Genomic ERBB2/ERBB3 mutations promote PD-L1-mediated immune escape in gallbladder cancer: a whole-exome sequencing analysis

Gut ◽  
2018 ◽  
Vol 68 (6) ◽  
pp. 1024-1033 ◽  
Author(s):  
Maolan Li ◽  
Fatao Liu ◽  
Fei Zhang ◽  
Weiping Zhou ◽  
Xiaoqing Jiang ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Ectopic Expression ◽  
Sequencing Analysis ◽  
Antibody Treatment ◽  
Whole Exome ◽  
Recurrent Mutations

ObjectivesPatients with gallbladder carcinoma (GBC) lack effective treatment methods largely due to the inadequacy of both molecular characterisation and potential therapeutic targets. We previously uncovered a spectrum of genomic alterations and identified recurrent mutations in the ErbB pathway in GBC. Here, we aimed to study recurrent mutations of genes and pathways in a larger cohort of patients with GBC and investigate the potential mechanisms and clinical significance of these mutations.DesignWe performed whole-exome sequencing (WES) in 157 patients with GBC. Functional experiments were applied in GBC cell lines to explore the oncogenic roles of ERBB2/ERBB3 hotspot mutations, their correlation with PD-L1 expression and the underlying mechanisms. ERBB inhibitors and a PD-L1 blocker were used to evaluate the anticancer activities in co-culture systems in vitro and in vivo.ResultsWES identified ERBB2 and ERBB3 mutations at a frequency of 7%–8% in the expanded cohort, and patients with ERBB2/ERBB3 mutations exhibited poorer prognoses. A set of in vitro and in vivo experiments revealed increased proliferation/migration on ERBB2/ERBB3 mutation. Ectopic expression of ERBB2/ERBB3 mutants upregulated PD-L1 expression in GBC cells, effectively suppressed normal T-cell-mediated cytotoxicity in vitro through activation of the PI3K/Akt signalling pathway and contributed to the growth and progression of GBC in vivo. Treatment with an ERBB2/ERBB3 inhibitor or a PD-L1 monoclonal antibody reversed these immunosuppressive effects, and combined therapy revealed promising therapeutic activities.ConclusionsERBB2/ERBB3 mutations may serve as useful biomarkers in identifying patients who are sensitive to ERBB2/ERBB3 inhibitors and PD-L1 monoclonal antibody treatment.Trial registration numberNCT02442414;Pre-results.

scholarly journals Whole-exome sequencing of cervical carcinomas identifies activating ERBB2 and PIK3CA mutations as targets for combination therapy

2019 ◽  
Vol 116 (45) ◽  
pp. 22730-22736 ◽  
Author(s):  
Luca Zammataro ◽  
Salvatore Lopez ◽  
Stefania Bellone ◽  
Francesca Pettinella ◽  
Elena Bonazzoli ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Cell Lines ◽  
Copy Number ◽  
Mtor Pathway ◽  
In Vivo Models ◽  
Whole Exome

The prognosis of advanced/recurrent cervical cancer patients remains poor. We analyzed 54 fresh-frozen and 15 primary cervical cancer cell lines, along with matched-normal DNA, by whole-exome sequencing (WES), most of which harboring Human-Papillomavirus-type-16/18. We found recurrent somatic missense mutations in 22 genes (including PIK3CA, ERBB2, and GNAS) and a widespread APOBEC cytidine deaminase mutagenesis pattern (TCW motif) in both adenocarcinoma (ACC) and squamous cell carcinomas (SCCs). Somatic copy number variants (CNVs) identified 12 copy number gains and 40 losses, occurring more often than expected by chance, with the most frequent events in pathways similar to those found from analysis of single nucleotide variants (SNVs), including the ERBB2/PI3K/AKT/mTOR, apoptosis, chromatin remodeling, and cell cycle. To validate specific SNVs as targets, we took advantage of primary cervical tumor cell lines and xenografts to preclinically evaluate the activity of pan-HER (afatinib and neratinib) and PIK3CA (copanlisib) inhibitors, alone and in combination, against tumors harboring alterations in the ERBB2/PI3K/AKT/mTOR pathway (71%). Tumors harboring ERBB2 (5.8%) domain mutations were significantly more sensitive to single agents afatinib or neratinib when compared to wild-type tumors in preclinical in vitro and in vivo models (P = 0.001). In contrast, pan-HER and PIK3CA inhibitors demonstrated limited in vitro activity and were only transiently effective in controlling in vivo growth of PIK3CA-mutated cervical cancer xenografts. Importantly, combinations of copanlisib and neratinib were highly synergistic, inducing long-lasting regression of tumors harboring alterations in the ERBB2/PI3K/AKT/mTOR pathway. These findings define the genetic landscape of cervical cancer, suggesting that a large subset of cervical tumors might benefit from existing ERBB2/PIK3CA/AKT/mTOR-targeted drugs.

