OP64 Implementation Of Whole Exome Sequencing For Rare Diseases

IntroductionThe Victorian Department of Health and Human Services provided AUD 25 million (i.e. USD 17.3 million) over four years to determine the place of whole exome sequencing (WES) for patients attending public genetics clinics. Comparative analysis of WES and ‘usual care’ determined that WES increased diagnosis rate (from 14 to 58 percent), changed clinical management in one third of patients and identified relatives and couples at high risk of recurrence in future pregnancies. Translating this into routine care requires co-design with clinical and laboratory stakeholders.MethodsVictoria's clinical and laboratory genetics service system uses a ‘hub and spoke’ model. Representatives from these were invited to join a ‘Clinical Adoption Group’ (CAG) to oversight implementation of new government funding (AUD 2 million (i.e. USD 1.4 million) per year) to ensure statewide access to, and funding of, WES for children with rare undiagnosed genetic conditions. The CAG developed terms of reference, ‘traffic light’ evidence-based eligibility criteria, a pricing model and reporting mechanism, and recommended funding for sequencing, curation, curator training and multidisciplinary team (MDT) meetings to support implementation.ResultsFunding was distributed across hub and spoke sites reflecting clinical and laboratory demand and workforce requirements. All cases demonstrated clinical utility and were reviewed at MDT meetings. To date, 37 percent of patients have received a diagnosis changing management, with equity of access between metropolitan and regional areas demonstrated. Eligibility criteria are reviewed as new evidence is published to ensure new evidence is incorporated, although curation capacity limits turn-around-times.ConclusionsCo-designing a statewide and evidence-based clinical model has resulted in sector (i.e. clinician and laboratory) buy-in and supported broad access to funded WES. In addition, the sector has developed a better understanding of how evidence informs policy and funding decisions, which has resulted in delivering equitable WES that provides early diagnosis leading to changed clinical management and cessation of unnecessary interventions.

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

Journal of Cardiovascular Development and Disease ◽

10.3390/jcdd9010002 ◽

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.

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Whole Exome Sequencing in Neurogenetic Diagnostic Odysseys: An Argentinian Experience

10.1101/060319 ◽

2016 ◽

Cited By ~ 1

Author(s):

M Córdoba ◽

SA Rodriguez-Quiroga ◽

PA Vega ◽

H Amartino ◽

C Vázquez-Dusefante ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Low Income ◽

Clinical Management ◽

Diagnostic Yield ◽

Genetic Disorders ◽

Potential Cost ◽

Low Income Country ◽

Whole Exome ◽

Neurogenetic Disorders

ABSTRACTClinical variability is a hallmark of neurogenetic disorders. They involve widespread neurological entities such as neuropathies, ataxias, myopathies, mitochondrial encephalopathies, leukodystrophies, epilepsy and intellectual disabilities. Despite the use of considerable time and resources, the diagnostic yield in this field has been disappointingly low. This etiologic search has been called a “diagnostic odyssey” for many families. Whole exome sequencing (WES) has proved to be useful across a variety of genetic disorders, simplifying the odyssey of many patients and their families and leading to subsequent changes in clinical management in a proportion of them. Although a diagnostic yield of about 30% in neurogenetic disorders can be extrapolated from the results of large series that have included other medical conditions as well, there are not specific reports assessing its utility in a setting such as ours: a neurogeneticist led academic group serving in a low-income country. Herein, we report on a series of our first 40 consecutive cases that were selected for WES in a research-based neurogenetics laboratory. We demonstrated the clinical utility of WES in our patient cohort, obtaining a diagnostic yield of 40% (95% CI, 24.8%-55.2%), describing cases in which clinical management was altered, and suggesting the potential cost-effectiveness of WES as a single test by examining the number and types of tests that were performed prior to WES which added up to a median cost of $3537.6 ($2892 to $5084) for the diagnostic odysseys experienced by our cohort.

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ClinLabGeneticist: a tool for clinical management of genetic variants from whole exome sequencing in clinical genetic laboratories

Genome Medicine ◽

10.1186/s13073-015-0207-6 ◽

2015 ◽

Vol 7 (1) ◽

Cited By ~ 4

Author(s):

Jinlian Wang ◽

Jun Liao ◽

Jinglan Zhang ◽

Wei-Yi Cheng ◽

Jörg Hakenberg ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Genetic Variants ◽

Clinical Management ◽

Clinical Genetic ◽

Whole Exome

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

Frontiers in Genetics ◽

10.3389/fgene.2021.674990 ◽

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.

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