There is growing interest in communicating clinically relevant DNA sequence findings to research participants who join projects with a primary research goal other than the clinical return of such ...results. Since Geisinger’s MyCode Community Health Initiative (MyCode) was launched in 2007, more than 200,000 participants have been broadly consented for discovery research. In 2013 the MyCode consent was amended to include a secondary analysis of research genomic sequences that allows for delivery of clinical results. Since May 2015, pathogenic and likely pathogenic variants from a set list of genes associated with monogenic conditions have prompted “genome-first” clinical encounters. The encounters are described as genome-first because they are identified independent of any clinical parameters. This article (1) details our process for generating clinical results from research data, delivering results to participants and providers, facilitating condition-specific clinical evaluations, and promoting cascade testing of relatives, and (2) summarizes early results and participant uptake. We report on 542 participants who had results uploaded to the electronic health record as of February 1, 2018 and 291 unique clinical providers notified with one or more participant results. Of these 542 participants, 515 (95.0%) were reached to disclose their results and 27 (5.0%) were lost to follow-up. We describe an exportable model for delivery of clinical care through secondary use of research data. In addition, subject and provider participation data from the initial phase of these efforts can inform other institutions planning similar programs.
The era of personalized medicine has arrived, and with it a need for leaders in this discipline. This generation of trainees requires a cadre of new skill sets to lead the implementation of ...personalized medicine into mainstream healthcare. Traditional training programs no longer provide trainees with all the skills they will need to optimize implementation of this revolution now underway in medicine. Today's trainees must manage clinical teams, act as clinical and molecular diagnostic consultants, train other healthcare professionals, teach future generations, and be knowledgeable about clinical trials to facilitate genomic-based therapies. To prepare trainees for the transition to junior faculty positions, contemporary genomic training programs must emphasize the development of these management, teaching, and clinical skills.
ABSTRACT
Affecting up to 10% to 15% of all clinically recognized pregnancies, pregnancy loss has many causes. Half of first-trimester losses come about due to chromosomal abnormalities and then ...decline in frequency through pregnancy, ultimately reaching a rate of 5% in stillbirths. Recurrent pregnancy loss occurs in 1% to 2% of couples, and identifying the genetic etiology of these losses can provide psychological benefits, eliminate other testing needs, and establish a risk of recurrence. As benefits of performing genetic testing on products of conception (POCs) are clear, various groups have published practice guidelines (American College of Obstetricians and Gynecologists, European Society of Human Reproduction and Embryology, American Society for Reproductive Medicine, and Royal College of Obstetricians and Gynaecologists). However, despite the consensus for the utility of testing on POCs, requirements for these tests vary. Most appropriate testing methodology, obstetric history, and gestational age are all variations that affect the benefit or utility of these tests. As there is a lack of consensus on how to use chromosomal microarray analysis (CMA) in assessment of POCs, this study assessed POC CMA data with available karyotype data and determined the positive CMA rate for POCs. The authors also included within this data set a comprehensive correlation of CMA correlations with pregnancy phenotype, gestational age, and prior prenatal screening results. Finally, the study also assessed the impact CMA results from early losses may have on clinical care.
This cohort included 323 POC samples processed by the Brigham and Women's Hospital Center for Advanced Molecular Diagnostics in the Clinical Cytogenetics Laboratory over a consecutive 42-month period. Collected variables included estimated gestational age at time of pregnancy loss, maternal age, pregnancy phenotype results of any orthogonal testing on POC tissue, noninvasive prenatal screen results, CMA findings, and available parental karyotypes. All cases recorded gestational age except 1 sample lacking documentation. Categories of phenotypic data included lymphatic malformations, anatomical abnormalities of the fetus or placenta, twin or higher-level multiple gestations, environmental complications, amniotic fluid disorders, or the combined influence of any of the above. A lack of definitive phenotypic data excluded 3 cases from the analysis. Analyses of CMA results were categorized as normal, abnormal, or variants of uncertain significance (VUSs). The cases defined as normal had no identifiable clinically significant copy number variants, and abnormal cases were defined as pathogenic.
