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Genome sequencing can generate findings beyond the initial test indication that may be relevant to a patient or research participant's health. In the decade since the American College of Medical Genetics and Genomics published its recommendations for reporting these findings, consensus regarding terminology has remained elusive and a variety of terms are in use globally. We conducted a scoping review to explore terminology choice and the justifications underlying those choices. Documents were included if they contained a justification for their choice of term(s) related to findings beyond the initial genomic test indication. From 3571 unique documents, 52 were included, just over half of which pertained to the clinical context (n = 29, 56%). We identified four inter-related concepts used to defend or oppose terms: expectedness of the finding, effective communication, relatedness to the original test indication, and how genomic information was generated. A variety of justifications were used to oppose the term "incidental," whereas "secondary" had broader support as a term to describe findings deliberately sought. Terminology choice would benefit from further work to include the views of patients. We contend that clear definitions will improve ethical debate and support communication about genomic findings beyond the initial test indication.

PURPOSE: This study aimed to assess the extent to which structured approaches to implementation of clinical genomics, proposed or adapted, are informed by evidence. METHODS: A systematic approach was used to identify peer-reviewed articles and gray literature to report on 4 research questions: 1. What structured approaches have been proposed to support implementation? 2. To what extent are the structured approaches informed by evidence? 3. How have structured approaches been deployed in the genomic setting? 4. What are the intended outcomes of the structured approaches? RESULTS: A total of 30 unique structured approaches to implementation were reported across 23 peer-reviewed publications and 11 gray literature articles. Most approaches were process models, applied in the preadoption implementation phase, focusing on a "service" outcome. Key findings included a lack of implementation science theory informing the development/implementation of newly designed structured approaches in the genomic setting and a lack of measures to assess implementation effectiveness. CONCLUSION: This scoping review identified a significant number of structured approaches developed to inform the implementation of genomic medicine into clinical practice, with limited use of implementation science to support the process. We recommend the use of existing implementation science theory and the expertise of implementation scientists to inform the design of genomic programs being implemented into clinical care.

BACKGROUND: Complex genomic profiling (CGP) has transformed cancer treatment decision making, yet there is a lack of robust and quantifiable evidence for how utilisation of CGP improves patient outcomes. OBJECTIVE: This study evaluated cohort level clinical effectiveness of CGP to improve overall survival (OS) in real-world advanced cancer patients using a registry-based matched control population. PATIENTS AND METHODS: Two cohorts of advanced and refractory cancer patients were seen in consecutive series for early phase trial enrolment consideration. The first cohort (CGP group) accessed tumour profiling via a research study; while the second cohort that followed was not profiled. Overall survival between cohorts was compared using Kaplan-Meier curves and Cox proportional hazard models. Potential confounding was analysed and adjusted for using stabilised weights based on propensity scores. RESULTS: Within the CGP group, 25 (17.6%) patients received treatment informed by CGP results and this subgroup had significantly improved survival compared with CGP patients in whom results did not impact their treatment (unadjusted HR = 0.44, (0.22-0.88), p = 0.02). However, when comparing the entire CGP cohort with the No CGP cohort, no significant survival benefit was evident with adjusted median OS for CGP of 13.5 months (9.2-17.0) compared with 11.0 (9.2-17.4) for No CGP (adjusted HR = 0.92, (0.65-1.30), p = 0.63). CONCLUSIONS: This study utilised real-world data to simulate a control arm and quantify the clinical effectiveness of genomic testing. The magnitude of survival benefit for patients who had CGP result-led treatments was insufficient to drive an overall survival gain for the entire tested population. Translation of CGP into clinics requires strategies to ensure higher rates of tested patients obtain clinical benefit to deliver on the value proposition of CGP in an advanced cancer population.

Background: Consumer genomic testing for nutrition and wellness, (nutritional genomics), is becoming increasingly popular. Concurrently, health-care practitioners (HPs) working in private practice (including doctors interested in integrative medicine, private genetic counsellors, pharmacists, dieticians, naturopaths and nutritionists) are involved as test facilitators or interpreters. Objective: To explore Australian consumers’ and HPs’ experiences with nutrigenomic testing. Method: Semi-structured in-depth interviews were conducted using predominantly purposive sampling. The two data sets were analysed individually, then combined, using a constant comparative, thematic approach. Results: Overall, 45 interviews were conducted with consumers (n = 18) and HPs (n = 27). Many of the consumer interviewees experienced chronic ill-health. Nutrigenomic testing was perceived as empowering and a source of hope for answers. While most made changes to their diet/supplements post-test, self-reported health improvements were small. A positive relationship with their HP appeared to minimize disappointment. HPs’ adoption and views of nutrigenomic testing varied. Those enthusiastic about testing saw the possibilities it could offer. However, many felt nutrigenomic testing was not the only ‘tool’ to utilize when offering health care. Discussion: This research highlights the important role HPs play in consumers’ experiences of nutrigenomics. The varied practice suggests relevant HPs require upskilling in this area to at least support their patients/clients, even if nutrigenomic testing is not part of their practice. Patient or public contribution: Advisory group included patient/public group representatives who informed study design; focus group participants gave feedback on the survey from which consumer interviewees were sourced. This informed the HP data set design. Interviewees from HP data set assisted with snowball sampling.

