-associated retinal degenerations.

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Section: Discussionmentioning

confidence: 99%

In Silico Analysis of Pathogenic CRB1 Single Nucleotide Variants and Their Amenability to Base Editing as a Potential Lead for Therapeutic Intervention

Bellingrath

McClements

Kaukonen

et al. 2021

Genes

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“…All RHO variants in the publicly available Leiden Open Variation Database (LOVD) 3.0 ( , accessed on 19 April 2022) [ 21 ], ClinVar ( , accessed on 19 April 2022) [ 22 ] and Genome Aggregation Database (gnomAD) v2.1.1 ( , accessed on 19 April 2022) [ 23 ] were downloaded on 19 April 2022 using the GRCh37/h19 genome build as the reference genome and ENST00000296271 as the reference transcript. First, each dataset was analyzed separately to characterize and compare their contents.…”

Section: Methodsmentioning

confidence: 99%

CRISPR DNA Base Editing Strategies for Treating Retinitis Pigmentosa Caused by Mutations in Rhodopsin

Kaukonen

McClements

MacLaren

2022

Genes

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Retinitis pigmentosa (RP) is the most common group of inherited retinal degenerations and pathogenic variants in the Rhodopsin (RHO) gene are major cause for autosomal dominant RP (adRP). Despite extensive attempts to treat RHO-associated adRP, standardized curative treatment is still lacking. Recently developed base editors offer an exciting opportunity to correct pathogenic single nucleotide variants and are currently able to correct all transition variants and some transversion variants. In this study, we analyzed previously reported pathogenic RHO variants (n = 247) for suitable PAM sites for currently available base editors utilizing the Streptococcus pyogenes Cas9 (SpCas9), Staphylococcus aureus Cas9 (SaCas9) or the KKH variant of SaCas9 (KKH-SaCas9) to assess DNA base editing as a treatment option for RHO-associated adRP. As a result, 55% of all the analyzed variants could, in theory, be corrected with base editors, however, PAM sites were available for only 32% of them and unwanted bystander edits were predicted for the majority of the designed guide RNAs. As a conclusion, base editing offers exciting possibilities to treat RHO-associated adRP in the future, but further research is needed to develop base editing constructs that will provide available PAM sites for more variants and that will not introduce potentially harmful bystander edits.

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“…Clinical database information was obtained from NF2 registries located in the Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester, England, UK and The University of Alabama at Birmingham, AL, USA. The publically accessible variant databases included were Leiden Open Variation Database (LOVD) (http://www.lovd.nl) (Fokkema et al, 2021), ClinVar NCBI (http://www.ncbi.nlm.nih.gov/clinvar) (Landrum et al, 2018), the Human Gene Mutation Database (HGMD) (http://www.hgmd.cf.ac.uk/ac/all.php) (Stenson et al, 2020), Clinical Interpretation of Variants in Cancer (CIViC) (https://civicdb.org/home) and Mastermind Genomic Search Engine (https://www.genomenon.com/mastermind). Details of duplicate variants were merged to retain relevant clinical information.…”

Section: Methodsmentioning

confidence: 99%

Re‐evaluation of missense variant classifications in NF2

et al. 2022

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Missense variants in the NF2 gene result in variable NF2 disease presentation. Clinical classification of missense variants often represents a challenge, due to lack of evidence for pathogenicity and function. This study provides a summary of NF2 missense variants, with variant classifications based on currently available evidence. NF2 missense variants were collated from pathology‐associated databases and existing literature. Association for Clinical Genomic Sciences Best Practice Guidelines (2020) were followed in the application of evidence for variant interpretation and classification. The majority of NF2 missense variants remain classified as variants of uncertain significance. However, NF2 missense variants identified in gnomAD occurred at a consistent rate across the gene, while variants compiled from pathology‐associated databases displayed differing rates of variation by exon of NF2. The highest rate of NF2 disease‐associated variants was observed in exon 7, while lower rates were observed toward the C‐terminus of the NF2 protein, merlin. Further phenotypic information associated with variants, alongside variant‐specific functional analysis, is necessary for more definitive variant interpretation. Our data identified differences in frequency of NF2 missense variants by exon between gnomAD population data and NF2 disease‐associated variants, suggesting a potential genotype‐phenotype correlation; further work is necessary to substantiate this.

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The LOVD3 platform: efficient genome-wide sharing of genetic variants

Cited by 90 publications

References 12 publications

In Silico Analysis of Pathogenic CRB1 Single Nucleotide Variants and Their Amenability to Base Editing as a Potential Lead for Therapeutic Intervention

In Silico Analysis of Pathogenic CRB1 Single Nucleotide Variants and Their Amenability to Base Editing as a Potential Lead for Therapeutic Intervention

CRISPR DNA Base Editing Strategies for Treating Retinitis Pigmentosa Caused by Mutations in Rhodopsin

Re‐evaluation of missense variant classifications in NF2

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