scholarly journals Η γενετική αρχιτεκτονική των εκ γενετής ανατομικών και νευρο-αναπτυξιακών διαταραχών

2021 ◽  
Author(s):  
Γεώργιος Κελλάρης
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Danio Rerio ◽  
Array Cgh ◽  
Loss Of Function ◽  
Whole Exome

Εισαγωγή: Οι νευρο-αναπτυξιακές ασθένειες, αποτελούν μια γενική κατηγορία ασθενειών οι οποίες σχετίζονταιμε την διαταραχή της ανάπτυξης και εύρυθμης λειτουργίας του εγκεφάλου και έχουν αρνητικές επιπτώσεις στηνοητική και συμπεριφορική λειτουργία των ασθενών. Οι ασθένειες αυτές εμφανίζουν μεγάλη κλινική και γενετικήετερογένεια καθώς περιλαμβάνουν συνδρομικές και μη συνδρομικές μορφές, συχνά δυσδιάκριτες που καθιστούνδύσκολη τη κλινική γενετική εκτίμηση και διάγνωση. Κατά συνέπεια, πολλές από αυτές τις περιπτώσειςπαραμένουν αδιάγνωστες και απαιτούν περαιτέρω διερεύνηση. Η αξιοποίηση των νέων τεχνολογιών όπως οΜοριακός Καρυότυπος (array-CGH) αλλά και η αλληλούχιση επόμενης γενιάς έχουν συμβάλει στην ανίχνευσηυποχρωμοσωμικών γενωμικών αναδιατάξεων και σημειακών παραλλαγών και στη ταυτοποίηση νέων γονιδίωνκαι παραλλαγών που μπορεί να συμβάλουν στο παρατηρούμενο φαινότυπο. Ταυτόχρονα, η αξιοποίησηπειραματικών ζωικών μοντέλων, όπως το zebrafish, έχει δειχθεί ότι μπορεί να συμβάλλει σημαντικά στηπροσπάθεια για τη κατανόηση των μοριακών και κυτταρικών διαδικασιών που σχετίζονται με την εμφάνισησυγκεκριμένων φαινοτύπων και το χαρακτηρισμό της παθογένειας των παραλλαγών που ανιχνεύονται στουςασθενείς.Σκοπός της μελέτης: Η παρούσα μελέτη επικεντρώνεται στη γενετική διερεύνηση ασθενών μενευροαναπτυξιακά και συγγενή νοσήματα, με αξιοποίηση των τεχνολογιών όπως ο Μοριακός Καρυότυπος(array-CGH) και η αλληλούχιση επόμενης γενιάς (Whole Exome Sequencing). Ταυτόχρονα, σε συνεργασία μεδιεθνώς αναγνωρισμένα Πανεπιστήμια του εξωτερικού αξιοποιήθηκε το πειραματικό ζωικό μοντέλο zebrafishγια τη μοντελοποίηση σπάνιων περιπτώσεων ασθενών με νευροαναπτυξιακά νοσήματα.Υλικό και μέθοδος: Υλικό του πρώτου μέρους της μελέτης, αποτέλεσε μια κοόρτη 97 ασθενών με σύνθετανευρο-αναπτυξιακά και συγγενή νοσήματα, όπως αλλαγές στο μέγεθος της κεφαλής (μικροκεφαλία, ήμακροκεφαλία), σε συνδυασμό με άλλα νευρο-αναπτυξιακά συμπτώματα. Για το πρώτο μέρος της μελέτηςαξιοποιήθηκαν o Μοριακός Καρυότυπος (array-CGH) και η αλληλούχιση επόμενης γενιάς (Whole