scholarly journals Systematic validation of variants of unknown significance in PSEN1

2021 ◽  
Vol 17 (S5) ◽  
Author(s):  
Bhagyashri Burgute ◽  
Alan E. Renton ◽  
Ellen Ziegemeier ◽  
Carlos Cruchaga ◽  
Alison M. Goate ◽  
...  
Keyword(s):  
Variants Of Unknown Significance ◽  
Unknown Significance

scholarly journals Predicting the Functional Impact of KCNQ1 Variants of Unknown Significance

2017 ◽  
Vol 10 (5) ◽  
Author(s):  
Bian Li ◽  
Jeffrey L. Mendenhall ◽  
Brett M. Kroncke ◽  
Keenan C. Taylor ◽  
Hui Huang ◽  
...  
Keyword(s):  
Functional Impact ◽  
Variants Of Unknown Significance ◽  
Unknown Significance

scholarly journals Management of Gene Variants of Unknown Significance: Analysis Method and Risk Assessment of the VHL Mutation p.P81S (c.241C>T)

2016 ◽  
Vol 18 (1) ◽  
pp. 93-103
Author(s):  
Daniela Alosi ◽  
Marie Bisgaard ◽  
Sophie Hemmingsen ◽  
Lotte Krogh ◽  
Hanne Mikkelsen ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Gene Variants ◽  
Analysis Method ◽  
Variants Of Unknown Significance ◽  
Significance Analysis ◽  
Unknown Significance

scholarly journals Very Elevated IgE, Atopy, and Severe Infection: A Genomics-Based Diagnostic Approach to a Spectrum of Diseases

2021 ◽  
Vol 2021 ◽  
pp. 1-5
Author(s):  
A. Chin ◽  
S. Balasubramanyam ◽  
C. M. Davis
Keyword(s):  
Autosomal Dominant ◽  
Severe Infection ◽  
Severe Atopic Dermatitis ◽  
Genomic Testing ◽  
Atopic Diseases ◽  
Variants Of Unknown Significance ◽  
Hyper Ige Syndrome ◽  
Heterozygous Variant ◽  
Unknown Significance ◽  
Multiple Variants

Elevated IgE has been long recognized as an important clinical marker of atopy but can be seen in a myriad of conditions. The discovery of autosomal dominant STAT3 deficiency marked the first recognition of hyper-IgE syndrome (HIES) and the first primary immunodeficiency linked to elevated IgE. Since then, genomic testing has increased the number of defects with associated mutations causing hyper-IgE syndrome and atopic diseases with FLG, DOCK8, SPINK5, and CARD11, among others. A spectrum of recurrent infections and atopy are hallmarks of elevated IgE with significant phenotypic overlap between each underlying condition. As treatment is predicated on early diagnosis, genomic testing is becoming a more commonly used diagnostic tool. We present a 6-year-old male patient with markedly elevated IgE and severe atopic dermatitis presenting with staphylococcal bacteremia found to have a heterozygous variant in FLG (p.S3247X) and multiple variants of unknown significance in BCL11B, ZAP70, LYST, and PTPRC. We review the genetic defects underpinning elevated IgE and highlight the spectrum of atopy and immunodeficiency seen in patients with underlying mutations. Although no one mutation is completely causative of the constellation of symptoms in this patient, we suggest the synergism of these variants is an impetus of disease.

scholarly journals A computational and structural analysis of germline and somatic variants affecting the DDR mechanism, and their impact on human diseases

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lorena Magraner-Pardo ◽  
Roman A. Laskowski ◽  
Tirso Pons ◽  
Janet M. Thornton
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Protein Interaction ◽  
Three Dimensional ◽  
Protein Protein Interaction ◽  
Variants Of Unknown Significance ◽  
Damage Response ◽  
Dna Variants ◽  
Unknown Significance

