Predicting the effects of frameshifting indels

Hu, Jing; Ng, Pauline C.

doi:10.1186/gb-2012-13-2-r9

Cited by 105 publications

(110 citation statements)

References 50 publications

(65 reference statements)

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“…To our knowledge, this is the first reported disease allele outside LRAT exon2 48 51–53. The c.613_614del is predicted to change the 205–230 amino acids in the C terminus of LRAT protein, which is thought to be important for the LRAT protein enzymatic activity and its localisation to the endoplasmic reticulum membrane 54 55. Second, eight patients carried one reported mutation plus one novel LOF mutation.…”

Section: Resultsmentioning

confidence: 99%

Comprehensive molecular diagnosis of 179 Leber congenital amaurosis and juvenile retinitis pigmentosa patients by targeted next generation sequencing

et al. 2013

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Background Leber congenital amaurosis (LCA) and juvenile retinitis pigmentosa (RP) are inherited retinal diseases that cause early onset severe visual impairment. An accurate molecular diagnosis can refine the clinical diagnosis and allow gene specific treatments. Methods We developed a capture panel that enriches the exonic DNA of 163 known retinal disease genes. Using this panel, we performed targeted next generation sequencing (NGS) for a large cohort of 179 unrelated and prescreened patients with the clinical diagnosis of LCA or juvenile RP. Systematic NGS data analysis, Sanger sequencing validation, and segregation analysis were utilised to identify the pathogenic mutations. Patients were revisited to examine the potential phenotypic ambiguity at the time of initial diagnosis. Results Pathogenic mutations for 72 patients (40%) were identified, including 45 novel mutations. Of these 72 patients, 58 carried mutations in known LCA or juvenile RP genes and exhibited corresponding phenotypes, while 14 carried mutations in retinal disease genes that were not consistent with their initial clinical diagnosis. We revisited patients in the latter case and found that homozygous mutations in PRPH2 can cause LCA/juvenile RP. Guided by the molecular diagnosis, we reclassified the clinical diagnosis in two patients. Conclusions We have identified a novel gene and a large number of novel mutations that are associated with LCA/juvenile RP. Our results highlight the importance of molecular diagnosis as an integral part of clinical diagnosis.

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Section: Resultsmentioning

confidence: 99%

Comprehensive molecular diagnosis of 179 Leber congenital amaurosis and juvenile retinitis pigmentosa patients by targeted next generation sequencing

et al. 2013

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“…That is, the fitness of the allele with respect to its associated biological function is likely an underlying trend that appears only after averaging (removing noise from other factors). In previous studies (Hu and Ng 2012;Zhao et al 2013), the expectation that highly populated genetic variants on average should be less likely to be associated with diseases was used successfully as an independent support for predicted disease susceptibility of genetic variants. Thus, if mutation-induced disruption of functional RNA structures is one of the potential causes of diseases (Halvorsen et al 2010), we would expect that predicted RNA accessibilities at mutation sites positively correlate with average MAF values, similar to predicted protein solvent accessibility (Zhao et al 2013).…”

Section: Resultsmentioning

confidence: 99%

Genome-scale characterization of RNA tertiary structures and their functional impact by RNA solvent accessibility prediction

Yang

Zhao

et al. 2016

RNA

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As most RNA structures are elusive to structure determination, obtaining solvent accessible surface areas (ASAs) of nucleotides in an RNA structure is an important first step to characterize potential functional sites and core structural regions. Here, we developed RNAsnap, the first machine-learning method trained on protein-bound RNA structures for solvent accessibility prediction. Built on sequence profiles from multiple sequence alignment (RNAsnap-prof), the method provided robust prediction in fivefold cross-validation and an independent test (Pearson correlation coefficients, r, between predicted and actual ASA values are 0.66 and 0.63, respectively). Application of the method to 6178 mRNAs revealed its positive correlation to mRNA accessibility by dimethyl sulphate (DMS) experimentally measured in vivo (r = 0.37) but not in vitro (r = 0.07), despite the lack of training on mRNAs and the fact that DMS accessibility is only an approximation to solvent accessibility. We further found strong association across coding and noncoding regions between predicted solvent accessibility of the mutation site of a single nucleotide variant (SNV) and the frequency of that variant in the population for 2.2 million SNVs obtained in the 1000 Genomes Project. Moreover, mapping solvent accessibility of RNAs to the human genome indicated that introns, 5 ′ cap of 5 ′ and 3 ′ cap of 3 ′ untranslated regions, are more solvent accessible, consistent with their respective functional roles. These results support conformational selections as the mechanism for the formation of RNA-protein complexes and highlight the utility of genome-scale characterization of RNA tertiary structures by RNAsnap. The server and its stand-alone downloadable version are available at http://sparks-lab.org.

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“…Our first variant category consists of variants identified in an individual where the alleles are found in Human Genome Mutation Database (HGMD) (13,14) and labeled disease-causing mutations (DM). These alleles also were required to be rare [<1% allele frequency in 6,500 exomes from the National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (15) and the 1,000 Genomes Project Genomes (16,17)] and predicted to be damaging to protein function by two of three predictions algorithms [Polyphen 2.0 (18), Sift (19)(20)(21)(22)(23)(24), and MutationTaster (25)] using Database of Human Non-synonymous SNVs and their functional predictions and annotations (dbNSFP) (26) as described in Fig. 2.…”

Section: Resultsmentioning

confidence: 99%

Personalized genomic disease risk of volunteers

Gonzalez-Garay

McGuire

Pereira

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Significance Replacing traditional methods for genetic testing of inheritable disorders with next-generation sequencing (NGS) will reduce the cost of genetic testing and increase the information available for the patients. NGS will become an invaluable resource for the patient and physicians, especially if the sequencing information is stored properly and reanalyzed as bioinformatics tools and annotations improve. NGS is still at the early stages of development, and it is full of false-positive and -negative results and requires infrastructure and specialized personnel to properly analyze the results. This paper will explain our experience with an adult population, our bioinformatics analysis, and our clinical decisions to assure that our genetic diagnostics were accurate to detect carrier status and serious medical conditions in our volunteers.

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Predicting the effects of frameshifting indels

Cited by 105 publications

References 50 publications

Comprehensive molecular diagnosis of 179 Leber congenital amaurosis and juvenile retinitis pigmentosa patients by targeted next generation sequencing

Comprehensive molecular diagnosis of 179 Leber congenital amaurosis and juvenile retinitis pigmentosa patients by targeted next generation sequencing

Genome-scale characterization of RNA tertiary structures and their functional impact by RNA solvent accessibility prediction

Personalized genomic disease risk of volunteers

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