scholarly journals Rare Missense Functional Variants at COL4A1 and COL4A2 in Sporadic Intracerebral Hemorrhage

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012227
Author(s):  
Jaeyoon Chung ◽  
Graham Hamilton ◽  
Minsup Kim ◽  
Sandro Marini ◽  
Bailey Montgomery ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
In Silico ◽  
Minor Allele ◽  
Sequencing Data ◽  
Functional Impact ◽  
Impact Prediction ◽  
Missense Variants ◽  
Association Testing ◽  
Rare Variant Analysis ◽  
Functional Variants

ObjectiveTo test the genetic contribution of rare missense variants in COL4A1 and COL4A2 in which common variants are genetically associated with sporadic intracerebral hemorrhage (ICH), we performed rare variant analysis in multiple sequencing data for the risk for sporadic ICH.MethodsWe performed sequencing across 559Kbp at 13q34 including COL4A1 and COL4A2 among 2,133 individuals (1,055 ICH cases; 1,078 controls) in US-based and 1,492 individuals (192 ICH cases; 1,189 controls) from Scotland-based cohorts, followed by sequence annotation, functional impact prediction, genetic association testing, and in silico thermodynamic modeling.ResultsWe identified 107 rare nonsynonymous variants in sporadic ICH, of which two missense variants, rs138269346 (COL4A1I110T) and rs201716258 (COL4A2H203L), were predicted to be highly functional and occurred in multiple ICH cases but not in controls from the US-based cohort. The minor allele of rs201716258 was also present in Scottish ICH patients, and rs138269346 was observed in two ICH-free controls with a history of hypertension and myocardial infarction. Rs138269346 was nominally associated with non-lobar ICH risk (P=0.05), but not with lobar ICH (P=0.08), while associations between rs201716258 and ICH subtypes were non-significant (P>0.12). Both variants were considered pathogenic based on minor allele frequency (<0.00035 in EUR), predicted functional impact (deleterious or probably damaging), and in silico modeling studies (substantially altered physical length and thermal stability of collagen).ConclusionsWe identified rare missense variants in COL4A1/A2 in association with sporadic ICH. Our annotation and simulation studies suggest that these variants are highly functional and may represent targets for translational follow-up.

scholarly journals Damaging coding variants within kainate receptor channel genes are enriched in individuals with schizophrenia, autism and intellectual disabilities

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Maria Koromina ◽  
Miles Flitton ◽  
Alix Blockley ◽  
Ian R. Mellor ◽  
Helen M. Knight
Keyword(s):  
Intellectual Disability ◽  
Ion Channels ◽  
Autism Spectrum ◽  
Decay Rates ◽  
Kainate Receptors ◽  
Sequencing Data ◽  
Missense Variants ◽  
Functional Studies ◽  
Neurodevelopmental Disease ◽  
Functional Variants

AbstractSchizophrenia (Scz), autism spectrum disorder (ASD) and intellectual disability are common complex neurodevelopmental disorders. Kainate receptors (KARs) are ionotropic glutamate ion channels involved in synaptic plasticity which are modulated by auxiliary NETO proteins. Using UK10K exome sequencing data, we interrogated the coding regions of KAR and NETO genes in individuals with Scz, ASD or intellectual disability and population controls; performed follow-up genetic replication studies; and, conducted in silico and in vitro functional studies. We found an excess of Loss-of-Function and missense variants in individuals with Scz compared with control individuals (p = 1.8 × 10−10), and identified a significant burden of functional variants for Scz (p < 1.6 × 10−11) and ASD (p = 6.9 × 10−18). Single allele associations for 6 damaging missense variants were significantly replicated (p < 5.0 × 10−15) and confirmed GRIK3 S310A as a protective genetic factor. Functional studies demonstrated that three missense variants located within GluK2 and GluK4, GluK2 (K525E) and GluK4 (Y555N, L825W), affect agonist sensitivity and current decay rates. These findings establish that genetic variation in KAR receptor ion channels confers risk for schizophrenia, autism and intellectual disability and provide new genetic and pharmacogenetic biomarkers for neurodevelopmental disease.