ExomeSequencing). Υλικό του δεύτερου μέρους της μελέτης, αποτέλεσαν 2 αδέλφια αρσενικού γένους με νοητικήυστέρηση, μακροκεφαλία και πρόβλημα στην άρθρωση. Για το δεύτερο μέρος της μελέτης αξιοποιήθηκε τοπειραματικό ζωικό μοντέλο zebrafish για τη μοντελοποίηση των παραλλαγών που ανιχνεύθηκαν στους δύοασθενείς. Υλικό του τρίτου μέρους της μελέτης, αποτέλεσαν 7 ασθενείς από τρεις διαφορετικές οικογένειες,κλινικά χαρακτηριστικά όπως εντερική δυσλειτουργία και νευρολογικά συμπτώματα που παραπέμπουν σεδιάγνωση μιτοχονδριακής νευρο-εντερικής εγκεφαλο-μυοπάθειας. Για το τρίτο μέρος της μελέτης, αξιοποιήθηκαντο πειραματικό μοντέλο zebrafish και κυτταρολογικές μεθοδολογίες για τη μελέτη της λειτουργικότητας τωνμιτοχονδρίων για τη ταυτοποίηση ενός νέου υποψήφιου γονιδίου που σχετίζεται με την εμφάνιση τωνφαινοτύπων στους ασθενείς.Αποτελέσματα: Στο πρώτο μέρος της μελέτης, η χρωμοσωμική ανάλυση μικρο-συστοιχειών οδήγησε στηνανίχνευση παθολογικών και άγνωστης κλινικής σημασίας CNVs σε 31/75 άτομα που εξετάσθηκαν (41%). Απότο σύνολο των 45 CNVs που ανιχνεύθηκαν τα 29/45 (64%) αφορούσαν ελλείματα (deletions), τα 15/45 (33%)αφορούσαν διπλασιασμούς (duplications), ενώ παρατηρήθηκε και ένας τριπλασιασμός 1/45 (2%). Σε 13/75άτομα (17%) τα CNVs χαρακτηρίστηκαν ως παθογενή και σε 18/75 άτομα (24%) χαρακτηρίστηκαν ως άγνωστηςκλινικής σημασίας και χρήζουν περαιτέρω διερεύνησης. Ταυτόχρονα, η αλληλούχιση επόμενης γενιάς ανίχνευσε παθολογικές ή πιθανώς παθολογικές παραλλαγές σε γονίδια που σχετίζονται με την εμφάνιση κάποιου νευροαναπτυξιακού σύνδρομου, σε 39/95 άτομα (40.43%), ενώ σε 2/95 άτομα (2.13%) παρατηρήθηκανπαραλλαγές που άγνωστης κλινικής σημασίας σε γονίδια που προκαλούν κάποιο νευρο-αναπτυξιακό σύνδρομο. Από την άλλη πλευρά, σε 27/95 άτομα (28.7%) δεν ανιχνεύθηκε παραλλαγή σε κάποιο γονίδιο που έχει καταγραφεί ως τη προετοιμασία της παρούσας εργασίας να οδηγεί σε κάποιο γνωστό νευρο-αναπτυξιακό σύνδρομο και καταγράφηκαν ως αρνητικά (negative).