scholarly journals Prioritizing variants in complete Hereditary Breast and Ovarian Cancer (HBOC) genes in patients lacking known BRCA mutations

2016 ◽  
Author(s):  
Natasha G Caminsky ◽  
Eliseos J Mucaki ◽  
Ami M. Perri ◽  
Ruipeng Lu ◽  
Joan H.M. Knoll ◽  
...  
Keyword(s):  
Binding Sites ◽  
Rna Binding ◽  
Wide Spectrum ◽  
Pedigree Information ◽  
Brca Mutations ◽  
Pathogenic Variants ◽  
Uncertain Significance ◽  
Common Framework ◽  
Flanking Sequences ◽  
Coding Variants

BRCA1andBRCA2testing for HBOC does not identify all pathogenic variants. Sequencing of 20 complete genes in HBOC patients with uninformative test results (N=287), including non-coding and flanking sequences ofATM,BARD1,BRCA1,BRCA2,CDH1,CHEK2,EPCAM,MLH1,MRE11A,MSH2,MSH6,MUTYH,NBN,PALB2,PMS2,PTEN,RAD51B,STK11,TP53, andXRCC2, identified 38,372 unique variants. We apply information theory (IT) to predict novel functions for and prioritize non-coding variants of uncertain significance (VUS) in throughout regulatory, coding, and intronic regions based on changes in binding sites in these genesof these genes. Besides mRNA splicing, IT provides a common framework to evaluate potential affinity changes inin transcription factor (TFBSs), splicing regulatory (SRBSs), and RNA-binding protein (RBBSs) protein binding sites following mutationat mutated binding sites. We prioritized variants affecting the strengths of 10 variants affecting splice sites (4 natural, 6 cryptic), 148 SRBS, 36 TFBS, and 31 RBBS binding strength-affecting variantss. Three variants were also prioritized based on their predicted effects on mRNA secondary (2°) structure, and 17 for pseudoexon activation. Additionally, 4 frameshift, 2 in-frame deletions, and 5 stop-gain mutations were identified. When combined with pedigree information, complete gene sequence analysis can focus attention on a limited set of variants in a wide spectrum of functional mutation types for downstream functional and co-segregation analysis.

scholarly journals Genetic Basis of Alternative Polyadenylation is an Emerging Molecular Phenotype for Human Traits and Diseases

2019 ◽  
Author(s):  
Lei Li ◽  
Yipeng Gao ◽  
Fanglue Peng ◽  
Eric J. Wagner ◽  
Wei Li
Keyword(s):  
Genetic Variants ◽  
Binding Sites ◽  
Genetic Basis ◽  
Target Genes ◽  
Rna Binding ◽  
Rna Binding Protein ◽  
Alternative Polyadenylation ◽  
Molecular Phenotype ◽  
Protein Binding Sites ◽  
Coding Variants

SUMMARYGenome-wide association studies have identified thousands of non-coding variants that are statistically associated with human traits and diseases. However, functional interpretation of these variants remains a major challenge. Here, we describe the first atlas of human 3’-UTR alternative polyadenylation (APA) Quantitative Trait Loci (3’QTLs), i.e. ∼0.4 million genetic variants associated with APA of target genes across 46 Genotype-Tissue Expression (GTEx) tissues from 467 individuals. APA occurs in approximately 70% of human genes and substantively impacts cellular proliferation, differentiation and tumorigenesis. Mechanistically, 3’QTLs could alter polyA motifs and RNA-binding protein binding sites, leading to thousands of APA changes. Importantly, 3’QTLs can be used to interpret ∼16.1% of trait-associated variants and are largely distinct from other QTLs such as eQTLs. The genetic basis of APA (3’QTLs) thus represent a novel molecular phenotype to explain a large fraction of non-coding variants and to provide new insights into complex traits and disease etiologies.HighlightsThe first atlas of human 3’QTLs: ∼0.4 million genetic variants associated with alternative polyadenylation of target genes across 46 tissues from 467 individuals3’QTLs could alter polyA motifs and RNA-binding protein binding sites3’QTLs can be used to interpret ∼16.1% of trait-associated variantsMany disease-associated 3’QTLs contribute to phenotype independent of gene expression

scholarly journals Combined analysis of genome sequencing and RNA-motifs reveals novel damaging non-coding mutations in human tumors