Background: Despite the emergence of diagnostic and clinical utility evidence in nephrology, publicly funded access to genomic testing is restricted in most health care systems. To establish genomic sequencing as a clinical test, an evaluation of cost-effectiveness is urgently required. Method(s): An economic evaluation, informed by a primary clinical study and available clinical evidence and guidelines in nephrology, was performed to evaluate the cost-effectiveness and optimal timing of exome sequencing (ES) in adults and children with suspected monogenic glomerular diseases compared with nongenomic investigations (NGIs). Six diagnostic strategies reflecting current practice and recommended models of care in Australia were modeled: (i) NGIs, (ii) late gene panel followed by ES, (iii) late ES, (iv) early gene panel, (v) early gene panel followed by ES, and (vi) early ES. Result(s): ES with targeted analysis achieved a diagnosis in 23 of 63 (36.5%) adults and 10 of 24 (41.6%) children. NGIs were estimated to diagnose 4.0% of children, with an average estimated cost of AU$6120 per child. Integrating ES as a first-line test in children was cost saving, with an incremental cost saving of AU$3230 per additional diagnosis compared with NGIs. In adults, NGIs was estimated to diagnose 8% of patients, with an average estimated cost of AU$1830 per person. In adults, integrating ES early resulted in an incremental cost per additional diagnosis of AU$5460 relative to NGIs. Conclusion(s): Early ES with targeted analysis was effective for diagnosing monogenic kidney disease, with substantial cost savings in children.Copyright © 2021

Purpose: To determine the diagnostic yield and clinical impact of exome sequencing (ES) in patients with suspected monogenic kidney disease. Method(s): We performed clinically accredited singleton ES in a prospectively ascertained cohort of 204 patients assessed in multidisciplinary renal genetics clinics at four tertiary hospitals in Melbourne, Australia. Result(s): ES identified a molecular diagnosis in 80 (39%) patients, encompassing 35 distinct genetic disorders. Younger age at presentation was independently associated with an ES diagnosis (p < 0.001). Of those diagnosed, 31/80 (39%) had a change in their clinical diagnosis. ES diagnosis was considered to have contributed to management in 47/80 (59%), including negating the need for diagnostic renal biopsy in 10/80 (13%), changing surveillance in 35/80 (44%), and changing the treatment plan in 16/80 (20%). In cases with no change to management in the proband, the ES result had implications for the management of family members in 26/33 (79%). Cascade testing was subsequently offered to 40/80 families (50%). Conclusion(s): In this pragmatic pediatric and adult cohort with suspected monogenic kidney disease, ES had high diagnostic and clinical utility. Our findings, including predictors of positive diagnosis, can be used to guide clinical practice and health service design.Copyright © 2020, The Author(s).

Background: Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk. Method(s): We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy. Result(s): Genetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07-1.30, P = 0.11 x 10-2), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78-1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect. Conclusion(s): Our MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.Copyright © 2021, The Author(s).

Currently there is no secured ongoing funding in Australia for next generation sequencing (NGS) such as exome sequencing (ES) for adult neurological disorders. Studies have focused on paediatric populations in research or highly specialised settings, utilised standard NGS pipelines focusing only on small insertions, deletions and single nucleotide variants, and not explored impacts on management in detail. This prospective multi-site study performed ES and an extended bioinformatics repeat expansion analysis pipeline, on patients with broad phenotypes (ataxia, dementia, dystonia, spastic paraparesis, motor neuron disease, Parkinson's disease and complex/not-otherwise-specified), with symptom onset between 2 and 60 years. Genomic data analysis was phenotype-driven, using virtual gene panels, reported according to American College of Medical Genetics and Genomics guidelines. One-hundred-and-sixty patients (51% female) were included, median age 52 years (range 14-79) and median 9 years of symptoms. 34/160 (21%) patients received a genetic diagnosis. Highest diagnostic rates were in spastic paraparesis (10/25, 40%), complex/not-otherwise-specified (10/38, 26%) and ataxia (7/28, 25%) groups. Findings were considered 'possible/uncertain' in 21/160 patients. Repeat expansion detection identified an unexpected diagnosis of Huntington disease in an ataxic patient with negative ES. Impacts on management, such as more precise and tailored care, were seen in most diagnosed patients (23/34, 68%). ES and a novel bioinformatics analysis pipepline had a substantial diagnostic yield (21%) and management impacts for most diagnosed patients, in heterogeneous, complex, mainly adult-onset neurological disorders in real-world settings in Australia, providing evidence for NGS and complementary multiple, new technologies as valuable diagnostic tools.Copyright © 2020 Elsevier B.V.