Results of the study included gestational age for 322 of 323 cases, which was then used to determine the rate of fetal demise or miscarriage at different gestational ages in the cohort, with first-trimester losses at <14 weeks (n = 230) and later losses defined as occurring at >14 weeks gestational age (n = 92).
The results demonstrated that frequency and genetic abnormality types (as identified by CMA) align closely with karyotype studies previously published. This means that an approximate half of the first-trimester loss cohort have a genetic abnormality, with trisomies as the most common finding. Very early losses tend to have a high positive rate of abnormalities (45.6%), which further supported CMA use in first-trimester losses. Inadvertent assessment and reporting of maternal metaphases were reduced, and yield of results improved with the implementation of CMA. Abnormal POC results may suggest balanced parental abnormalities, and follow-up parental testing in such cases is recommended. A need for additional studies exists to determine the parental follow-up studies yield.
In conclusion, POC tissue genetic testing following pregnancy loss can aid in clinical management via identification of genetic etiologies, thereby refining recurrence risk. However, lack of consensus in terms of testing strategies and methodologies indicates a need for standardized methodology. This study demonstrated CMA results consistent with published karyotype studies established CMA analysis advantages over POC karyotype in all gestational ages. Even in early first-trimester losses, these results support the efficacy of CMA in POC testing.
Clinically relevant variants exhibit a wide range of penetrance. Medical practice has traditionally focused on highly penetrant variants with large effect sizes and, consequently, classification and ...clinical reporting frameworks are tailored to that variant type. At the other end of the penetrance spectrum, where variants are often referred to as "risk alleles," traditional frameworks are no longer appropriate. This has led to inconsistency in how such variants are interpreted and classified. Here, we describe a conceptual framework to begin addressing this gap.
We used a set of risk alleles to define data elements that can characterize the validity of reported disease associations. We assigned weight to these data elements and established classification categories expressing confidence levels. This framework was then expanded to develop criteria for inclusion of risk alleles on clinical reports.
Foundational data elements include cohort size, quality of phenotyping, statistical significance, and replication of results. Criteria for determining inclusion of risk alleles on clinical reports include presence of clinical management guidelines, effect size, severity of the associated phenotype, and effectiveness of intervention.
This framework represents an approach for classifying risk alleles and can serve as a foundation to catalyze community efforts for refinement.
Genetic analysis is a critical component in the male infertility workup. For male infertility due to oligospermia/azoospermia, standard guidelines recommend karyotype and Y-chromosome microdeletion ...analyses. A karyotype is used to identify structural and numerical chromosome abnormalities, whereas Y-chromosome microdeletions are commonly evaluated by multiplex PCR analysis because of their submicroscopic size. Because these assays often require different Vacutainer tubes to be sent to different laboratories, ordering is prone to errors. In addition, this workflow limits the ability for sequential testing and a comprehensive test result. A potential solution includes performing Y-microdeletion and numerical chromosome analysis—the most common genetic causes of oligospermia/azoospermia—by chromosomal microarray (CMA) and reflexing to karyotype as both assays are often offered in the cytogenetics laboratory. Such analyses can be performed using one sodium heparin Vacutainer tube sample. To determine the effectiveness of CMA for the detection of clinically significant Y-chromosome microdeletions, 21 cases with known Y microdeletions were tested by CytoScan HD platform. CMA studies identified all known Y-chromosome microdeletions, and in 11 cases (52%) identified additional clinically important cytogenetic anomalies, including six cases of 46, XX males, one case of isodicentric Y, two cases of a dicentric Y, and three cases of terminal Yq deletions. These findings demonstrate that this testing strategy would simplify ordering and allow for an integrated interpretation of test results.
Pathogenic DNA variants associated with familial hypercholesterolemia, hereditary breast and ovarian cancer syndrome, and Lynch syndrome are widely recognized as clinically important and actionable ...when identified, leading some clinicians to recommend population-wide genomic screening.
To assess the prevalence and clinical importance of pathogenic or likely pathogenic variants associated with each of 3 genomic conditions (familial hypercholesterolemia, hereditary breast and ovarian cancer syndrome, and Lynch syndrome) within the context of contemporary clinical care.