scholarly journals Prediction of the functional impact of missense variants in BRCA1 and BRCA2 with BRCA-ML

2019 ◽  
Author(s):  
Steven N. Hart ◽  
Eric C. Polley ◽  
Hermella Shimelis ◽  
Siddhartha Yadav ◽  
Fergus J. Couch
Keyword(s):  
Machine Learning ◽  
In Silico ◽  
Accurate Method ◽  
Machine Learning Algorithms ◽  
Data Sources ◽  
Brca1 And Brca2 ◽  
Functional Impact ◽  
Missense Variants ◽  
Functional Assays ◽  
Uncertain Significance

AbstractIn silico predictions of missense variants is an important consideration when interpreting variants of uncertain significance (VUS) in the BRCA1 and BRCA2 genes. We trained and evaluated hundreds of machine learning algorithms based on results from validated functional assays to better predict missense variants in these genes as damaging or neutral. This new optimal “BRCA-ML” model yielded a substantially more accurate method than current algorithms for interpreting the functional impact of variants in these genes, making BRCA-ML a valuable addition to data sources for VUS classification.

3D mapping and in silico predictions of the DEHAL1 enzyme as a tool to discriminate pathogenic mutations from non-functional variants in hypothyroidism

2019 ◽  
Author(s):  
Garcia-Gimenez Jorge ◽  
Gonzalez Wong Angel ◽  
Gonzalez-Guerrero Cristian ◽  
Iglesias Ainhoa ◽  
Styrers Emily ◽  
...  
Keyword(s):  
In Silico ◽  
3D Mapping ◽  
Functional Variants ◽  
Pathogenic Mutations ◽  
In Silico Predictions

An Update of In Silico Tools for the Prediction of Pathogenesis in Missense Variants

2011 ◽  
Vol 6 (2) ◽  
pp. 185-198
Author(s):  
Alejandro j. Brea-Fernandez ◽  
Marta Ferro ◽  
Ceres Fernandez-Rozadilla ◽  
Ana Blanco ◽  
Laura Fachal ◽  
...  
Keyword(s):  
In Silico ◽  
Missense Variants ◽  
In Silico Tools

scholarly journals Common Treatment, Common Variant: Evolutionary Prediction of Functional Pharmacogenomic Variants

2021 ◽  
Vol 11 (2) ◽  
pp. 131
Author(s):  
Laura B. Scheinfeldt ◽  
Andrew Brangan ◽  
Dara M. Kusic ◽  
Sudhir Kumar ◽  
Neda Gharani
Keyword(s):  
In Silico ◽  
Drug Efficacy ◽  
Common Variant ◽  
Genomic Research ◽  
Whole Genome Sequencing Data ◽  
Mendelian Disease ◽  
Allele Frequency Distribution ◽  
Sequencing Data ◽  
Patient Race ◽  
The Impact

Pharmacogenomics holds the promise of personalized drug efficacy optimization and drug toxicity minimization. Much of the research conducted to date, however, suffers from an ascertainment bias towards European participants. Here, we leverage publicly available, whole genome sequencing data collected from global populations, evolutionary characteristics, and annotated protein features to construct a new in silico machine learning pharmacogenetic identification method called XGB-PGX. When applied to pharmacogenetic data, XGB-PGX outperformed all existing prediction methods and identified over 2000 new pharmacogenetic variants. While there are modest pharmacogenetic allele frequency distribution differences across global population samples, the most striking distinction is between the relatively rare putatively neutral pharmacogene variants and the relatively common established and newly predicted functional pharamacogenetic variants. Our findings therefore support a focus on individual patient pharmacogenetic testing rather than on clinical presumptions about patient race, ethnicity, or ancestral geographic residence. We further encourage more attention be given to the impact of common variation on drug response and propose a new ‘common treatment, common variant’ perspective for pharmacogenetic prediction that is distinct from the types of variation that underlie complex and Mendelian disease. XGB-PGX has identified many new pharmacovariants that are present across all global communities; however, communities that have been underrepresented in genomic research are likely to benefit the most from XGB-PGX’s in silico predictions.