The diagnosis of children with genetic conditions places a significant economic burden on health care services. The lack of well-defined comparative cohorts has been a limitation of health economic studies comparing first-line genomic sequencing (GS) against traditional approaches. Aim(s): To evaluate utility and cost effectiveness of early GS in pediatric patients with complex monogenic conditions compared to a matched historical cohort. Method(s): Data, including diagnosis rate and investigation costs, were collected in a prospective cohort of 92 pediatric patients who underwent singleton GS over an 18-month period (2016-2017). Inclusion required patients to have two of the following: a condition with high morbidity or mortality, a multi-system disease involving three or more organ systems, or severe limitation of daily function. For comparison, data were collected in a historical patient cohort fulfilling the inclusion criteria who underwent traditional investigations in the two years (2012-2013) prior to the availability of clinical genomic sequencing. Result(s): Genomic sequencing yielded a diagnosis in 42% while traditional investigations yielded a diagnosis in 23% (p = 0.003). 75% of diagnosed patients experienced a change in management, compared to 33% of diagnosed patients who underwent traditional investigations. In the GS cohort, four times fewer invasive investigations were observed. Compared to traditional investigations, singleton genomic sequencing at a cost of $3100 AUD resulted in a mean saving per person of $2780 AUD (95%CI $1585-$3974). Conclusion(s): Early genomic sequencing is highly costeffective while doubling the diagnostic yield of traditional approaches and improving the care of patients with complex genetic conditions.

Background: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. Method(s): We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. Result(s): For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (-49.2%, 95% CI -56.1% to -41.1%, P = 3.1 x 10-18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (-26.7%, 95% CI -39.4% to -11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82-0.91, P = 6.9 x 10-8). Conclusion(s): The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.Copyright © 2021, The Author(s).

Aim: To evaluate the cost-effectiveness of exome sequencing (ES) in patients with suspected genetic kidney disease (GKD) compared with current standard diagnostic care, and to evaluate the optimal timing of ES. Background(s): There is an urgent need to determine the health economic value of genomic testing in kidney disease patients. Method(s): This model based economic analysis was informed by a pragmatic, multicentre study which included 87 patients with suspected monogenic glomerular disease. Resource use for non-genomic investigations were also informed by data from the cohort, in addition to current guidelines. Six diagnostic strategies reflecting current practice were compared. Result(s): ES achieved a diagnosis in 23/63 (36.5%) adults and 10/24 (41.6%) children. The average cost of ES (including sequencing, analysis, and related consultations) was $2,355 in both children and adults. Children: Standard investigations were estimated to diagnose 4.0%, with an average estimated cost of $6,119 per child. Integrating ES as a first line test was cost saving, with an incremental cost saving per additional diagnosis of $3,230 compared to standard diagnostic care. Adults: Standard investigations were estimated to diagnose 7.9%, with an average estimated cost of $1,834 per adult, (including a biopsy rate of 70%). Integrating ES early resulted in an incremental cost per additional diagnosis of $5,456 relative to standard care. Conclusion(s): Integrating ES early in the diagnostic pathway is likely to be more effective and less costly for establishing a diagnosis and informing care in children. In adults, the incremental cost per additional diagnosis may be justified, depending on the value of a genomic diagnosis. Applying ES as a last resort test resulted in considerably higher cost compared with earlier application in the diagnostic trajectory.

BACKGROUND AND OBJECTIVES: Genomics is moving rapidly into mainstream medicine through clinical genomic testing and consumer-initiated online DNA testing. The aim of this study was to identify Australian general practitioners' (GPs') views on genomics, impact on practice and educational needs to inform continuing education. METHOD: Semi-structured interviews were conducted, with constant comparative inductive analysis and governance from a national taskforce. RESULTS: Twenty-eight GPs (43% female) were interviewed; 71% worked in a metropolitan workplace. Most initially reported little experience with genetic/genomic tests but, when prompted, recognised encountering genomics, mainly non-invasive prenatal and single-gene tests. Many GPs referred patients for cancer screening to genetic services or specialists. GPs reported needing continuing education and resources, with preferences underpinned by relevance to practice. DISCUSSION: GPs are integrating genomic testing into care, mainly through prenatal screening, and anticipate further impact. They want diverse and context-dependent education but are unaware of some available resources, such as The Royal Australian College of General Practitioners' Genomics in general practice guideline.

Despite the overwhelming interest in clinical genomics, uptake has been slow. Implementation science offers a systematic approach to reveal pathways to adoption and a theory informed approach to addressing barriers presented. Using case study methodology, we undertook 16 in-depth interviews with nongenetic medical specialists to identify barriers and enablers to the uptake of clinical genomics. Data collection and analysis was guided by two evidence-based behaviour change models: the Theoretical Domains Framework (TDF), and the Capability, Opportunity Motivation Behaviour model (COM-B). Our findings revealed the use of implementation science not only provided a theoretical structure to frame the study but also facilitated uncovering of traditionally difficult to access responses from participants, e.g., "safety in feeling vulnerable" (TDF code emotion/COM-B code motivation). The most challenging phase for participants was ensuring appropriate patients were offered genomic testing. There were several consistent TDF codes: professional identity, social influences, and environmental context and resources and COM-B codes opportunity and motivation, with others varying along the patient journey. We conclude that implementation science methods can maximise the value created by the exploration of factors affecting the uptake of clinical genomics to ensure future interventions are designed to meet the needs of novice nongenetic medical specialists.