Στο δεύτερο μέρος της μελέτης, αξιοποίηση της τεχνολογίας αλληλούχισης επόμενης γενιάς (Quad-basedwholeexome sequencing) επέτρεψε την ταυτοποίηση της μη-συνώνυμης παραλλαγής p.R79K στο γονίδιοDDX3X. Η παραλλαγή ανιχνεύθηκε στο δείγμα και των δύο ασθενών, ενώ η γενετική ανάλυση επιβεβαίωσε ότιη παραλλαγή κληρονομήθηκε από την ασυμπτωματική μητέρα (μητρικής προέλευσης), ενώ δεν ταυτοποιήθηκεκάποιο άλλο παθολογικό εύρημα. Στη συνέχεια, για να εξεταστεί η πιθανή συσχέτιση της παραλλαγή με τονφαινότυπο των ασθενών, αξιοποιήσαμε το πειραματικό μοντέλο danio rerio (zebrafish). Μελέτη τηςλειτουργικότητας της DDX3X με το zebrafish έδειξε ότι η παραλλαγή p.R79K οδηγεί σε απώλεια λειτουργίας(Loss of function) και είναι υπομορφική (hypomorphic).Στο τρίτο μέρος της μελέτης συμμετείχαν 7 ασθενείς από τρεις διαφορετικές οικογένειες, με κλινικά ευρήματαόπως εντερική δυσλειτουργία και νευρολογικά συμπτώματα που παραπέμπουν σε διάγνωση μιτοχονδριακήςνευρο-εντερικής εγκεφαλο-μυοπάθειας. Ανάλυση των κωδικών περιοχών του γενωμικού DNA με αλληλούχισηεπόμενης γενιάς (Whole exome sequencing), ανίχνευσε παραλλαγές σε ένα νέο γονίδιο, LIG3, το οποίο δεν έχειχαρακτηριστεί ως υπεύθυνο για την εμφάνιση κάποιας ασθένειας. Αξιοποίηση in vitro μεθοδολογιών με χρήσηκυττάρων απομονωμένα από ασθενείς έδειξε μειωμένα επίπεδα της πρωτεΐνης LIG3 ενώ μειωμένη ήταν και ηενεργότητα της λιγάσης. Παράλληλα, η δυσλειτουργία του LIG3 είχε αρνητική επίδραση στη συντήρηση τουμιτοχονδριακού DNA, με αποτέλεσμα την μείωση των επιπέδων μιτοχονδριακού DNA, χωρίς την παρουσίαπολλαπλών ελλείψεων που είναι χαρακτηριστικό άλλων μιτοχονδριακών ασθενειών. Έτσι, είναι πιθανό ηπαρατηρούμενη μιτοχονδριακή δυσλειτουργία να είναι υπεύθυνη για τη παρατηρούμενη παθολογία στουςασθενείς. In vivo λειτουργικές μελέτες με χρήση του πειραματικού μοντέλου danio rerio (zebrafish) έδειξαν ότι ηδυσλειτουργία του lig3 μπορεί να οδηγήσει σε παθολογικούς φαινοτύπους του εγκεφάλου και του εντέρου, σεαντιστοιχία με αυτούς που παρατηρήθηκαν στους ασθενείς.Συζήτηση/συμπεράσματα: Η αξιοποίηση των σύγχρονων τεχνολογιών όπως o Μοριακός Καρυότυπος και ηαληλούχιση επόμενης γενιάς (Whole Exome Sequencing) επιτρέπουν τη γρήγορη και ακριβέστερή διάγνωση καιτη καλύτερη συσχέτιση φαινοτύπου/γονοτύπου και κατά συνέπεια την ορθότερη και πιο ολοκληρωμένη γενετικήσυμβουλευτική. Όταν είναι δυνατό, η αξιοποίηση in vitro μεθοδολογιών για τη περαιτέρω διερεύνηση τωνμοριακών μηχανισμών που σχετίζονται με το παρατηρούμενο φαινότυπο αλλά και πειραματικών ζωικώνμοντέλων όπως το zebrafish μπορεί να συμβάλλει στη ταυτοποίηση νέων γονιδίων και το χαρακτηρισμό τωνπαραλλαγών που ανιχνεύονται σε αυτά.

