scholarly journals Identification of BRCA2 Cis Double Heterozygous Breast Cancer Cases Using Whole Exome Sequencing: Phenotypic Expression and Impact on Personalized Oncology

2021 ◽  
Vol 12 ◽  
Author(s):  
Yosr Hamdi ◽  
Maroua Boujemaa ◽  
Najah Mighri ◽  
Nesrine Mejri ◽  
Olfa Jaidane ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Genetic Testing ◽  
High Risk ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Clinical Management ◽  
Phenotypic Expression ◽  
Cancer Susceptibility Genes ◽  
Mutation Carriers ◽  
Whole Exome

BRCA1 and BRCA2 are the most commonly mutated breast cancer susceptibility genes that convey a high risk of breast and ovarian cancer. Most BRCA1 or BRCA2 mutation carriers have inherited a single heterozygous mutation. In recent years, very rare cases with biallelic or trans double heterozygous mutations on BRCA1 and or BRCA2 have been identified and seem to be associated with distinctive phenotypes. Given that this genotype-phenotype correlation in cancer predisposing hereditary conditions is of relevance for oncological prevention and genetic testing, it is important to investigate these rare BRCA genotypes for better clinical management of BRCA mutation carriers. Here we present the first report on Cis double heterozygosity (Cis DH) on BRCA2 gene identified using Whole exome sequencing (WES) in a Tunisian family with two BRCA2 mutations namely: c.632-1G>A and c.1310_1313DelAAGA that are both reported as pathogenic in ClinVar database. Subsequent analysis in 300 high-risk Tunisian breast cancer families detected this Cis double heterozygous genotype in 8 additional individuals belonging to 5 families from the same geographic origin suggesting a founder effect. Moreover, the observed Cis DH seems to be associated with an early age of onset (mean age = 35.33 years) and severe phenotype of the disease with high breast cancer grade and multiple cancer cases in the family. The identification of unusual BRCA genotypes in this Tunisian cohort highlights the importance of performing genetic studies in under-investigated populations. This will also potentially help avoiding erroneous classifications of genetic variants in African population and therefore avoiding clinical misdiagnosis of BRCA related cancers. Our findings will also have an impact on the genetic testing and the clinical management of North African breast cancer patients as well as patients from different other ethnic groups in regard to several emerging target therapies such as PARP inhibitors.

scholarly journals Not Only Diagnostic Yield: Whole-Exome Sequencing in Infantile Cardiomyopathies Impacts on Clinical and Family Management

2021 ◽  
Vol 9 (1) ◽  
pp. 2
Author(s):  
Laura Pezzoli ◽  
Lidia Pezzani ◽  
Ezio Bonanomi ◽  
Chiara Marrone ◽  
Agnese Scatigno ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Molecular Diagnosis ◽  
Clinical Management ◽  
Genetic Diagnosis ◽  
Family Management ◽  
Whole Exome ◽  
Time To Diagnosis ◽  
The Mean ◽  
Mean Time

Whole-exome sequencing (WES) is a powerful and comprehensive tool for the genetic diagnosis of rare diseases, but few reports describe its timely application and clinical impact on infantile cardiomyopathies (CM). We conducted a retrospective analysis of patients with infantile CMs who had trio (proband and parents)-WES to determine whether results contributed to clinical management in urgent and non-urgent settings. Twenty-nine out of 42 enrolled patients (69.0%) received a definitive molecular diagnosis. The mean time-to-diagnosis was 9.7 days in urgent settings, and 17 out of 24 patients (70.8%) obtained an etiological classification. In non-urgent settings, the mean time-to-diagnosis was 225 days, and 12 out of 18 patients (66.7%) had a molecular diagnosis. In 37 out of 42 patients (88.1%), the genetic findings contributed to clinical management, including heart transplantation, palliative care, or medical treatment, independent of the patient’s critical condition. All 29 patients and families with a definitive diagnosis received specific counseling about recurrence risk, and in seven (24.1%) cases, the result facilitated diagnosis in parents or siblings. In conclusion, genetic diagnosis significantly contributes to patients’ clinical and family management, and trio-WES should be performed promptly to be an essential part of care in infantile cardiomyopathy, maximizing its clinical utility.