Despite the plethora of empirical studies conducted to date, debate continues about whether and to what extent results should be returned to participants of genomic research. We aimed to systematically review the empirical literature exploring stakeholders' perspectives on return of individual research results (IRR) from genomic research. We examined preferences for receiving or willingness to return IRR, and experiences with either receiving or returning them. The systematic searches were conducted across five major databases in August 2018 and repeated in April 2020, and included studies reporting findings from primary research regardless of method (quantitative, qualitative, mixed). Articles that related to the clinical setting were excluded. Our search identified 221 articles that met our search criteria. This included 118 quantitative, 69 qualitative and 34 mixed methods studies. These articles included a total number of 118,874 stakeholders with research participants (85,270/72%) and members of the general public (40,967/35%) being the largest groups represented. The articles spanned at least 22 different countries with most (144/65%) being from the USA. Most (76%) discussed clinical research projects, rather than biobanks. More than half (58%) gauged views that were hypothetical. We found overwhelming evidence of high interest in return of IRR from potential and actual genomic research participants. There is also a general willingness to provide such results by researchers and health professionals, although they tend to adopt a more cautious stance. While all results are desired to some degree, those that have the potential to change clinical management are generally prioritized by all stakeholders. Professional stakeholders appear more willing to return results that are reliable and clinically relevant than those that are less reliable and lack clinical relevance. The lack of evidence for significant enduring psychological harm and the clear benefits to some

Bone marrow failure (BMF) related to hypoplasia of hematopoietic elements in the bone marrow is a heterogeneous clinical entity with a broad differential diagnosis including both inherited and acquired causes. Accurate diagnostic categorization is critical to optimal patient care and detection of genomic variants in these patients may provide this important diagnostic and prognostic information. We performed real-time, accredited (ISO15189) comprehensive genomic characterization including targeted sequencing and whole exome sequencing in 115 patients with BMF syndrome (median age 24 years, range 3 months - 81 years). In patients with clinical diagnoses of inherited BMF syndromes, acquired BMF syndromes or clinically unclassifiable BMF we detected variants in 52% (12/23), 53% (25/47) and 56% (25/45) respectively. Genomic characterization resulted in a change of diagnosis in 30/115 (26%) including the identification of germline causes for 3/47 and 16/45 cases with pre-test diagnoses of acquired and clinically unclassifiable BMF respectively. The observed clinical impact of accurate diagnostic categorization included choice to perform allogeneic stem cell transplantation, disease-specific targeted treatments, identification of at-risk family members and influence of sibling allogeneic stem cell donor choice. Multiple novel pathogenic variants and copy number changes were identified in our cohort including in TERT, FANCA, RPS7 and SAMD9. Whole exome sequence analysis facilitated the identification of variants in two genes not typically associated with a primary clinical manifestation of BMF but also demonstrated reduced sensitivity for detecting low level acquired variants. In conclusion, genomic characterization can improve diagnostic categorization of patients presenting with hypoplastic BMF syndromes and should be routinely performed in this group of patients.

BACKGROUND: Despite the emergence of diagnostic and clinical utility evidence in nephrology, publicly funded access to genomic testing is restricted in most health care systems. To establish genomic sequencing as a clinical test, an evaluation of cost-effectiveness is urgently required. METHODS: An economic evaluation, informed by a primary clinical study and available clinical evidence and guidelines in nephrology, was performed to evaluate the cost-effectiveness and optimal timing of exome sequencing (ES) in adults and children with suspected monogenic glomerular diseases compared with nongenomic investigations (NGIs). Six diagnostic strategies reflecting current practice and recommended models of care in Australia were modeled: (i) NGIs, (ii) late gene panel followed by ES, (iii) late ES, (iv) early gene panel, (v) early gene panel followed by ES, and (vi) early ES. RESULTS: ES with targeted analysis achieved a diagnosis in 23 of 63 (36.5%) adults and 10 of 24 (41.6%) children. NGIs were estimated to diagnose 4.0% of children, with an average estimated cost of AU$6120 per child. Integrating ES as a first-line test in children was cost saving, with an incremental cost saving of AU$3230 per additional diagnosis compared with NGIs. In adults, NGIs was estimated to diagnose 8% of patients, with an average estimated cost of AU$1830 per person. In adults, integrating ES early resulted in an incremental cost per additional diagnosis of AU$5460 relative to NGIs. CONCLUSIONS: Early ES with targeted analysis was effective for diagnosing monogenic kidney disease, with substantial cost savings in children.

