Cost-effectiveness of genome sequencing for diagnosing patients with undiagnosed rare genetic diseases

PurposeTo estimate the cost-effectiveness of genome sequencing (GS) for diagnosing critically ill infants and noncritically ill pediatric patients (children) with suspected rare genetic diseases from a United States health sector perspective.MethodsA decision-analytic model was developed to simulate the diagnostic trajectory of patients. Parameter estimates were derived from a targeted literature review and meta-analysis. The model simulated clinical and economic outcomes associated with 3 diagnostic pathways: (1) standard diagnostic care, (2) GS, and (3) standard diagnostic care followed by GS.ResultsFor children, costs of GS ($7284) were similar to that of standard care ($7355) and lower than that of standard care followed by GS pathways ($12,030). In critically ill infants, when cost estimates were based on the length of stay in the neonatal intensive care unit, the lowest cost pathway was GS ($209,472). When only diagnostic test costs were included, the cost per diagnosis was $17,940 for standard, $17,019 for GS, and $20,255 for standard care followed by GS.ConclusionThe results of this economic model suggest that GS may be cost neutral or possibly cost saving as a first line diagnostic tool for children and critically ill infants.     

Copy-number variants in clinical genome sequencing: deployment and interpretation for rare and undiagnosed disease

PurposeCurrent diagnostic testing for genetic disorders involves serial use of specialized assays spanning multiple technologies. In principle, genome sequencing (GS) can detect all genomic pathogenic variant types on a single platform. Here we evaluate copy-number variant (CNV) calling as part of a clinically accredited GS test.MethodsWe performed analytical validation of CNV calling on 17 reference samples, compared the sensitivity of GS-based variants with those from a clinical microarray, and set a bound on precision using orthogonal technologies. We developed a protocol for family-based analysis of GS-based CNV calls, and deployed this across a clinical cohort of 79 rare and undiagnosed cases.ResultsWe found that CNV calls from GS are at least as sensitive as those from microarrays, while only creating a modest increase in the number of variants interpreted (~10 CNVs per case). We identified clinically significant CNVs in 15% of the first 79 cases analyzed, all of which were confirmed by an orthogonal approach. The pipeline also enabled discovery of a uniparental disomy (UPD) and a 50% mosaic trisomy 14. Directed analysis of select CNVs enabled breakpoint level resolution of genomic rearrangements and phasing of de novo CNVs.ConclusionRobust identification of CNVs by GS is possible within a clinical testing environment.     

Evaluating the clinical utility of a molecular genetic test for polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is estimated to affect 1/600-1/1000 individuals worldwide. The disease is characterized by age dependent renal cyst formation that results in kidney failure during adulthood. Although ultrasound imaging may be an adequate diagnostic tool in at risk individuals older than 30, this modality may not be sufficiently sensitive in younger individuals or for those from PKD2 families who have milder disease. DNA based assays may be indicated in certain clinical situations where imaging cannot provide a definitive clinical diagnosis. The goal of this study was to evaluate the utility of direct DNA analysis in a test sample of 82 individuals who were judged to have polycystic kidney disease by standard clinical criteria. The samples were analyzed using a commercially available assay that employs sequencing of both genes responsible for the disorder. Definite disease causing mutations were identified in 34 (approximately 42%) study participants. An additional 30 (approximately 37%) subjects had either in frame insertions/deletions, non-canonical splice site alterations or a combination of missense changes that were also judged likely to be pathogenic. We noted striking sequence variability in the PKD1 gene, with a mean of 13.1 variants per participant (range 0-60). Our results and analysis highlight the complexity of assessing the pathogenicity of missense variants particularly when individuals have multiple amino acid substitutions. We conclude that a significant fraction of ADPKD mutations are caused by amino acid substitutions that need to be interpreted carefully when utilized in clinical decision-making.     

Clinical dividends from the molecular genetic diagnosis of craniosynostosis

A dozen years have passed since the first genetic lesion was identified in a family with craniosynostosis, the premature fusion of the cranial sutures. Subsequently, mutations in the FGFR2, FGFR3, TWIST1, and EFNB1 genes have been shown to account for approximately 25% of craniosynostosis, whilst several additional genes make minor contributions. Using specific examples, we show how these discoveries have enabled refinement of information on diagnosis, recurrence risk, prognosis for mental development, and surgical planning. However, phenotypic variability can present a significant challenge to the clinical interpretation of molecular genetic tests. In particular, the difficulty of analyzing the complex interaction of genetic background and prenatal environment in determining clinical features, limits the value of identifying low penetrance mutations.     