2017 ◽  
Author(s):  
Babita Singh ◽  
Juan L. Trincado ◽  
PJ Tatlow ◽  
Stephen R. Piccolo ◽  
Eduardo Eyras
Keyword(s):  
Binding Sites ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Sequencing Data ◽  
Rna Motifs ◽  
Regulatory Motifs ◽  
Coding Regions ◽  
Selection Processes ◽  
Coding Variants ◽  
Regulatory Sites

AbstractA major challenge in cancer research is to determine the biological and clinical significance of somatic mutations in non-coding regions. This has been studied in terms of recurrence, functional impact, and association to individual regulatory sites, but the combinatorial contribution of mutations to common RNA regulatory motifs has not been explored. We developed a new method, MIRA, to perform the first comprehensive study of significantly mutated regions (SMRs) affecting binding sites for RNA-binding proteins (RBPs) in cancer. Extracting signals related to RNA-related selection processes and using RNA sequencing data from the same samples we identified alterations in RNA expression and splicing linked to mutations on RBP binding sites. We found SRSF10 and MBNL1 motifs in introns, HNRPLL motifs at 5’ UTRs, as well as 5’ and 3’ splice-site motifs, among others, with specific mutational patterns that disrupt the motif and impact RNA processing. MIRA facilitates the integrative analysis of multiple genome sites that operate collectively through common RBPs and can aid in the interpretation of non-coding variants in cancer. MIRA is available athttps://github.com/comprna/mira.

scholarly journals Case Report: Functional Investigation of an Undescribed Missense Variant Affecting Splicing in a Patient With Dravet Syndrome

2021 ◽  
Vol 12 ◽  
Author(s):  
Peter Sparber ◽  
Svetlana Mikhaylova ◽  
Varvara Galkina ◽  
Yulia Itkis ◽  
Mikhail Skoblov
Keyword(s):  
Missense Variant ◽  
Febrile Seizures ◽  
Dravet Syndrome ◽  
Loss Of Function ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Pathogenic Variants ◽  
Uncertain Significance ◽  
Functional Investigation ◽  
Coding Variants

Pathogenic variants in the SCN1A gene are associated with a spectrum of epileptic disorders ranging in severity from familial febrile seizures to Dravet syndrome. Large proportions of reported pathogenic variants in SCN1A are annotated as missense variants and are often classified as variants of uncertain significance when no functional data are available. Although loss-of-function variants are associated with a more severe phenotype in SCN1A, the molecular mechanism of single nucleotide variants is often not clear, and genotype-phenotype correlations in SCN1A-related epilepsy remain uncertain. Coding variants can affect splicing by creating novel cryptic splicing sites in exons or by disrupting exonic cis-regulation elements crucial for proper pre-mRNA splicing. Here, we report a novel case of Dravet syndrome caused by an undescribed missense variant, c.4852G>A (p.(Gly1618Ser)). By midigene splicing assay, we demonstrated that the identified variant is in fact splice-affecting. To our knowledge, this is the first report on the functional investigation of a missense variant affecting splicing in Dravet syndrome.

CSBPI_Site：Multi-Information Sources of Features to RNA Binding Sites Prediction

2021 ◽  
Vol 15 ◽  
Author(s):  
Lichao Zhang ◽  
Zihong Huang ◽  
Liang Kong
Keyword(s):  
Computational Model ◽  
Binding Sites ◽  
Noncoding Rna ◽  
Computational Models ◽  
Information Sources ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Gradient Boosting ◽  
Position Information ◽  
Rna Binding Sites

Background: RNA-binding proteins establish posttranscriptional gene regulation by coordinating the maturation, editing, transport, stability, and translation of cellular RNAs. The immunoprecipitation experiments could identify interaction between RNA and proteins, but they are limited due to the experimental environment and material. Therefore, it is essential to construct computational models to identify the function sites. Objective: Although some computational methods have been proposed to predict RNA binding sites, the accuracy could be further improved. Moreover, it is necessary to construct a dataset with more samples to design a reliable model. Here we present a computational model based on multi-information sources to identify RNA binding sites. Method: We construct an accurate computational model named CSBPI_Site, based on xtreme gradient boosting. The specifically designed 15-dimensional feature vector captures four types of information (chemical shift, chemical bond, chemical properties and position information). Results: The satisfied accuracy of 0.86 and AUC of 0.89 were obtained by leave-one-out cross validation. Meanwhile, the accuracies were slightly different (range from 0.83 to 0.85) among three classifiers algorithm, which showed the novel features are stable and fit to multiple classifiers. These results showed that the proposed method is effective and robust for noncoding RNA binding sites identification. Conclusion: Our method based on multi-information sources is effective to represent the binding sites information among ncRNAs. The satisfied prediction results of Diels-Alder riboz-yme based on CSBPI_Site indicates that our model is valuable to identify the function site.