scholarly journals Searching for the missing genetic determinants of hereditary breast cancer risk by whole-exome sequencing of BRCA-negative patients: new candidate genes USP39, SLIT3, CREB3

2021 ◽  
Vol 67 (1) ◽  
pp. 111-116
Author(s):  
Kirill Zagorodnev ◽  
Aleksandr Romanko ◽  
Uliy Gorgul ◽  
Aleksandr Ivantsov ◽  
Anna Sokolenko ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Exome Sequencing ◽  
Candidate Genes ◽  
Whole Exome Sequencing ◽  
Hereditary Breast Cancer ◽  
Germ Line ◽  
Genetic Diagnosis ◽  
Clinical Signs ◽  
Causative Mutation ◽  
Whole Exome

The search for the new hereditary mutations and a precise molecular genetic diagnosis that determines the causative mutation in each specific case of hereditary breast cancer (BC) is a clinically important task since it helps to define the personal therapeutic approach and increase the effectiveness of preventive measures. Using whole-exome sequencing (WES) we analyzed the full spectrum of hereditary variations in 49 Russian patients with clinical signs of a hereditary disease which allowed us to compile a list of 229 candidate probably pathogenic germ-line variants. Then, the selected candidate mutations were validated by Sanger sequencing and molecular-epidemiological studies, the predisposing roles of three oncologically relevant mutations (USP39 c.*208G>C, SLIT3 p.Arg154Cys, and CREB3 p.Lys157Glu) were confirmed. Our candidate genes are first mentioned in connection with the hereditary risk of BC. The final proofs of the causative roles of these variants could be obtained through functional tests as well as via the analysis of the mutations segregation in BC families.

Abstract 16468: Results of Research Genetic Testing in Pediatric Cardiomyopathy Patients Justify Broader Clinical Genetic Testing

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Stephanie M Ware ◽  
Steven E Lipshultz ◽  
Steven D Colan ◽  
Ling Shi ◽  
Charles E Canter ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Family History ◽  
Risk Stratification ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Clinical Genetic ◽  
Clinical Genetic Testing ◽  
Whole Exome ◽  
Pediatric Cardiomyopathy ◽  
History Of

Introduction: Pediatric cardiomyopathies are genetically heterogeneous diseases with high risk of death or cardiac transplant. Despite progress in identifying causes, the majority of cases remain idiopathic. Currrently, genetic testing is not performed in all children with cardiomyopathy. Gene identification leads to better individual risk stratification and has the potential to stimulate the development of therapies based on the underlying mutation. The aim of this study is to identify genetic mutations in pediatric cardiomyopathy patients using whole exome sequencing. Hypothesis: Sarcomeric mutations are under-diagnosed causes of all forms of cardiomyopathy in children. Methods: Probands with cardiomyopathy were recruited from 11 institutions. Results of clinical genetic testing prior to enrollment were collected. Whole exome sequencing was performed and mutations were identified in 35 genes currently available on clinical genetic testing panels. Results: The initial 154 probands subjected to exome included 78 patients with DCM, 43 with HCM, 14 with RCM, and 19 with LVNC, mixed, or unknown types. Familial disease was present in 38% and the remainder were idiopathic. Twenty-seven percent had positive clinical genetic testing prior to enrollment. Exome testing identified mutations in 38 subjects who had not had clinical testing, increasing the cohort positive testing rate to 55% (DCM, 34.6%; HCM, 74.4%; RCM, 71.4%). Forty-five percent of subjects with no family history of disease had an identifiable mutation. Conclusions: Pediatric cardiomyopathy patients have a high incidence of mutations that can be identified by clinically available genetic testing. Lack of a family history of cardiomyopathy was not predictive of normal genetic testing. These results support the broader use of genetic testing in pediatric patients with all functional phenotypes of cardiomyopathy to identify disease causation allowing better family risk stratification.

scholarly journals Fundoscopy-directed genetic testing to re-evaluate negative whole exome sequencing results