scholarly journals Host Genetics and Antiviral Immune Responses in Adult Patients With Multisystem Inflammatory Syndrome

2021 ◽  
Vol 12 ◽  
Author(s):  
Andreas Ronit ◽  
Sofie E. Jørgensen ◽  
Casper Roed ◽  
Robert Eriksson ◽  
Ulrik W. Iepsen ◽  
...  
Keyword(s):  
Immune Responses ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Mononuclear Cells ◽  
Type I ◽  
Sequencing Analysis ◽  
Healthy Controls ◽  
Whole Exome ◽  
Inflammatory Syndrome

COVID-19 associated multisystem inflammatory syndrome (MIS) is a rare condition mostly affecting children but also adults (MIS-A). Although severe systemic inflammation and multiorgan dysfunction are hallmarks of the syndrome, the underlying pathogenesis is unclear. We aimed to provide novel immunological and genetic descriptions of MIS-A patients. Cytokine responses (IL-6, IL-1β, TNFα, CXCL10, type I, II and III interferons) following SARS-CoV-2 infection of peripheral blood mononuclear cells in vitro were analyzed as well as antibodies against IFNα and IFNω (by ELISA) in patients and healthy controls. We also performed whole exome sequencing (WES) of patient DNA. A total of five patients (ages 19, 23, 33, 38, 50 years) were included. The patients shared characteristic features, although organ involvement and the time course of disease varied slightly. SARS-CoV-2 in vitro infection of patient PBMCs revealed impaired type I and III interferon responses and reduced CXCL10 expression, whereas production of proinflammatory cytokines were less affected, compared to healthy controls. Presence of interferon autoantibodies was not detected. Whole exome sequencing analysis of patient DNA revealed 12 rare potentially disease-causing variants in genes related to autophagy, classical Kawasaki disease, restriction factors and immune responses. In conclusion, we observed an impaired production of type I and III interferons in response to SARS-CoV-2 infection and detected several rare potentially disease-causing gene variants potentially contributing to MIS-A.

Whole Exome Sequencing Analysis in AML with Normal Karyotype Not Harboring FLT3/ITD Mutation Reveals Novel Genetic Alterations.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2593-2593
Author(s):  
Il-Kwon Lee ◽  
Namshin Kim ◽  
Yeo-Kyeoung Kim ◽  
Dennis Dong Hwan Kim ◽  
Quang Trinh ◽  
...  
Keyword(s):  
Complete Remission ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Conflicts Of Interest ◽  
Genetic Alterations ◽  
Sequencing Analysis ◽  
Novel Mutations ◽  
Whole Exome ◽  
Recurrent Mutations ◽  
Custom Made

Abstract Abstract 2593 Background: NK-AML represents genetically heterogeneous group of disease. However genetic lesions affecting treatment outcome in patients with NK-AML are relatively unknown. Methods: The discovery cohort consists of 67 NK-AML patients in complete remission (median age: 49.2, ranges: 19–70) without FLT-3 mutations. Genomic DNA was extracted from enriched AML cells at diagnosis or control specimens obtained after complete remission. Whole exomes were captured using Agilent SureSelect and sequencing were performed by HiSeq2000 with 41∼89× coverage. Bioinformatics analysis and identification of somatic mutation has been done by series of software such as BWA, Picard, GATK, VarScan 2, and custom-made scripts. All the data has been re-checked by manual inspection. Validation has been done independent set of cohort (358 NK-AML patients, median age: 51, ranges: 15–85) with Sanger sequencing on highly mutated target sites. Results: Filtering against dbSNP and COSMIC database generated 485 genes with somatic and structural variations. Among them, 41 genes were detected in more than two patients. In addition to well-known 28 mutations, 13 novel mutations with different frequencies were identified including genes responsible for structural maintenance of chromosome (SMC1A, 6.0%) and tumor suppressor function (FAT1, 6.0%). Most common type of mutation was missense mutation (70.8%), and substantial fraction of mutation was splicing site mutations (3.8%). The hematological system development and hematologic function were most highly enriched by the Ingenuity Pathway Analysis (IPA) as expected. CIRCOS plot analysis showed similar co-occurring pattern of recurrent mutations with previous reports. Hierarchical clustering analysis divided into four different groups according to the number of harboring mutations. In network analysis four distinct subgroups were observed ranging 21 to 3 gene network. Conclusion: Using whole exome sequencing approach, a catalog of recurrent mutations was successfully defined in the patients with NK-AML without FLT3/ITD mutation. This candidate list of novel mutations should be tested further for therapeutic target and prognostic marker in the patients with NK-AML. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Functionally pathogenic EARS2 variants in vitro may not manifest a phenotype in vivo

2017 ◽  
Vol 3 (4) ◽  
pp. e162 ◽  
Author(s):  
Nathan McNeill ◽  
Alessia Nasca ◽  
Aurelio Reyes ◽  
Benjamin Lemoine ◽  
Brandi Cantarel ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Protein Function ◽  
In Silico ◽  
In Silico Analysis ◽  
Compound Heterozygous ◽  
Functional Testing ◽  
Whole Exome