AbstractDNA-Damage Response (DDR) proteins are crucial for maintaining the integrity of the genome by identifying and repairing errors in DNA. Variants affecting their function can have severe consequences since failure to repair damaged DNA can result in cells turning cancerous. Here, we compare germline and somatic variants in DDR genes, specifically looking at their locations in the corresponding three-dimensional (3D) structures, Pfam domains, and protein–protein interaction interfaces. We show that somatic variants in metastatic cases are more likely to be found in Pfam domains and protein interaction interfaces than are pathogenic germline variants or variants of unknown significance (VUS). We also show that there are hotspots in the structures of ATM and BRCA2 proteins where pathogenic germline, and recurrent somatic variants from primary and metastatic tumours, cluster together in 3D. Moreover, in the ATM, BRCA1 and BRCA2 genes from prostate cancer patients, the distributions of germline benign, pathogenic, VUS, and recurrent somatic variants differ across Pfam domains. Together, these results provide a better characterisation of the most recurrent affected regions in DDRs and could help in the understanding of individual susceptibility to tumour development.

scholarly journals Additive effects of variants of unknown significance in replication repair-associated DNA polymerase genes on mutational burden and prognosis across diverse cancers

2021 ◽  
Vol 9 (9) ◽  
pp. e002336
Author(s):  
Jieer Ying ◽  
Lin Yang ◽  
Jiani C Yin ◽  
Guojie Xia ◽  
Minyan Xing ◽  
...  
Keyword(s):  
Hot Spot ◽  
The Cancer Genome Atlas ◽  
Driver Mutations ◽  
Cancer Type ◽  
Additive Effects ◽  
Variants Of Unknown Significance ◽  
Mutational Burden ◽  
Pathway Gene ◽  
Exonuclease Domain ◽  
Unknown Significance

BackgroundDefects in replication repair-associated DNA polymerases often manifest an ultra-high tumor mutational burden (TMB), which is associated with higher probabilities of response to immunotherapies. The functional and clinical implications of different polymerase variants remain unclear.MethodsTargeted next-generation sequencing using a 425-cancer gene panel, which covers all exonic regions of three polymerase genes (POLE, POLD1, and POLH), was conducted in a cohort of 12,266 patients across 16 different tumor types from January 2017 to January 2019. Prognostication of POL variant-positive patients was performed using a cohort of 4679 patients from the The Cancer Genome Atlas (TCGA) datasets.ResultsThe overall prevalence of somatic and germline polymerase variants was 4.2% (95% CI 3.8% to 4.5%) and 0.7% (95% CI 0.5% to 0.8%), respectively, with highest frequencies in endometrial, urinary, prostate, and colorectal cancers (CRCs). While most germline polymerase variants showed no clear functional consequences, we identified a candidate p.T466A affecting the exonuclease domain of POLE, which might be underlying the early onset in a case with childhood CRC. Low frequencies of known hot-spot somatic mutations in POLE were detected and were associated with younger age, the male sex, and microsatellite stability. In both the panel and TCGA cohorts, POLE drivers exhibited high frequencies of alterations in genes in the DNA damage and repair (DDR) pathways, including BRCA2, ATM, MSH6, and ATR. Variants of unknown significance (VUS) of different polymerase domains showed variable penetrance with those in the exonuclease domain of POLE and POLD1 displaying high TMB. VUS in POL genes exhibited an additive effect as carriers of multiple VUS had exponentially increased TMB and prolonged overall survival. Similar to cases with driver mutations, the TMB-high POL VUS samples showed DDR pathway involvement and polymerase hypermutation signatures. Combinatorial analysis of POL and DDR pathway status further supported the potential additive effects of POL VUS and DDR pathway genes and revealed distinct prognostic subclasses that were independent of cancer type and TMB.ConclusionsOur results demonstrate the pathogenicity and additive prognostic value of POL VUS and DDR pathway gene alterations and suggest that genetic testing may be warranted in patients with diverse solid tumors.