scholarly journals Massive parallel sequencing in a family with rectal cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Karin Wallander ◽  
Jessada Thutkawkorapin ◽  
Ellika Sahlin ◽  
Annika Lindblom ◽  
Kristina Lagerstedt-Robinson
Keyword(s):  
Rectal Cancer ◽  
Genetic Variant ◽  
Family Members ◽  
Wnt Signaling Pathway ◽  
Massive Parallel Sequencing ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Cancer Syndrome ◽  
Parallel Sequencing ◽  
Missense Variants

Abstract Background We have previously reported a family with a suspected autosomal dominant rectal and gastric cancer syndrome without any obvious causative genetic variant. Here, we focused the study on a potentially isolated rectal cancer syndrome in this family. Methods We included seven family members (six obligate carriers). Whole-exome sequencing and whole-genome sequencing data were analyzed and filtered for shared coding and splicing sequence and structural variants among the affected individuals. Results When considering family members with rectal cancer or advanced adenomas as affected, we found six new potentially cancer-associated variants in the genes CENPB, ZBTB20, CLINK, LRRC26, TRPM1, and NPEPL1. All variants were missense variants and none of the genes have previously been linked to inherited rectal cancer. No structural variant was found. Conclusion By massive parallel sequencing in a family suspected of carrying a highly penetrant rectal cancer predisposing genetic variant, we found six genetic missense variants with a potential connection to the rectal cancer in this family. One of them could be a high-risk genetic variant, or one or more of them could be low risk variants. The p.(Glu438Lys) variant in the CENPB gene was found to be of particular interest. The CENPB protein binds DNA and helps form centromeres during mitosis. It is involved in the WNT signaling pathway, which is critical for colorectal cancer development and its role in inherited rectal cancer needs to be further examined.

scholarly journals Characterisation of protein-truncating and missense variants in PALB2 in 15 768 women from Malaysia and Singapore

2021 ◽  
pp. jmedgenet-2020-107471
Author(s):  
Pei Sze Ng ◽  
Rick ACM Boonen ◽  
Eldarina Wijaya ◽  
Chan Eng Chong ◽  
Milan Sharma ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Rare Variants ◽  
Embryonic Stem ◽  
Mouse Embryonic Stem Cell ◽  
Population Based ◽  
Breast Cancer Patients ◽  
Dna Double Strand Breaks ◽  
Functional Impact ◽  
Missense Variants ◽  
Increased Risk

BackgroundRare protein-truncating variants (PTVs) in partner and localiser of BRCA2 (PALB2) confer increased risk to breast cancer, but relatively few studies have reported the prevalence in South-East Asian populations. Here, we describe the prevalence of rare variants in PALB2 in a population-based study of 7840 breast cancer cases and 7928 healthy Chinese, Malay and Indian women from Malaysia and Singapore, and describe the functional impact of germline missense variants identified in this population.MethodsMutation testing was performed on germline DNA (n=15 768) using targeted sequencing panels. The functional impact of missense variants was tested in mouse embryonic stem cell based functional assays.ResultsPTVs in PALB2 were found in 0.73% of breast cancer patients and 0.14% of healthy individuals (OR=5.44; 95% CI 2.85 to 10.39, p<0.0001). In contrast, rare missense variants in PALB2 were not associated with increased risk of breast cancer. Whereas PTVs were associated with later stage of presentation and higher-grade tumours, no significant association was observed with missense variants in PALB2. However, two novel rare missense variants (p.L1027R and p.G1043V) produced unstable proteins and resulted in a decrease in homologous recombination-mediated repair of DNA double-strand breaks.ConclusionDespite genetic and lifestyle differences between Asian and other populations, the population prevalence of PALB2 PTVs and associated relative risk of breast cancer, are similar to those reported in European populations.

scholarly journals Rare variant pathogenicity triage and inclusion of synonymous variants improves analysis of disease associations