Objective:To investigate the genetic etiology of a patient diagnosed with leukoencephalopathy, brain calcifications, and cysts (LCC).Methods:Whole-exome sequencing was performed on a patient with LCC and his unaffected family members. The variants were subject to in silico and in vitro functional testing to determine pathogenicity.Results:Whole-exome sequencing uncovered compound heterozygous mutations in EARS2, c.328G>A (p.G110S), and c.1045G>A (p.E349K). This gene has previously been implicated in the autosomal recessive leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL). The p.G110S mutation has been found in multiple patients with LTBL. In silico analysis supported pathogenicity in the second variant. In vitro functional testing showed a significant mitochondrial dysfunction demonstrated by an ∼11% decrease in the oxygen consumption rate and ∼43% decrease in the maximum respiratory rate in the patient's skin fibroblasts compared with the control. EARS2 protein levels were reduced to 30% of normal controls in the patient's fibroblasts. These deficiencies were corrected by the expression of the wild-type EARS2 protein. However, a further unrelated genetic investigation of our patient revealed the presence of biallelic variants in a small nucleolar RNA (SNORD118) responsible for LCC.Conclusions:Here, we report seemingly pathogenic EARS2 mutations in a single patient with LCC with no biochemical or neuroimaging presentations of LTBL. This patient illustrates that variants with demonstrated impact on protein function should not necessarily be considered clinically relevant.ClinicalTrials.gov identifier:NCT00001671.

scholarly journals Whole-exome sequencing with targeted analysis and epilepsy after acute symptomatic neonatal seizures

2021 ◽  
Author(s):  
Adam L. Numis ◽  
Gilberto da Gente ◽  
Elliott H. Sherr ◽  
Hannah C. Glass
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
List Type ◽  
Sequencing Analysis ◽  
Neonatal Seizures ◽  
Pathogenic Variants ◽  
Targeted Analysis ◽  
Whole Exome ◽  
Epilepsy Gene

Abstract Background The contribution of pathogenic gene variants with development of epilepsy after acute symptomatic neonatal seizures is not known. Methods Case–control study of 20 trios in children with a history of acute symptomatic neonatal seizures: 10 with and 10 without post-neonatal epilepsy. We performed whole-exome sequencing (WES) and identified pathogenic de novo, transmitted, and non-transmitted variants from established and candidate epilepsy association genes and correlated prevalence of these variants with epilepsy outcomes. We performed a sensitivity analysis with genes associated with coronary artery disease (CAD). We analyzed variants throughout the exome to evaluate for differential enrichment of functional properties using exploratory KEGG searches. Results Querying 200 established and candidate epilepsy genes, pathogenic variants were identified in 5 children with post-neonatal epilepsy yet in only 1 child without subsequent epilepsy. There was no difference in the number of trios with non-transmitted pathogenic variants in epilepsy or CAD genes. An exploratory KEGG analysis demonstrated a relative enrichment in cell death pathways in children without subsequent epilepsy. Conclusions In this pilot study, children with epilepsy after acute symptomatic neonatal seizures had a higher prevalence of coding variants with a targeted epilepsy gene sequencing analysis compared to those patients without subsequent epilepsy. Impact We performed whole-exome sequencing (WES) in 20 trios, including 10 children with epilepsy and 10 without epilepsy, both after acute symptomatic neonatal seizures. Children with post-neonatal epilepsy had a higher burden of pathogenic variants in epilepsy-associated genes compared to those without post-neonatal epilepsy. Future studies evaluating this association may lead to a better understanding of the risk of epilepsy after acute symptomatic neonatal seizures and elucidate molecular pathways that are dysregulated after brain injury and implicated in epileptogenesis.

scholarly journals NAPG mutation in family members with hereditary hemorrhagic telangiectasia in China

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yu Xu ◽  
Yong-Biao Zhang ◽  
Li-Jun Liang ◽  
Jia-Li Tian ◽  
Jin-Ming Lin ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Sanger Sequencing ◽  
Conformational Stability ◽  
Sequencing Analysis ◽  
Large Pedigree ◽  
Whole Exome ◽  
Variant Filtering ◽  
Genetic Contributions