OBJECTIVE: Even as genomic medicine is implemented globally, there remains a lack of rigorous, national assessments of physicians' current genomic practice and continuing genomics education needs. The aim of this study was to address this gap. DESIGN: A cross-sectional survey, informed by qualitative data and behaviour change theory, to assess the current landscape of Australian physicians' genomic medicine practice, perceptions of proximity and individual preparedness, and preferred models of practice and continuing education. The survey was advertised nationally through 10 medical colleges, 24 societies, 62 hospitals, social media, professional networks and snowballing. RESULTS: 409 medical specialists across Australia responded, representing 30 specialties (majority paediatricians, 20%), from mainly public hospitals (70%) in metropolitan areas (75%). Half (53%) had contacted their local genetics services and half (54%) had ordered or referred for a gene panel or exome/genome sequencing test in the last year. Two-thirds (67%) think genomics will soon impact their practice, with a significant preference for models that involved genetics services (p<0.0001). Currently, respondents mainly perform tasks associated with pretest family history taking and counselling, but more respondents expect to perform tasks at all stages of testing in the future, including tasks related to the test itself, and reporting results. While one-third (34%) recently completed education in genomics, only a quarter (25%) felt prepared to practise. Specialists would like (more) education, particularly on genomic technologies and clinical utility, and prefer this to be through varied educational strategies. CONCLUSIONS: This survey provides data from a breadth of physician specialties that can inform models of genetic service delivery and genomics education. The findings support education providers designing and delivering education that best meet learner needs to build a competent, genomic-li

Currently there is no secured ongoing funding in Australia for next generation sequencing (NGS) such as exome sequencing (ES) for adult neurological disorders. Studies have focused on paediatric populations in research or highly specialised settings, utilised standard NGS pipelines focusing only on small insertions, deletions and single nucleotide variants, and not explored impacts on management in detail. This prospective multi-site study performed ES and an extended bioinformatics repeat expansion analysis pipeline, on patients with broad phenotypes (ataxia, dementia, dystonia, spastic paraparesis, motor neuron disease, Parkinson's disease and complex/not-otherwise-specified), with symptom onset between 2 and 60 years. Genomic data analysis was phenotype-driven, using virtual gene panels, reported according to American College of Medical Genetics and Genomics guidelines. One-hundred-and-sixty patients (51% female) were included, median age 52 years (range 14-79) and median 9 years of symptoms. 34/160 (21%) patients received a genetic diagnosis. Highest diagnostic rates were in spastic paraparesis (10/25, 40%), complex/not-otherwise-specified (10/38, 26%) and ataxia (7/28, 25%) groups. Findings were considered 'possible/uncertain' in 21/160 patients. Repeat expansion detection identified an unexpected diagnosis of Huntington disease in an ataxic patient with negative ES. Impacts on management, such as more precise and tailored care, were seen in most diagnosed patients (23/34, 68%). ES and a novel bioinformatics analysis pipepline had a substantial diagnostic yield (21%) and management impacts for most diagnosed patients, in heterogeneous, complex, mainly adult-onset neurological disorders in real-world settings in Australia, providing evidence for NGS and complementary multiple, new technologies as valuable diagnostic tools.

Background: Despite increasing evidence of benefit supporting CGP in personalizing cancer therapy, its widespread uptake remains limited. Barriers include low patient understanding, unmet patient expectations related to low utility, clinician concerns over cost-effectiveness, perceived value, and discomfort in management of complex genomic results. Method(s): This prospective cross-institutional demonstration study was designed to evaluate implementation of CGP in the care of adult and paediatric advanced cancer pts, incorporating pt reported outcomes (PROMs), discrete choice experiment (DCE), ongoing process optimization and clinician evaluations. DNA sequencing of FFPE tumor and matched blood was completed with CGP (PMCC Comprehensive Cancer Panel; 391 genes) via central laboratory. A tumor board reported results weekly with emphasis on therapeutic relevance. Oncologists performed consent and results delivery. Pts completed pre-and post-test surveys, including validated and study-specific questions, DCE and if eligible, semi-structured interviews. Qualitative interviews were undertaken with study clinicians and laboratory staff to evaluate processes. Result(s): 86% (315) of 365 enrolled pts had successful CGP; of these 63% (199) had relevant therapeutic, diagnostic or germline results. 50 (16%) had treatment change at 6m, 49 (16%) had germline mutations. 293 (88% of adult pts) completed PROMs. 17 of 19 clinicians/laboratory staff approached consented to an interview. At consent pts cited multifaceted value in testing, showed good understanding of basic concepts, but most (69%) overestimated the likelihood of result-led change. Post-test pts remained consistently satisfied with accessing CGP; valuing research contribution, taking opportunities and information for family. 21% struggled with understanding results but there were low levels of decisional regret following participation (89% had nil/mild regret). Pt-elicited preferences (via DCE) indicated priority for h

Genomic classification is rapidly becoming a routine and integral part of diagnosis in pathology. Perinatal pathology is following this trend. The aims of this study were to determine the utility of WES in perinatal autopsy for congenital anomalies and to model the outcome of WES as a prenatal test. A total of 131 probands with congenital anomalies who underwent post mortem examination were referred by pathologists to the study. 82 probands were considered suitable for sequencing. The parents of 5 declined enrolment and 10 could not be consented. 67 probands were enrolled. Autopsy identified specific diagnoses in 11 cases (17%). WES identified specific diagnoses ('pathogenic' or 'likely pathogenic' variants) in 23 cases - a diagnostic rate of 35%. The combined diagnostic rate of autopsy and sequencing was 38%. A geneticist blinded to the autopsy findings reviewed the probands' antenatal imaging reports and recommended a gene list to model the clinical utility of prenatal WES. The use of antenatal sequencing in this cohort would have identified a specific diagnosis in 18 of the 23 cases with positive sequencing findings. In conclusion, WES doubles the diagnostic rate of autopsy for congenital anomalies and our data supports the prenatal use of genomic sequencing.Copyright © 2020