This cohort study used gene-sequencing data from 49 738 participants in the UK Biobank who were recruited from 22 sites across the UK between March 21, 2006, and October 1, 2010. Inpatient hospital data date back to 1977; cancer registry data, to 1957; and death registry data, to 2006. Statistical analysis was performed from July 22, 2019, to November 15, 2019.
Pathogenic or likely pathogenic DNA variants classified by a clinical laboratory geneticist.
Composite end point specific to each genomic condition based on atherosclerotic cardiovascular disease events for familial hypercholesterolemia, breast or ovarian cancer for hereditary breast and ovarian cancer syndrome, and colorectal or uterine cancer for Lynch syndrome.
Among 49 738 participants (mean SD age, 57 8 years; 27 144 female 55%), 441 (0.9%) harbored a pathogenic or likely pathogenic variant associated with any of 3 genomic conditions, including 131 (0.3%) for familial hypercholesterolemia, 235 (0.5%) for hereditary breast and ovarian cancer syndrome, and 76 (0.2%) for Lynch syndrome. Presence of these variants was associated with increased risk of disease: for familial hypercholesterolemia, 28 of 131 carriers (21.4%) vs 4663 of 49 607 noncarriers (9.4%) developed atherosclerotic cardiovascular disease; for hereditary breast and ovarian cancer syndrome, 32 of 116 female carriers (27.6%) vs 2080 of 27 028 female noncarriers (7.7%) developed associated cancers; and for Lynch syndrome, 17 of 76 carriers (22.4%) vs 929 of 49 662 noncarriers (1.9%) developed colorectal or uterine cancer. The predicted probability of disease at age 75 years despite contemporary clinical care was 45.3% for carriers of familial hypercholesterolemia, 41.1% for hereditary breast and ovarian cancer syndrome, and 38.3% for Lynch syndrome. Across the 3 conditions, 39.7% (175 of 441) of the carriers reported a family history of disease vs 23.2% (34 517 of 148 772) of noncarriers.
The findings suggest that approximately 1% of the middle-aged adult population in the UK Biobank harbored a pathogenic variant associated with any of 3 genomic conditions. These variants were associated with an increased risk of disease despite contemporary clinical care and were not reliably detected by family history.
Sudden cardiac death occurs in ∼220,000 U.S. adults annually, the majority of whom have no prior symptoms or cardiovascular diagnosis. Rare pathogenic DNA variants in any of 49 genes can pre-dispose ...to 4 important causes of sudden cardiac death: cardiomyopathy, coronary artery disease, inherited arrhythmia syndrome, and aortopathy or aortic dissection.
This study assessed the prevalence of rare pathogenic variants in sudden cardiac death cases versus controls, and the prevalence and clinical importance of such mutations in an asymptomatic adult population.
The authors performed whole-exome sequencing in a case-control cohort of 600 adult-onset sudden cardiac death cases and 600 matched controls from 106,098 participants of 6 prospective cohort studies. Observed DNA sequence variants in any of 49 genes with known association to cardiovascular disease were classified as pathogenic or likely pathogenic by a clinical laboratory geneticist blinded to case status. In an independent population of 4,525 asymptomatic adult participants of a prospective cohort study, the authors performed whole-genome sequencing and determined the prevalence of pathogenic or likely pathogenic variants and prospective association with cardiovascular death.
Among the 1,200 sudden cardiac death cases and controls, the authors identified 5,178 genetic variants and classified 14 as pathogenic or likely pathogenic. These 14 variants were present in 15 individuals, all of whom had experienced sudden cardiac death—corresponding to a pathogenic variant prevalence of 2.5% in cases and 0% in controls (p < 0.0001). Among the 4,525 participants of the prospective cohort study, 41 (0.9%) carried a pathogenic or likely pathogenic variant and these individuals had 3.24-fold higher risk of cardiovascular death over a median follow-up of 14.3 years (p = 0.02).
Gene sequencing identifies a pathogenic or likely pathogenic variant in a small but potentially important subset of adults experiencing sudden cardiac death; these variants are present in ∼1% of asymptomatic adults.
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