Abstract Background Hereditary hemorrhagic telangiectasia (HHT) is a disease characterized by arteriovenous malformations in the skin and mucous membranes. We enrolled a large pedigree comprising 32 living members, and screened for mutations responsible for HHT. Methods We performed whole-exome sequencing to identify novel mutations in the pedigree after excluding three previously reported HHT-related genes using Sanger sequencing. We then performed in silico functional analysis of candidate mutations that were obtained using a variant filtering strategy to identify mutations responsible for HHT. Results After screening the HHT-related genes, activin A receptor-like type 1 (ACVRL1), endoglin (ENG), and SMAD family member 4 (SMAD4), we did not detect any co-segregated mutations in this pedigree. Whole-exome sequencing analysis of 7 members and Sanger sequencing analysis of 16 additional members identified a mutation (c.784A > G) in the NSF attachment protein gamma (NAPG) gene that co-segregated with the disease. Functional prediction showed that the mutation was deleterious and might change the conformational stability of the NAPG protein. Conclusions NAPG c.784A > G may potentially lead to HHT. These results expand the current understanding of the genetic contributions to HHT pathogenesis.

scholarly journals Whole-exome sequencing reveals a novel homozygous mutation in the COQ8B gene associated with nephrotic syndrome

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mohd Fareed ◽  
Vikas Makkar ◽  
Ravi Angral ◽  
Mohammad Afzal ◽  
Gurdarshan Singh
Keyword(s):  
Nephrotic Syndrome ◽  
Disease Management ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Homozygous Mutation ◽  
Consanguineous Family ◽  
Clinical Prognosis ◽  
Whole Exome ◽  
Recurrent Mutations ◽  
Ckd Stage

AbstractNephrotic syndrome arising from monogenic mutations differs substantially from acquired ones in their clinical prognosis, progression, and disease management. Several pathogenic mutations in the COQ8B gene are known to cause nephrotic syndrome. Here, we used the whole-exome sequencing (WES) technology to decipher the genetic cause of nephrotic syndrome (CKD stage-V) in a large affected consanguineous family. Our study exposed a novel missense homozygous mutation NC_000019.9:g.41209497C > T; NM_024876.4:c.748G > A; NP_079152.3:p.(Asp250Asn) in the 9th exon of the COQ8B gene, co-segregated well with the disease phenotype. Our study provides the first insight into this homozygous condition, which has not been previously reported in 1000Genome, ClinVar, ExAC, and genomAD databases. In addition to the pathogenic COQ8B variant, the WES data also revealed some novel and recurrent mutations in the GLA, NUP107, COQ2, COQ6, COQ7 and COQ9 genes. The novel variants observed in this study have been submitted to the ClinVar database and are publicly available online with the accessions: SCV001451361.1, SCV001451725.1 and SCV001451724.1. Based on the patient's clinical history and genomic data with in silico validation, we conclude that pathogenic mutation in the COQ8B gene was causing kidney failure in an autosomal recessive manner. We recommend WES technology for genetic testing in such a consanguineous family to not only prevent the future generation, but early detection can help in disease management and therapeutic interventions.

scholarly journals TP53 and PTEN mutations were shared in concurrent germ cell tumor and acute megakaryoblastic leukemia

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Keiichi Akizuki ◽  
Masaaki Sekine ◽  
Yasunori Kogure ◽  
Takuro Kameda ◽  
Kotaro Shide ◽  
...  
Keyword(s):  
Germ Cell ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Germ Cell Tumor ◽  
Somatic Mutations ◽  
Cell Tumor ◽  
Sequencing Analysis ◽  
Male Adult ◽  
Clonal Relationship ◽  
Whole Exome

Abstract Background The occurrence of a mediastinal germ cell tumor (GCT) and hematological malignancy in the same patient is very rare. Due to its rarity, there have been only two reports of the concurrent cases undergoing detailed genetic analysis with whole-exome sequencing (WES), and the possible clonal relationship between the both tumors remained not fully elucidated. Methods We performed whole-exome sequencing analysis of mediastinal GCT and acute myeloid leukemia (AML) samples obtained from one young Japanese male adult patient with concurrent both tumors, and investigated the possible clonal relationship between them. Results Sixteen somatic mutations were detected in the mediastinal GCT sample and 18 somatic mutations in the AML sample. Mutations in nine genes, including TP53 and PTEN both known as tumor suppressor genes, were shared in both tumors. Conclusions All in our case and in the previous two cases with concurrent mediastinal GCT and AML undergoing with whole-exome sequencing analysis, TP53 and PTEN mutations were commonly shared in both tumors. These data not only suggest that these tumors share a common founding clone, but also indicate that associated mediastinal GCT and AML harboring TP53 and PTEN mutations represent a unique biological entity.

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