2018 ◽  
Author(s):  
Ridge Dershem ◽  
Raghu P.R. Metpally ◽  
Kirk Jeffreys ◽  
Sarathbabu Krishnamurthy ◽  
Diane T. Smelser ◽  
...  
Keyword(s):  
Rare Variant ◽  
Functional Characterization ◽  
Data Sets ◽  
Common Variants ◽  
Loss Of Function ◽  
Altered Expression ◽  
Missense Variants ◽  
Association Testing ◽  
Disease Associations ◽  
Causes Of Disease

AbstractMany G protein-coupled receptors (GPCRs) lack common variants that lead to reproducible genome-wide disease associations. Here we used rare variant approaches to assess the disease associations of 85 orphan or understudied GPCRs in an unselected cohort of 51,289 individuals. Rare loss-of-function variants, missense variants predicted to be pathogenic or likely pathogenic, and a subset of rare synonymous variants were used as independent data sets for sequence kernel association testing (SKAT). Strong, phenome-wide disease associations shared by two or more variant categories were found for 39% of the GPCRs. Validating the bioinformatics and SKAT analyses, functional characterization of rare missense and synonymous variants of GPR39, a Family A GPCR, showed altered expression and/or Zn2+-mediated signaling for members of both variant classes. Results support the utility of rare variant analyses for identifying disease associations for genes that lack common variants, while also highlighting the functional importance of rare synonymous variants.Author summaryRare variant approaches have emerged as a viable way to identify disease associations for genes without clinically important common variants. Rare synonymous variants are generally considered benign. We demonstrate that rare synonymous variants represent a potentially important dataset for deriving disease associations, here applied to analysis of a set of orphan or understudied GPCRs. Synonymous variants yielded disease associations in common with loss-of-function or missense variants in the same gene. We rationalize their associations with disease by confirming their impact on expression and agonist activation of a representative example, GPR39. This study highlights the importance of rare synonymous variants in human physiology, and argues for their routine inclusion in any comprehensive analysis of genomic variants as potential causes of disease.

scholarly journals A combined in silico, in vitro and clinical approach to characterise novel pathogenic missense variants in PRPF31 in retinitis pigmentosa

2018 ◽  
Author(s):  
Gabrielle Wheway ◽  
Liliya Nazlamova ◽  
Nervine Meshad ◽  
Samantha Hunt ◽  
Nicola Jackson ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
In Silico ◽  
Autosomal Dominant ◽  
Missense Variant ◽  
Incomplete Penetrance ◽  
Clinical Approach ◽  
Loss Of Function ◽  
Autosomal Dominant Retinitis Pigmentosa ◽  
Missense Variants

AbstractAt least six different proteins of the spliceosome, including PRPF3, PRPF4, PRPF6, PRPF8, PRPF31 and SNRNP200, are mutated in autosomal dominant retinitis pigmentosa (adRP). These proteins have recently been shown to localise to the base of the connecting cilium of the retinal photoreceptor cells, elucidating this form of RP as a retinal ciliopathy. In the case of loss-of-function variants in these genes, pathogenicity can easily be ascribed. In the case of missense variants, this is more challenging. Furthermore, the exact molecular mechanism of disease in this form of RP remains poorly understood.In this paper we take advantage of the recently published cryo EM-resolved structure of the entire human spliceosome, to predict the effect of a novel missense variant in one component of the spliceosome; PRPF31, found in a patient attending the genetics eye clinic at Bristol Eye Hospital. Monoallelic variants in PRPF31 are a common cause of autosomal dominant retinitis pigmentosa (adRP) with incomplete penetrance. We use in vitro studies to confirm pathogenicity of this novel variant PRPF31 c.341T>A, p.Ile114Asn.This work demonstrates how in silico modelling of structural effects of missense variants on cryo-EM resolved protein complexes can contribute to predicting pathogenicity of novel variants, in combination with in vitro and clinical studies. It is currently a considerable challenge to assign pathogenic status to missense variants in these proteins.

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