scholarly journals Returning Actionable Genomic Results in a Research Biobank: Analytic Validity, Clinical Implementation and Resource Utilization

2021 ◽  
Author(s):  
Carrie L. Blout Zawatsky ◽  
Nidhi Shah ◽  
Kalotina Machini ◽  
Emma Perez ◽  
Kurt D. Christensen ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Laboratory Testing ◽  
Clinical Implementation ◽  
Research Staff ◽  
Staff Support ◽  
Pathogenic Variants ◽  
The World ◽  
Genomic Results ◽  
Protocol Cost ◽  
Analytic Validity

Over 100 million research participants around the world have had research array-based genotyping (GT) or sequencing (GS), but only a small fraction of these have been offered return of actionable genomic findings (gRoR). Between 2017 and 2021, we analyzed genomic results from 36,417 participants in the Mass General Brigham Biobank and offered to confirm and return pathogenic and likely pathogenic variants (PLPVs) in 59 genes. Variant verification prior to patient recontact revealed that GT falsely identified PLPVs in 44.9% of samples, and GT failed to identify 72.0% of PLPVs detected in a subset of samples that were also sequenced. GT and GS detected verified PLPVs in 1% and 2.5% of the cohort, respectively. Of 256 participants who were alerted that they carried actionable PLPVs, 37.5% actively or passively declined further disclosure. 76.3% of those carrying PLPVs were unaware that they were carrying the variant and over half of those met published professional criteria for genetic testing but had never been tested. This gRoR protocol cost approximately $129,000 USD per year in laboratory testing and research staff support, representing $14 per participant whose DNA was analyzed or $3,224 per participant in whom a PLPV was confirmed and disclosed. These data provide logistical details around gRoR that could help other investigators planning to return genomic results.

scholarly journals Genetic testing in women with early-onset breast cancer: a Traceback pilot study

2021 ◽  
Author(s):  
Annelie Augustinsson ◽  
Martin P. Nilsson ◽  
Carolina Ellberg ◽  
Ulf Kristoffersson ◽  
Håkan Olsson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Genetic Counseling ◽  
Genetic Testing ◽  
Pilot Study ◽  
Early Onset ◽  
Early Onset Breast Cancer ◽  
Clinical Implementation ◽  
Test Information ◽  
Pathogenic Variants ◽  
Post Test

Abstract Purpose In Sweden, a Traceback approach, i.e., a retrospective genetic outreach activity, among cancer patients is not normally used in clinical practice. In this pilot study, we wanted to evaluate a Traceback strategy for possible future clinical implementation and investigate why not all women with early-onset breast cancer underwent genetic testing when they were first diagnosed. Methods Out of all women (n = 409) diagnosed with breast cancer at ≤ 35 years in Southern Sweden between 2000 and 2017, 63 had not previously been tested. These women were offered an analysis of the genes BRCA1, BRCA2, PALB2, CHEK2, and ATM through a standardized letter. Subsequently, women with normal test results were informed through a letter and carriers of pathogenic variants were contacted through a telephone call and offered in-person genetic counseling. All tested women were asked to complete a follow-up questionnaire regarding previously not having attended genetic counseling and testing and their experiences of the current retrospective approach. Results Out of the invited women, 29 (46%) underwent genetic testing and 27 (43%) answered the questionnaire. Pathogenic variants were identified in BRCA1 (n = 2), CHEK2 (n = 1), and ATM (n = 1). The main reason for previously not having undergone genetic testing was not having received any information from their physicians. Most study participants were satisfied with both written pre- and post-test information. Conclusion The process with retrospective identification, written pre-test information, and genetic testing, followed by in-person counseling for carriers of pathogenic variants only, was well accepted. This has implications for future Traceback implementation programs.

Frequency and characterization of mutations in genes in a large cohort of patients referred to MODY registry

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Emily Breidbart ◽  
Liyong Deng ◽  
Patricia Lanzano ◽  
Xiao Fan ◽  
Jiancheng Guo ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Exome Sequencing ◽  
Large Scale ◽  
Age Of Onset ◽  
Family Members ◽  
Ethnically Diverse ◽  
Monogenic Diabetes ◽  
Diabetes Diagnosis ◽  
Pathogenic Variants ◽  
Atypical Diabetes