scholarly journals Contribution of SLC22A12 on hypouricemia and its clinical significance for screening purposes

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Do Hyeon Cha ◽  
Heon Yung Gee ◽  
Raul Cachau ◽  
Jong Mun Choi ◽  
Daeui Park ◽  
...  
Keyword(s):  
Genetic Diagnosis ◽  
Kidney Injury ◽  
Genetic Identification ◽  
Diagnostic Screening ◽  
Renal Hypouricemia ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Causal Variants ◽  
Coding Variants ◽  
Independent Cohort

Abstract Differentiating between inherited renal hypouricemia and transient hypouricemic status is challenging. Here, we aimed to describe the genetic background of hypouricemia patients using whole-exome sequencing (WES) and assess the feasibility for genetic diagnosis using two founder variants in primary screening. We selected all cases (N = 31) with extreme hypouricemia (<1.3 mg/dl) from a Korean urban cohort of 179,381 subjects without underlying conditions. WES and corresponding downstream analyses were performed for the discovery of rare causal variants for hypouricemia. Two known recessive variants within SLC22A12 (p.Trp258*, pArg90His) were identified in 24 out of 31 subjects (77.4%). In an independent cohort, we identified 50 individuals with hypouricemia and genotyped the p.Trp258* and p.Arg90His variants; 47 of the 50 (94%) hypouricemia cases were explained by only two mutations. Four novel coding variants in SLC22A12, p.Asn136Lys, p.Thr225Lys, p.Arg284Gln, and p.Glu429Lys, were additionally identified. In silico studies predict these as pathogenic variants. This is the first study to show the value of genetic diagnostic screening for hypouricemia in the clinical setting. Screening of just two ethnic-specific variants (p.Trp258* and p.Arg90His) identified 87.7% (71/81) of Korean patients with monogenic hypouricemia. Early genetic identification of constitutive hypouricemia may prevent acute kidney injury by avoidance of dehydration and excessive exercise.

scholarly journals Tumour Versus Germline BRCA Testing in Ovarian Cancer: A Single-Site Institution Experience in the United Kingdom

Diagnostics ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 547
Author(s):  
Iolia Akaev ◽  
Siavash Rahimi ◽  
Olubukola Onifade ◽  
Francis John Edward Gardner ◽  
David Castells-Rufas ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Unknown Origin ◽  
Parp Inhibitors ◽  
Serous Carcinoma ◽  
High Grade ◽  
Brca1 And Brca2 ◽  
Brca Mutations ◽  
Epithelial Cancers ◽  
Pathogenic Variants ◽  
Pathogenic Mutations

The aim of this audit was to evaluate the usefulness and serviceability of testing for pathogenic mutations in BRCA1 or BRCA2 (BRCA1/2) genes in ovarian cancer (OC) patients. One hundred and thirty-five patients with more common histological sub-types of OC were retrospectively identified between 2011 and 2019. The fail rate of the molecular analysis was 7.4% (10/135). One hundred and twenty-five records were evaluated: 99 (79.2%) patients had wild-type BRCA (both somatic and germline); tumour BRCA1/2 (tBRCA1/2) pathogenic mutations were found in 20 (16%) patients with distribution between BRCA1 and BRCA2 being 40% and 60%, respectively; 13 (10.4%) patients with pathogenic variants had germline mutations; and tBRCA1/2 with variant of unknown significance (VUS), in the absence of pathogenic BRCA1 or BRCA2 variants, was detected in 6 (4.8%) patients. Our data show that expanding the molecular service to the routine first-tumour testing for patients with OC will potentially increase the detection rate of BRCA mutations, thereby providing early benefits of PARP inhibitors therapy. The tumour testing service should continue to be offered to newly diagnosed patients with high-grade epithelial cancers, including high-grade serous carcinoma, but also with carcinosarcomas and poorly-differentiated metastatic adenocarcinomas of unknown origin.