Clinical dividends from the molecular genetic diagnosis of craniosynostosis

A dozen years have passed since the first genetic lesion was identified in a family with craniosynostosis, the premature fusion of the cranial sutures. Subsequently, mutations in the FGFR2, FGFR3, TWIST1, and EFNB1 genes have been shown to account for approximately 25% of craniosynostosis, whilst several additional genes make minor contributions. Using specific examples, we show how these discoveries have enabled refinement of information on diagnosis, recurrence risk, prognosis for mental development, and surgical planning. However, phenotypic variability can present a significant challenge to the clinical interpretation of molecular genetic tests. In particular, the difficulty of analyzing the complex interaction of genetic background and prenatal environment in determining clinical features, limits the value of identifying low penetrance mutations.     

The performance of genome sequencing as a first-tier test for neurodevelopmental disorders

Genome sequencing (GS) can identify novel diagnoses for patients who remain undiagnosed after routine diagnostic procedures. We tested whether GS is a better first-tier genetic diagnostic test than current standard of care (SOC) by assessing the technical and clinical validity of GS for patients with neurodevelopmental disorders (NDD). We performed both GS and exome sequencing in 150 consecutive NDD patient-parent trios. The primary outcome was diagnostic yield, calculated from disease-causing variants affecting exonic sequence of known NDD genes. GS (30%, n = 45) and SOC (28.7%, n = 43) had similar diagnostic yield. All 43 conclusive diagnoses obtained with SOC testing were also identified by GS. SOC, however, required integration of multiple test results to obtain these diagnoses. GS yielded two more conclusive diagnoses, and four more possible diagnoses than ES-based SOC (35 vs. 31). Interestingly, these six variants detected only by GS were copy number variants (CNVs). Our data demonstrate the technical and clinical validity of GS to serve as routine first-tier genetic test for patients with NDD. Although the additional diagnostic yield from GS is limited, GS comprehensively identified all variants in a single experiment, suggesting that GS constitutes a more efficient genetic diagnostic workflow.Subject terms: Neurodevelopmental disorders, DNA sequencing, Genetic techniques, Genomic analysis, Genetics research     

The implementation of an enhanced clinical model to improve the diagnostic yield of exome sequencing for patients with a rare genetic disease: A Canadian experience

The introduction of clinical exome sequencing (ES) has provided a unique opportunity to decrease the diagnostic odyssey for patients living with a rare genetic disease (RGD). ES has been shown to provide a diagnosis in 29%–57% of patients with a suspected RGD, with as many as 70% remaining undiagnosed. There is a need to advance the clinical model of care by more formally integrating approaches that were previously considered research into an enhanced diagnostic workflow. We developed an Exome Clinic, which set out to evaluate a workflow for improving the diagnostic yield of ES for patients with an undiagnosed RGD. Here, we report the outcomes of 47 families who underwent clinical ES in the first year of the clinic. The diagnostic yield from clinical ES was 40% (19/47). Families who remained undiagnosed after ES had the opportunity for follow-up studies that included phenotyping and candidate variant segregation in relatives, genomic matchmaking, and ES reanalysis. This enhanced diagnostic workflow increased the diagnostic yield to 55% (26/47), predominantly through the resolution of variants and genes of uncertain significance. We advocate that this approach be integrated into mainstream clinical practice and highlight the importance of a coordinated translational approach for patients with RGD.     

A model program to increase translation of rare disease genetic tests: collaboration,education, and test translation program

In 2006, The National Institutes of Health Office of Rare Diseases announced the Collaboration, Education, and Test Translation (CETT) Program, a pilot project to increase and improve the translation of genetic tests for rare diseases from research laboratories to clinical laboratories. The CETT Program created a new paradigm in which applicants must form a collaborative group consisting of a clinical laboratory, researcher, research laboratory, clinical expert, and disease-specific advocacy group. In addition, each collaborative group must assure that test results are written in a style and format appropriate for nonexpert clinicians; provide educational materials for clinicians and patients about the disease, as well as the use and limitations of the test in the care of persons with the disease; agree to collect clinical data necessary for test result interpretation; and store genotype information and clinical data in a publicly accessible deidentified database.     