Abstract Objectives There have been few large-scale studies utilizing exome sequencing for genetically undiagnosed maturity onset diabetes of the young (MODY), a monogenic form of diabetes that is under-recognized. We describe a cohort of 160 individuals with suspected monogenic diabetes who were genetically assessed for mutations in genes known to cause MODY. Methods We used a tiered testing approach focusing initially on GCK and HNF1A and then expanding to exome sequencing for those individuals without identified mutations in GCK or HNF1A. The average age of onset of hyperglycemia or diabetes diagnosis was 19 years (median 14 years) with an average HbA1C of 7.1%. Results Sixty (37.5%) probands had heterozygous likely pathogenic/pathogenic variants in one of the MODY genes, 90% of which were in GCK or HNF1A. Less frequently, mutations were identified in PDX1, HNF4A, HNF1B, and KCNJ11. For those probands with available family members, 100% of the variants segregated with diabetes in the family. Cascade genetic testing in families identified 75 additional family members with a familial MODY mutation. Conclusions Our study is one of the largest and most ethnically diverse studies using exome sequencing to assess MODY genes. Tiered testing is an effective strategy to genetically diagnose atypical diabetes, and familial cascade genetic testing identified on average one additional family member with monogenic diabetes for each mutation identified in a proband.

scholarly journals Extended gene panel testing in lobular breast cancer

2021 ◽  
Author(s):  
Elke M. van Veen ◽  
D. Gareth Evans ◽  
Elaine F. Harkness ◽  
Helen J. Byers ◽  
Jamie M. Ellingford ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Genetic Testing ◽  
Detection Rate ◽  
Gene Panel ◽  
Lobular Breast Cancer ◽  
Germline Variants ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Panel Testing ◽  
Increased Risk

AbstractPurpose: Lobular breast cancer (LBC) accounts for ~ 15% of breast cancer. Here, we studied the frequency of pathogenic germline variants (PGVs) in an extended panel of genes in women affected with LBC. Methods: 302 women with LBC and 1567 without breast cancer were tested for BRCA1/2 PGVs. A subset of 134 LBC affected women who tested negative for BRCA1/2 PGVs underwent extended screening, including: ATM, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, RAD51D, and TP53.Results: 35 PGVs were identified in the group with LBC, of which 22 were in BRCA1/2. Ten actionable PGVs were identified in additional genes (ATM(4), CDH1(1), CHEK2(1), PALB2(2) and TP53(2)). Overall, PGVs in three genes conferred a significant increased risk for LBC. Odds ratios (ORs) were: BRCA1: OR = 13.17 (95%CI 2.83–66.38; P = 0.0017), BRCA2: OR = 10.33 (95%CI 4.58–23.95; P < 0.0001); and ATM: OR = 8.01 (95%CI 2.52–29.92; P = 0.0053). We did not detect an increased risk of LBC for PALB2, CDH1 or CHEK2. Conclusion: The overall PGV detection rate was 11.59%, with similar rates of BRCA1/2 (7.28%) PGVs as for other actionable PGVs (7.46%), indicating a benefit for extended panel genetic testing in LBC. We also report a previously unrecognised association of pathogenic variants in ATM with LBC.

Combined Muscle Biopsy and Comprehensive Electrophysiology in General Anesthesia is Valuable in Diagnosis of Neuromuscular Disease in Children

2021 ◽  
Author(s):  
Christina E. Hoei-Hansen ◽  
Marie L. B. Tygesen ◽  
Morten Dunø ◽  
John Vissing ◽  
Martin Ballegaard ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Muscle Biopsy ◽  
Neuromuscular Disease ◽  
Genetic Diagnosis ◽  
Congenital Myasthenic Syndrome ◽  
Diagnostic Quality ◽  
Pathogenic Variants ◽  
Combined Use ◽  
Myasthenic Syndrome ◽  
Size Variability

Abstract Aim The diagnostic workup in patients with delayed motor milestones suspected of having either myopathy or a congenital myasthenic syndrome is complex. Our hypothesis was that performance of a muscle biopsy and neurophysiology including stimulated single-fiber electromyography during an anesthetic procedure, combined with genetic testing has a high diagnostic quality. Materials and Methods Clinical and paraclinical data were retrospectively collected from 24 patients aged from 1 month to 10 years (median: 5.2 years). Results Neurophysiology examination was performed in all patients and was abnormal in 11 of 24. No patients had findings suggestive of a myasthenic syndrome. Muscle biopsy was performed in 21 of 24 and was normal in 16. Diagnostic findings included nemaline rods, inclusion bodies, fiber size variability, and type-II fiber atrophy. Genetic testing with either a gene panel or exome sequencing was performed in 18 of 24 patients, with pathogenic variants detected in ACTA1, NEB, SELENON, GRIN2B, SCN8A, and COMP genes. Conclusion Results supporting a neuromuscular abnormality were found in 15 of 24. In six patients (25%), we confirmed a genetic diagnosis and 12 had a clinical neuromuscular diagnosis. The study suggests that combined use of neurophysiology and muscle biopsy in cases where genetic testing does not provide a diagnosis can be useful in children with delayed motor milestones and clinical evidence of a neuromuscular disease.

scholarly journals Assessment of genetic referrals and outcomes for women with triple negative breast cancer in regional cancer centres in Australia