Purpose: Cost-effectiveness evaluations of first-line genomic sequencing (GS) in the diagnosis of children with genetic conditions are limited by the lack of well-defined comparative cohorts. We sought to evaluate the cost-effectiveness of early GS in pediatric patients with complex monogenic conditions compared with a matched historical cohort. Method(s): Data, including investigation costs, were collected in a prospective cohort of 92 pediatric patients undergoing singleton GS over an 18-month period (2016-2017) with two of the following: a condition with high mortality, multisystem disease involving three or more organs, or severe limitation of daily function. Comparative data were collected in a matched historical cohort who underwent traditional investigations in the years 2012-2013. Result(s): GS yielded a diagnosis in 42% while traditional investigations yielded a diagnosis in 23% (p = 0.003). A change in management was experienced by 74% of patients diagnosed following GS, compared with 32% diagnosed following traditional investigations. Singleton GS at a cost of AU$3100 resulted in a mean saving per person of AU$3602 (95% confidence interval [CI] AU$2520-4685). Cost savings occurred across all investigation subtypes and were only minimally offset by clinical management costs. Conclusion(s): GS in complex pediatric patients saves significant costs and doubles the diagnostic yield of traditional approaches.Copyright © 2020, American College of Medical Genetics and Genomics.

Congenital hearing impairment (HI) is the most common sensory impairment and can be isolated or part of a syndrome. Diagnosis through newborn hearing screening and management through early intervention, hearing aids and cochlear implantation is well established in the Australian setting; however understanding the genetic basis of congenital HI has been missing. This population-derived cohort comprised infants with moderate-profound bilateral HI born in the 2016-2017 calendar years, detected through newborn hearing screening. Participants were recruited through an integrated paediatric, otolaryngology and genetics HI clinic and offered whole exome sequencing (WES) on a HiSeq4000 or NextSeq500 (Illumina) platform with a targeted average sequencing depth of 100x and chromosome microarray on the Illumina Infinium core exome-24v1.2 platform. Of those approached, 68% (106/156) consented to participate. The rate of genetic diagnosis was 56% (59/106), significantly higher than standard of care (GJB2/6 sequencing only), 21% (22/106). There were clinical implications for the 106 participants: 36% required no further screening, 9% had tailored screening initiated, 2% were offered treatment and 4% had informed care for a complex neurodevelopmental syndrome. WES in this cohort demonstrates the range of diagnoses associated with congenital HI and confirms the genetic heterogeneity of congenital HI. The high diagnostic yield and clinical implications emphasises the need for genomic sequencing to become standard of care.Copyright © 2019, The Author(s), under exclusive licence to European Society of Human Genetics.

Primary Immunodeficiency diseases (PID) are a heterogeneous group of conditions with variable clinical features that are frequently associated with significant diagnostic delay. Accurate diagnosis has significant therapeutic benefit and may lead to personalized therapies. We established the Immunology Flagship of Melbourne Genomics Health Alliance in Australia to determine the clinical utility of genomic sequencing for diagnosis and management of individuals with suspected and confirmed cases of PID. 198 adults and children with suspected or confirmed PID (n=153), autoinflammatory disease (n=33) and hereditary angioedema (HAE, n=11) were recruited to the Melbourne Genomics Immunology Flagship.Whole-exome sequencing (WES) was performed, with targeted gene analysis. Variant curation and reporting was performed according to the American Council of Medical Genetics guidelines. Overall, WES was diagnostic in 15% (30/198), confirming a preexisting diagnosis in 7% (14/198), and offering a new or more specific diagnosis in 8% (16/198). Variants of uncertain significance were identified in a further 28 patients (14%) in genes known to be associated with their clinical diagnosis, that warrant further functional validation. In the HAE group, diagnosis was confirmed in only 5 patients (45%), suggesting thatWES may not be the appropriate technique for genetic diagnosis in this condition. A higher diagnostic rate was observed for autoinflammatory disorders (20%; 8/40) compared to PID (12%; 18/146). Of those who received a diagnosis, immediate changes to patient management and treatment occurred for 17/29 patients (59%), including HSCT for 3 and specific targeted therapy for 11 (38%) individuals. We have demonstrated the utility ofWES for accurate diagnosis of complex immune diseases, with the potential to change diagnoses, guide therapeutic intervention and provide opportunities for genetic counseling. Further longitudinal analysis will determine clinical outcomes and health econ

