Molecular genetic analysis of cerebral cavernous malformations: an update

Ricci, Claudia; Riolo, Giulia; Battistini, Stefania

doi:10.20517/2574-1209.2021.28

Cited by 2 publications

(2 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since misclassification of variants have been reported for several diseases [128][129][130][131], an accurate evaluation of potential variant impact on splicing is recommended. A scheme resuming the strategy to characterize splice variants is depicted in Figure 6.…”

Section: Splice Variant Characterization In Diagnosticsmentioning

confidence: 99%

What’s Wrong in a Jump? Prediction and Validation of Splice Site Variants

Riolo

Cantara

Ricci

2021

MPs

Self Cite

View full text Add to dashboard Cite

Alternative splicing (AS) is a crucial process to enhance gene expression driving organism development. Interestingly, more than 95% of human genes undergo AS, producing multiple protein isoforms from the same transcript. Any alteration (e.g., nucleotide substitutions, insertions, and deletions) involving consensus splicing regulatory sequences in a specific gene may result in the production of aberrant and not properly working proteins. In this review, we introduce the key steps of splicing mechanism and describe all different types of genomic variants affecting this process (splicing variants in acceptor/donor sites or branch point or polypyrimidine tract, exonic, and deep intronic changes). Then, we provide an updated approach to improve splice variants detection. First, we review the main computational tools, including the recent Machine Learning-based algorithms, for the prediction of splice site variants, in order to characterize how a genomic variant interferes with splicing process. Next, we report the experimental methods to validate the predictive analyses are defined, distinguishing between methods testing RNA (transcriptomics analysis) or proteins (proteomics experiments). For both prediction and validation steps, benefits and weaknesses of each tool/procedure are accurately reported, as well as suggestions on which approaches are more suitable in diagnostic rather than in clinical research.

show abstract

Section: Splice Variant Characterization In Diagnosticsmentioning

confidence: 99%

What’s Wrong in a Jump? Prediction and Validation of Splice Site Variants

Riolo

Cantara

Ricci

2021

MPs

Self Cite

View full text Add to dashboard Cite

show abstract

“…Most of the known pathogenic variants are located in the coding region of the gene, with missense and frameshift variants accounting for the largest proportion. Variants in the non-coding region mainly alter the splicing process ( Spiegler et al, 2018b ; Ricci et al, 2021 ). Very little is known about variants in non-coding regions that potentially affect CCM1 gene expression or protein function.…”

Section: Introductionmentioning

confidence: 99%

Using CRISPR/Cas9 genome editing in human iPSCs for deciphering the pathogenicity of a novel CCM1 transcription start site deletion

Pilz

Skowronek

Hamed

et al. 2022

Front. Mol. Biosci.

View full text Add to dashboard Cite

Cerebral cavernous malformations are clusters of aberrant vessels that can lead to severe neurological complications. Pathogenic loss-of-function variants in the CCM1, CCM2, or CCM3 gene are associated with the autosomal dominant form of the disease. While interpretation of variants in protein-coding regions of the genes is relatively straightforward, functional analyses are often required to evaluate the impact of non-coding variants. Because of multiple alternatively spliced transcripts and different transcription start points, interpretation of variants in the 5′ untranslated and upstream regions of CCM1 is particularly challenging. Here, we identified a novel deletion of the non-coding exon 1 of CCM1 in a proband with multiple CCMs which was initially classified as a variant of unknown clinical significance. Using CRISPR/Cas9 genome editing in human iPSCs, we show that the deletion leads to loss of CCM1 protein and deregulation of KLF2, THBS1, NOS3, and HEY2 expression in iPSC-derived endothelial cells. Based on these results, the variant could be reclassified as likely pathogenic. Taken together, variants in regulatory regions need to be considered in genetic CCM analyses. Our study also demonstrates that modeling variants of unknown clinical significance in an iPSC-based system can help to come to a final diagnosis.

show abstract

Molecular genetic analysis of cerebral cavernous malformations: an update

Cited by 2 publications

References 62 publications

What’s Wrong in a Jump? Prediction and Validation of Splice Site Variants

What’s Wrong in a Jump? Prediction and Validation of Splice Site Variants

Using CRISPR/Cas9 genome editing in human iPSCs for deciphering the pathogenicity of a novel CCM1 transcription start site deletion

Contact Info

Product

Resources

About