Benefits of clinical criteria and high-throughput sequencing for diagnosing children with syndromic craniosynostosis

An accurate diagnosis of syndromic craniosynostosis (CS) is important for personalized treatment, surveillance, and genetic counselling. We describe detailed clinical criteria for syndromic CS and the distribution of genetic diagnoses within the cohort. The prospective registry of the Norwegian National Unit for Craniofacial Surgery was used to retrieve individuals with syndromic CS born between 1 January 2002 and 30 June 2019. All individuals were assessed by a clinical geneticist and classified using defined clinical criteria. A stepwise approach consisting of single-gene analysis, comparative genomic hybridization (aCGH), and exome-based high-throughput sequencing, first filtering for 72 genes associated with syndromic CS, followed by an extended trio-based panel of 1570 genes were offered to all syndromic CS cases. A total of 381 individuals were registered with CS, of whom 104 (27%) were clinically classified as syndromic CS. Using the single-gene analysis, aCGH, and custom-designed panel, a genetic diagnosis was confirmed in 73% of the individuals (n = 94). The diagnostic yield increased to 84% after adding the results from the extended trio-based panel. Common causes of syndromic CS were found in 53 individuals (56%), whereas 26 (28%) had other genetic syndromes, including 17 individuals with syndromes not commonly associated with CS. Only 15 individuals (16%) had negative genetic analyses. Using the defined combination of clinical criteria, we detected among the highest numbers of syndromic CS cases reported, confirmed by a high genetic diagnostic yield of 84%. The observed genetic heterogeneity encourages a broad genetic approach in diagnosing syndromic CS.Subject terms: Genetic testing, Genetics research, Diseases     

Shared decision making seen through the lens of professional identity formation

The finding in the article by Driever et al.; "Shared decision,making: Physicians' preferred role, usual role and their perception of its key components" of lower preferred and practiced SDM role in residents in favour of a paternalistic role, compared to their more seasoned colleagues deserves more in depth, qualitative research.Because our residents are tomorrows doctors, I would strongly encourage the authors of this insightful article to consider research focused on residents as the next step in their research on SDM and to see this future research through a 'medical-education-PIF-lens'. The multi-level professionalism framework, designed as a framework for reflection and development in medical education might be of help is this future research.     

Genetic diagnosis of autoinflammatory disease patients using clinical exome sequencing

Autoinflammatory diseases comprise a wide range of syndromes caused by dysregulation of the innate immune response. They are difficult to diagnose due to their phenotypic heterogeneity and variable expressivity. Thus, the genetic origin of the disease remains undetermined for an important proportion of patients. We aim to identify causal genetic variants in patients with suspected autoinflammatory disease and to test the advantages and limitations of the clinical exome gene panels for molecular diagnosis. Twenty-two unrelated patients with clinical features of autoinflammatory diseases were analyzed using clinical exome sequencing (~4800 genes), followed by bioinformatic analyses to detect likely pathogenic variants. By integrating genetic and clinical information, we found a likely causative heterozygous genetic variant in NFKBIA (p.D31N) in a North-African patient with a clinical picture resembling the deficiency of interleukin-1 receptor antagonist, and a heterozygous variant in DNASE2 (p.G322D) in a Spanish patient with a suspected lupus-like monogenic disorder. We also found variants likely to increase the susceptibility to autoinflammatory diseases in three additional Spanish patients: one with an initial diagnosis of juvenile idiopathic arthritis who carries two heterozygous UNC13D variants (p.R727Q and p.A59T), and two with early-onset inflammatory bowel disease harbouring NOD2 variants (p.L221R and p.A728V respectively). Our results show a similar proportion of molecular diagnosis to other studies using whole exome or targeted resequencing in primary immunodeficiencies. Thus, despite its main limitation of not including all candidate genes, clinical exome targeted sequencing can be an appropriate approach to detect likely causative variants in autoinflammatory diseases.     