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Ahra Cho ◽  
Jose Ronaldo Lima de Carvalho ◽  
Akemi J. Tanaka ◽  
Ruben Jauregui ◽  
Sarah R. Levi ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Whole Exome

P0066KIDNEYCODE: A GENETIC TESTING PROGRAM FOR PATIENTS WITH CHRONIC KIDNEY DISEASE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Prasad Devarajan ◽  
Geoffrey Block ◽  
Keisha Gibson ◽  
Jim McKay ◽  
Colin Meyer ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Genetic Testing ◽  
Kidney Disease ◽  
Exome Sequencing ◽  
Polycystic Kidney Disease ◽  
Whole Exome Sequencing ◽  
Alport Syndrome ◽  
Polycystic Kidney ◽  
Accuracy And Precision ◽  
Whole Exome

Abstract Background and Aims Knowledge about genetic causes of chronic kidney disease (CKD) is one of the key gaps in global kidney research and recent International Society of Nephrology recommendations encourage the adoption of genetic testing to enable a goal of providing precision medicine based on individual risk (1). A recent whole-exome sequencing study showed that genetic inheritance may be responsible for up to 10% of CKD diagnoses, many of which may be previously undiagnosed or mis-diagnosed (2). Continued advances in DNA sequencing technology have made genetic testing, even whole-exome sequencing, applicable to routine clinical diagnoses. In order to test the hypothesis that genetic testing can provide valuable information to increase the accuracy and precision of diagnosis in CKD, we designed a gene panel to prospectively provide genetic testing in a subset of patients with CKD defined by a specific set of inclusion criteria. Method Reata Pharmaceuticals is partnering with Invitae on a program called KidneyCode, which provides no-charge genetic testing to enable diagnosis of three specific rare monogenic causes of CKD: Alport syndrome (AS), autosomal dominant polycystic kidney disease (ADPKD) due to PKD2 mutations, and focal segmental glomerulosclerosis (FSGS), as well as detection of variants in one of the autosomal recessive polycystic kidney disease gene, PKHD1. Invitae’s renal disease panel includes 17 genes (ACTN4, ANLN, CD2AP, COL4A3, COL4A4, COL4A5, CRB2, HNF1A, INF2, LMX1B, MYO1E, NPHS1, NPHS2, PAX2, PKD2, PKHD1, and TRPC6), and its assay includes both full-gene sequencing and intragenic deletion/duplication analysis using next-generation sequencing (NGS). The assay targets the coding exons and flanking 10bp of intronic sequences. Invitae’s method of variant classification uses a systematic process for assessing evidence based on guidelines published by the American College of Medical Genetics (3). Patients in the US at risk for hereditary CKD (eGFR ≤ 90 mL/min/1.73m2 plus hematuria or a family history of CKD) or with a known diagnosis of AS or FSGS are eligible. Family members of those with suspected or known AS or FSGS are also eligible. All participants in the KidneyCode program have access to genetic counseling follow-up at no additional charge. Results In the first five months of the KidneyCode program, 152 genetic tests have been completed. A genetic variant was reported in 87 patients. Of those 87 patients, 67 patients had 75 variants in COL4A3, 4, or 5 genes (34 Pathogenic/Likely Pathogenic (P/LP), 41 Variants of Uncertain Significance (VUS)), 20 patients had 24 variants in genes associated with FSGS (3 P/LP, 21 VUS), 15 patients had 20 variants in PKHD1 (1 P/LP, 19 VUS), and 2 patients had variants in PKD2 (1 P/LP, 1 VUS). Of the 34 patients with Pathogenic or Likely Pathogenic COL4A variants, 19 reported a previous diagnosis of Alport syndrome. Other diagnoses in patients with COL4A mutations included FSGS, thin basement membrane disease, and familial hematuria. Extra-renal manifestations such as hearing loss and eye disease were reported in 7 of the 34 patients with COL4A variants. Conclusion Initial results with the KidneyCode panel demonstrate the utility of NGS and support the hypothesis that combining genetic testing with clinical presentation and medical history can significantly improve accuracy and precision of diagnosis in patients with hereditary CKD.

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