scholarly journals Mild Clinical Presentation of Joubert Syndrome in a Male Adult Carrying Biallelic MKS1 Truncating Variants

Diagnostics ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1218
Author(s):  
Raffaella Brunetti-Pierri ◽  
Marianthi Karali ◽  
Francesco Testa ◽  
Gerarda Cappuccio ◽  
Maria Elena Onore ◽  
...  
Keyword(s):  
Wide Spectrum ◽  
Clinical Manifestations ◽  
Brain Magnetic Resonance Imaging ◽  
Joubert Syndrome ◽  
Male Adult ◽  
Full Field ◽  
Pathogenic Variants ◽  
Disease Spectrum ◽  
Male Individual ◽  
The Central Nervous System

Pathogenic variants in the MKS1 gene are responsible for a ciliopathy with a wide spectrum of clinical manifestations ranging from Meckel and Joubert syndrome (JBTS) to Bardet-Biedl syndrome, and involving the central nervous system, liver, kidney, skeleton, and retina. We report a 39-year-old male individual presenting with isolated Retinitis Pigmentosa (RP), as assessed by full ophthalmological evaluation including Best-Corrected Visual Acuity measurements, fundus examination, Goldmann Visual Field test, and full-field Electroretinography. A clinical exome identified biallelic nonsense variants in MKS1 that prompted post-genotyping investigations for systemic abnormalities of ciliopathy. Brain magnetic resonance imaging revealed malformations of the posterior cranial fossa with the ‘molar tooth sign’ and cerebellar folia dysplasia, which are both distinctive features of JBTS. No other organ or skeletal abnormalities were detected. This case illustrates the power of clinical exome for the identification of the mildest forms of a disease spectrum, such as a mild JBTS with RP in the presented case of an individual carrying biallelic truncating variants in MKS1.

scholarly journals Janus-faced EPHB4-associated disorders: novel pathogenic variants and unreported intrafamilial overlapping phenotypes

2021 ◽  
Author(s):  
Silvia Martin-Almedina ◽  
Kazim Ogmen ◽  
Ege Sackey ◽  
Dionysios Grigoriadis ◽  
Christina Karapouliou ◽  
...  
Keyword(s):  
Subcellular Localization ◽  
Fetal Hydrops ◽  
Clinical Phenotypes ◽  
Functional Studies ◽  
Pathogenic Variants ◽  
Disease Mechanisms ◽  
Novel Variants ◽  
Uncertain Significance ◽  
Clinical Phenotyping

Abstract Purpose Several clinical phenotypes including fetal hydrops, central conducting lymphatic anomaly or capillary malformations with arteriovenous malformations 2 (CM-AVM2) have been associated with EPHB4 (Ephrin type B receptor 4) variants, demanding new approaches for deciphering pathogenesis of novel variants of uncertain significance (VUS) identified in EPHB4, and for the identification of differentiated disease mechanisms at the molecular level. Methods Ten index cases with various phenotypes, either fetal hydrops, CM-AVM2, or peripheral lower limb lymphedema, whose distinct clinical phenotypes are described in detail in this study, presented with a variant in EPHB4. In vitro functional studies were performed to confirm pathogenicity. Results Pathogenicity was demonstrated for six of the seven novel EPHB4 VUS investigated. A heterogeneity of molecular disease mechanisms was identified, from loss of protein production or aberrant subcellular localization to total reduction of the phosphorylation capability of the receptor. There was some phenotype–genotype correlation; however, previously unreported intrafamilial overlapping phenotypes such as lymphatic-related fetal hydrops (LRFH) and CM-AVM2 in the same family were observed. Conclusion This study highlights the usefulness of protein expression and subcellular localization studies to predict EPHB4 variant pathogenesis. Our accurate clinical phenotyping expands our interpretation of the Janus-faced spectrum of EPHB4-related disorders, introducing the discovery of cases with overlapping phenotypes.

scholarly journals Critical Flanking Sequences of PU.1 Binding Sites in Myeloid-specific Promoters

1999 ◽  
Vol 274 (45) ◽  
pp. 32453-32460 ◽  
Author(s):  
Sen-Lin Li ◽  
Werner Schlegel ◽  
Anthony J. Valente ◽  
Robert A. Clark
Keyword(s):  
Binding Sites ◽  
Flanking Sequences
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