How can Australia integrate routine genetic sequencing in oncology: a qualitative study through an implementation science lens

PurposeThis study sought to determine genetics and oncology specialists’ views of integrating BRCA1 and BRCA2 testing in epithelial ovarian and breast cancer into routine practice.MethodsQualitative interviews were designed using the Consolidated Framework for Implementation Research. Questions included experiences or views of the BRCA testing processes, implementation needs of oncology health professionals, perceived challenges, and future ideas for interventions to integrate genetic testing into oncology.ResultsTwenty-two participants were interviewed from twelve health organizations and four themes were identified: (1) embracing the shift to mainstream genetic testing, with the majority of participants viewing BRCA testing as clinically useful and routine use important for maintaining a patient centered process; (2) the need for communication networks and role delineation to integrate routine genetic testing; (3) factors that influence sustaining routine genetic testing, including ongoing training, resources and funding, real-world adaptation, system complexity, and champions; and (4) variation in system interventions for integrating routine genetic testing align to organizational context.ConclusionFindings illustrate the need for integrating genetic testing into routine oncology, and that adaptation of interventions and processes is essential to sustain a feasible model. An understanding of individual and organizational implementation factors will help to prepare for future integration of routine genetic testing in other cancers.     

Cost-effectiveness of exome and genome sequencing for children with rare and undiagnosed conditions

PurposeThis study aimed to estimate the cost-effectiveness of exome sequencing (ES) and genome sequencing (GS) for children.MethodsWe modeled costs, diagnoses, and quality-adjusted life years (QALYs) for diagnostic strategies for critically ill infants (aged <1 year) and children (aged <18 years) with suspected genetic conditions: (1) standard of care (SOC) testing, (2) ES, (3) GS, (4) SOC followed by ES, (5) SOC followed by GS, (6) ES followed by GS, and (7) SOC followed by ES followed by GS. We calculated the 10-year incremental cost per additional diagnosis, and lifetime incremental cost per QALY gained, from a health care perspective.ResultsFirst-line GS costs $15,048 per diagnosis vs SOC for infants and $27,349 per diagnosis for children. If GS is unavailable, ES represents the next most efficient option compared with SOC ($15,543 per diagnosis for infants and $28,822 per diagnosis for children). Other strategies provided the same or fewer diagnoses at a higher incremental cost per diagnosis. Lifetime results depend on the patient’s assumed long-term prognosis after diagnosis. For infants, GS ranged from cost-saving (vs all alternatives) to $18,877 per QALY (vs SOC). For children, GS (vs SOC) ranged from $119,705 to $490,047 per QALY.ConclusionFirst-line GS may be the most cost-effective strategy for diagnosing infants with suspected genetic conditions. For all children, GS may be cost-effective under certain assumptions. ES is nearly as efficient as GS and hence is a viable option when GS is unavailable.     

Participant experiences of genome sequencing for rare diseases in the 100,000 Genomes Project: a mixed methods study

In this mixed methods study, a survey and in-depth interviews were used to explore whether decision regret and the psychological impact of receiving genome sequencing (GS) results differed between parents and patients, and between those who received a genetic diagnosis and those who did not. Participants (n = 77) completed a survey that included the Decisional Regret Scale (DRS) and an adaptation of the Multidimensional Impact of Cancer Risk Assessment (MICRA) at least 12 months after consenting for GS for rare disease diagnosis in the 100,000 Genomes Project. Survey participants were invited to take part in an interview and 39 agreed; 12 with a diagnosis, 5 with variants of uncertain significance, and 19 with no pathogenic findings identified. Both survey and interview findings indicated that decision regret was low. DRS scores revealed no differences in levels of regret between parents and patients, or between those with a diagnosis and those without. Though MICRA scores indicated minimal evidence of negative psychological impacts of receiving GS results, subscale analysis revealed greater distress and uncertainty for parents compared to patients. Receiving a diagnosis was found not to influence MICRA scores, supporting interview findings of both positive and negative emotional and psychological impacts irrespective of a genetic diagnosis. Our findings have implications for policy and practice as GS is integrated into the UK and worldwide; notably, that expectation-setting is critical when offering GS, and that post-test counselling is important regardless of the GS result received, with parents perhaps needing additional emotional support.Subject terms: Social sciences, Genomics