Objectives: To determine the utility of exome sequencing as an adjunct to perinatal post mortem for congenital anomalies. To model the likely outcome of exome sequencing as a prenatal test in the same setting. Method(s): Probands with congenital anomalies were referred by perinatal pathologists. They were enrolled for sequencing if their microarray analysis was negative and their anomalies were considered to have a monogenic cause. Singleton or trio exome sequencing was performed as an adjunct to routine perinatal autopsy and the diagnostic outcomes were compared. A geneticist independently reviewed the probands' antenatal imaging findings and recommended a phenotype specific gene list to model the clinical utility of prenatal exome sequencing. Result(s): A prospective cohort of 131 probands was referred. Fortynine (37%) were unsuitable for inclusion. The parents of five (4%) declined enrolment and 10 (8%) could not be consented. Sixty-seven probands (52%) were enrolled. One proband could not be sequenced due to a degraded DNA sample. Results are available for 65 probands (32 singletons and 33 trios). Specific diagnoses were identified at autopsy in 11 cases (17%) including two cases with negative sequencing. Sequencing identified specific diagnoses ("pathogenic" or "likely pathogenic" variants) in 23 cases giving a diagnostic rate of 35%. The combined diagnostic rate of autopsy and exome was 38%. The individual autopsy and genomic diagnostic rates were highest in probands with significant skeletal findings (39% and 61% respectively, n = 18). Genomic diagnoses were obtained from 34% of singleton exomes, with segregation when required, and 36% of trio exomes. Variants of uncertain significance (VUS) were reported in 13 cases (20%). In four, a strong phenotype-genotype match together with plausible candidate variants indicated a need for additional studies. The combined rate of diagnostic or suspicious variants was 42%. The use of antenatal sequencing in this cohort u

In Table 3, on pages 591-592 of the original article, in the fourth row of the table, an alteration in GJB2 is shown as "c.429G>A p.(Glu147Lys)", but it should read "c.439G>A p.(Glu147Lys)".Copyright © 2020, The Author(s), under exclusive licence to European Society of Human Genetics.

Objective: To foster implementation of genomic testing in medical care by providing a cadre of physicians with 'hands on' experience in genomics, positioning them as opinion leaders in their medical speciality. This paper presents qualitative evaluation of immediate outcomes, in particular its impact on peer interactions. Method(s): Program design and delivery was informed by implementation science, behavior change and experiential learning theories. Inductive content analysis of transcribed audio-recordings from semi-structured post-project interviews with all participants (n = 12) was conducted. Result(s): Participants reported the immersion experience improved their genomic capability, established them as credible genomic experts within their speciality and altered their practice in genomic medicine. Participants reported strengthening and widening of peer-to-peer and interdisciplinary communication, with both passive diffusion and active dissemination of information to peers. Some also became a resource for genetic professionals. Conclusion(s): Genomic immersion participants described elements which support sustained integration of an innovation, including immediate changes (e.g. use of genomic tests) and wider impacts (e.g. professional networks). Practice implications: This study supports a role for immersion as a successful strategy for enhancing engagement of non-geneticist physicians in genomics. Additional study is needed to understand how immersion experiences change the delivery of genomic services at the provider, practice and health system level.Copyright © 2020 Elsevier B.V.

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.Copyright © 2020 American Society of Human Genetics

PURPOSE: To determine the diagnostic yield and clinical impact of exome sequencing (ES) in patients with suspected monogenic kidney disease. METHODS: We performed clinically accredited singleton ES in a prospectively ascertained cohort of 204 patients assessed in multidisciplinary renal genetics clinics at four tertiary hospitals in Melbourne, Australia. RESULTS: ES identified a molecular diagnosis in 80 (39%) patients, encompassing 35 distinct genetic disorders. Younger age at presentation was independently associated with an ES diagnosis (p < 0.001). Of those diagnosed, 31/80 (39%) had a change in their clinical diagnosis. ES diagnosis was considered to have contributed to management in 47/80 (59%), including negating the need for diagnostic renal biopsy in 10/80 (13%), changing surveillance in 35/80 (44%), and changing the treatment plan in 16/80 (20%). In cases with no change to management in the proband, the ES result had implications for the management of family members in 26/33 (79%). Cascade testing was subsequently offered to 40/80 families (50%). CONCLUSION: In this pragmatic pediatric and adult cohort with suspected monogenic kidney disease, ES had high diagnostic and clinical utility. Our findings, including predictors of positive diagnosis, can be used to guide clinical practice and health service design.

PURPOSE: Genomic newborn screening raises practical and ethical issues. Evidence is required to build a framework to introduce this technology safely and effectively. We investigated the choices made by a diverse group of parents with newborns when offered tiered genomic information from exome sequencing. METHODS: This population-derived cohort comprised infants with congenital deafness. Parents were offered exome sequencing and choice regarding the scope of analysis. Options were choice A, diagnostic analysis only; choice B, diagnostic analysis plus childhood-onset diseases with medical actionability; or choice C, diagnostic analysis plus childhood-onset diseases with or without medical actionability. RESULTS: Of the 106 participants, 72 (68%) consented to receive additional findings with 29 (27.4%) selecting choice B and 43 (40.6%) opting for choice C. Family size, ethnicity, and age of infant at time of recruitment were the significant predictors of choice. Parents who opted to have additional findings analysis demonstrated less anxiety and decisional conflict. CONCLUSIONS: These data provide evidence from a culturally diverse population that choice around additional findings is important and the age of the infant when this choice is offered impacts on their decision. We found no evidence that offering different levels of genomic information to parents of newborns has a negative psychological impact.