Whole‐Exome Sequencing of a Saudi Epilepsy Cohort Reveals Association Signals in Known and Potentially Novel Loci

2021 ◽  
Author(s):  
Amein Kadhem AlAli ◽  
Abdulrahman Al-Enazi ◽  
Ahmed Ammar ◽  
Mahmoud Hajj ◽  
Cyril Cyrus ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Rare Variants ◽  
High Rate ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Novel Variants ◽  
Unknown Significance ◽  
Rare Genetic Variants

Abstract Background Epilepsy, a serious chronic neurological condition effecting up to 100 million people globally, has clear genetic underpinnings including common and rare variants. In Saudi Arabia the prevalence of epilepsy is high and caused mainly by perinatal and genetic factors. No whole-exome sequencing (WES) studies have been performed to date in Saudi Arabian Epilepsy cohorts. This offers a unique opportunity for the discovery of rare genetic variants impacting this disease as there is a high rate of consanguinity amongst large tribal pedigrees. Results We performed WES on 144 individuals diagnosed with epilepsy, to interrogate known Epilepsy related genes for known and functional novel variants. We also used an American College of Medical Genetics (ACMG) guideline based variant prioritization approach in an attempt to discover putative causative variants. We identified a 32 potentially causative pathogenic variants across 30 different genes in 44/144 (30%) of these Saudi Epilepsy individuals. We also identified 232 variants of unknown significance (VUS) across 101 different genes in 133/144 (92%) subjects. Strong enrichment of variants of likely pathogenicity were observed in previously described epilepsy-associated loci, and a number of putative pathogenic variants in novel loci are also observed. Conclusion Several putative pathogenic variants known to be epilepsy-related loci were identified for the first time in our population, in addition to several potential new loci have been identified which may be prioritized for further investigation.

scholarly journals Targeted next generation sequencing identifies a genetic spectrum of DNA variants in patients with hemiplegic migraine

2019 ◽  
Vol 2 ◽  
pp. 251581631988163 ◽  
Author(s):  
Neven Maksemous ◽  
Robert A Smith ◽  
Heidi G Sutherland ◽  
Bridget H Maher ◽  
Omar Ibrahim ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Diagnostic Yield ◽  
Next Generation ◽  
Hemiplegic Migraine ◽  
Targeted Next Generation Sequencing ◽  
Variants Of Unknown Significance ◽  
High Mutation Frequency ◽  
Unknown Significance ◽  
Atp1a2 Gene ◽  
Generation Sequencing

Objective: Hemiplegic migraine in both familial (FHM) and sporadic (SHM) forms is a rare subtype of migraine with aura that can be traced to mutations in the CACNA1A, ATP1A2 and SCN1A genes. It is characterised by severe attacks of typical migraine accompanied by hemiparesis, as well as episodes of complex aura that vary significantly between individuals. Methods: Using a targeted next generation sequencing (NGS) multigene panel, we have sequenced the genomic DNA of 172 suspected hemiplegic migraine cases, in whom no mutation had previously been found by Sanger sequencing (SS) of a limited number of exons with high mutation frequency in FHM genes. Results: Genetic screening identified 29 variants, 10 of which were novel, in 35 cases in the three FHM genes ( CACNA1A, ATP1A2 and SCN1A). Interestingly, in this suspected HM cohort, the ATP1A2 gene harboured the highest number of variants with 24/35 cases (68.6%), while CACNA1A ranked the second gene, with 5 variants identified in 7/35 cases (20%). All detected variants were confirmed by SS and were absent in 100 non-migraine healthy control individuals. Assessment of variants with the American College of Medical Genetics and Genomics guidelines classified 8 variants as pathogenic, 3 as likely pathogenic and 18 as variants of unknown significance. Targeted NGS gene panel increased the diagnostic yield by fourfold over iterative SS in our diagnostics facility. Conclusion: We have identified 29 potentially causative variants in an Australian and New Zealand cohort of suspected HM cases and found that the ATP1A2 gene was the most commonly mutated gene. Our results suggest that screening using NGS multigene panels to investigate ATP1A2 alongside CACNA1A and SCN1A is a clinically useful and efficient method.

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