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Lucie G. Hallenstein ◽  
Carol Sorensen ◽  
Lorraine Hodgson ◽  
Shelly Wen ◽  
Justin Westhuyzen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Genetic Testing ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cancer Genetics ◽  
Eligibility Criteria ◽  
Pathogenic Variants ◽  
Genetics Services ◽  
Age Of Diagnosis ◽  
Over Time

Abstract Background Guidelines for referral to cancer genetics service for women diagnosed with triple negative breast cancer have changed over time. This study was conducted to assess the changing referral patterns and outcomes for women diagnosed with triple negative breast cancer across three regional cancer centres during the years 2014–2018. Methods Following ethical approval, a retrospective electronic medical record review was performed to identify those women diagnosed with triple negative breast cancer, and whether they were referred to a genetics service and if so, the outcome of that genetics assessment and/or genetic testing. Results There were 2441 women with newly diagnosed breast cancer seen at our cancer services during the years 2014–2018, of whom 237 women were diagnosed with triple negative breast cancer. Based on age of diagnosis criteria alone, 13% (31/237) of our cohort fulfilled criteria for genetic testing, with 81% (25/31) being referred to a cancer genetics service. Of this group 68% (21/31) were referred to genetics services within our regions and went on to have genetic testing with 10 pathogenic variants identified; 5x BRCA1, 4x BRCA2 and × 1 ATM:c.7271 T > G. Conclusions Referral pathways for women diagnosed with TNBC to cancer genetics services are performing well across our cancer centres. We identified a group of women who did not meet eligibility criteria for referral at their time of diagnosis, but would now be eligible, as guidelines have changed. The use of cross-discipline retrospective data reviews is a useful tool to identify patients who could benefit from being re-contacted over time for an updated cancer genetics assessment.

Development and assessment of an accessible communication system for population-based genetic testing: Method/design (Preprint)

2021 ◽  
Author(s):  
Tara Coffin ◽  
Deborah Bowen ◽  
Elizabeth Swisher ◽  
Karen Lu ◽  
Karen Lu ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Communication System ◽  
Formative Evaluation ◽  
Online Communication ◽  
Implementation Process ◽  
Usability Testing ◽  
Population Based ◽  
Ovarian Cancer Risk ◽  
Online System ◽  
Pathogenic Variants

BACKGROUND Genetic testing uptake is low, despite the well-established connection between pathogenic variants in certain cancer-linked susceptibility genes and ovarian cancer risk. Given that most major insurers cover genetic testing for those with a family history suggestive of hereditary cancer, the issue may lie in access to genetic testing. OBJECTIVE To present the development and formative evaluation of the multi-step online communication system required to support the democratization of genetic testing. METHODS While designing the multi-step online communication system, we considered various barriers and facilitators to genetic testing, guided by Levesque et al.’s dimensions of accessibility. In addition to conducting usability testing, we performed ongoing assessments focusing on function of the online system and participant response rates, with the goal of continuing to make modifications to the online communication system as it is in use. RESULTS The combined approach of usability testing and expert user experience (UX) consultation resulted in several modifications to the multi-step online communication system, including changes that related to imagery and content, web-accessibility, and general organization of the online system. All recommendations were made with the goal of improving the overall accessibility of the online communication system. CONCLUSIONS A multi-step online communication system appears to be an effective way to address many potential barriers to access, which may otherwise make genetic testing difficult for at-risk individuals to participate in. Importantly, some dimensions of access were easy to assess prior to study recruitment opening, but other aspects of the communication system required ongoing assessment during the implementation process of the Making Genetic Testing Accessible (MAGENTA) study.

scholarly journals A post mortem assessment of a 25-year-old man with ascending aortic dissection and a novel MYLK variant

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Katelyn Hodge ◽  
Katherine G. Spoonamore ◽  
Christopher B. Griffith ◽  
David D. Weaver ◽  
Patricia B.S. Celestino-Soper ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Aortic Aneurysm ◽  
Aortic Dissection ◽  
Thoracic Aortic Aneurysm ◽  
Aortic Rupture ◽  
Clinical Consequence ◽  
Post Mortem ◽  
Variant Of Uncertain Significance ◽  
Pathogenic Variants ◽  
Aortic Aneurysm And Dissection

We report on the process of <em>post mortem</em> evaluation and genetic testing following the death of a 25-year-old man due to ascending aortic dissection leading to aortic rupture. Following the negative clinical testing of a 12- gene thoracic aortic aneurysm and dissection panel, research testing revealed a novel c.5732A&gt;T (p.E1911V) variant in exon 34 of the MYLK gene (NM_053025). Two likely pathogenic variants in this gene have been reported previously in individuals with familial thoracic aortic aneurysm and dissection. Given the unclear clinical consequence of the variant found in our proband, we have classified this change as a variant of uncertain significance. In addition to discussing the complexity involved in variant interpretation, we recognize the need for additional research for more accurate <em>MYLK</em> interpretation. Finally, we comment on the unique challenges of <em>post mortem</em> genetic testing.

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