Despite some early implementation of genomic medicine globally, there is a lack of rigorous, large-scale assessments of medical specialists' current practice and continuing education needs. As a first step to addressing this gap, we describe the development of a robust, expert-reviewed, survey using a mixed-methods sequential study design. We conducted semi-structured qualitative interviews with 32 education providers and 86 non-genetic medical specialists about current genomic medicine practice and need for continuing education. Key concepts were identified and used as an initial framework for the survey. These were: personal characteristics (medical specialty, years of practice); current practice of genomics in clinical and research settings; perception of how proximal genomic medicine is to practice; perception of preparedness (competence and confidence); and, preferences for future roles and models of care in genomic medicine and for continuing education. Potential survey questions that related to at least one of these concepts were identified from the literature or were created if no suitable question existed. Using a modified, reactive Delphi approach, questions were reviewed by a panel of 22 experts. Experts were selected purposefully representing four areas of expertise: non-genetic medical specialties; clinical genetics; genetic/genomic education and evaluation; and implementation science. Three Delphi rounds assessed relevance, clarity and importance of each question. The questions were also mapped to the behaviour change wheel theoretical framework which encompasses capability, opportunity and motivation (COM-B). The survey (included as supplementary material) was then tested with a small group of non-genetic medical specialists and feedback was written or verbal in 'talk-aloud', cognitive interviews. The final survey was then piloted with a further 29 specialists. We describe the methodology to create a robust, data- and theory-informed survey. The final

In Table 3, on pages 591–592 of the original article, in the fourth row of the table, an alteration in GJB2 is shown as “c.429G>A p.(Glu147Lys)”, but it should read “c.439G>A p.(Glu147Lys)”.

Background: Personal genomic testing (PGT) offers individuals genetic information about relationships, wellness, sporting ability, and health. PGT is increasingly accessible online, including in emerging markets such as Australia. Little is known about what consumers expect from these tests and whether their reflections on testing resonate with bioethics concepts such as autonomy.Methods: We report findings from focus groups and semi-structured interviews that explored attitudes to and experiences of PGT. Focus group participants had little experience with PGT, while interview participants had undergone testing. Recordings were transcribed and analyzed using thematic analysis. Findings were critically interpreted with reference to bioethics scholarship on autonomy.Results: Fifty-six members of the public participated in seven focus groups, and 40 individuals were interviewed separately. Both groups valued the choice of PGT, and believed that it could motivate relevant actions. Focus group themes centered on the perceived value of choices, knowledge enabling action and knowledge about the self. Interview themes suggest that participants reflexively engage with their PGT information to make meaning, and that some appreciate its shortcomings. Critical interpretation of findings shows that while consumers of PGT are able to exercise a degree of autonomy in choosing, they may not be able to achieve a substantive conceptualization of autonomy, one that promotes alignment with higher-order desires.Conclusions: PGT consumers can critically reason about testing. However, they may uncritically accept test results, may not appreciate drawbacks of increased choice, or may overestimate the potential for information to motivate behavioral change. While consumers appear to be capable of substantive autonomy, they do so without ongoing support from companies. PGT companies promote a problematic ("default") account of autonomy, reliant on empowerment rhetoric. This leaves consumers

PURPOSE: To investigate leadership in clinical genomics and identify likely implications of different leadership approaches for future implementation of clinical genomics. METHODS: We undertook 37 interviews in a cross-sectional qualitative study examining implementation of clinical genomics in Australia. Participants were either nongenetic medical specialists working with genomic initiatives (e.g., immunologists, nephrologists) or working at a service/organizational level (e.g., department heads, chief medical officers). We identified participants as genomic migrants (long-established practitioners) and genomic natives (those medical specialists coming into independent practice with genomic technology in situ). Data were analyzed deductively with reference to leadership approach. RESULTS: Leadership approaches were often blended or reported to iteratively support development of another. There was concern at both the absence or the excess of entrepreneurial leadership (i.e., risk-taking). CONCLUSION: Entrepreneurial leadership is needed to promote innovativeness, risk-taking, and proactivity, essential in these early stages of clinical genomics. Shared decision-making is required from a wide range of clinicians, calling for both clinical and distributed leadership. Sharing leadership, and the potential loss of positional status from formal senior positions, may prove challenging to genomics "migrants," who are essential for nurturing genomic "natives." Clinicians will need support from their organizations and professional bodies to manage the transition.

As a result of the ongoing global expansion of genetic counseling, the need to formalize a system of professional regulation for genetic counselors was identified in Australasia. In June 2017, under the auspices of the Human Genetics Society of Australasia (HGSA), a working party was convened. The purpose of the working party was to provide strategic leadership for the profession of Australasian genetic counselors with a goal to formalize a national regulatory framework for genetic counselors across both Australian and New Zealand jurisdictions. This was ultimately achieved in Australia through full membership with the National Alliance of Self-Regulating Health Professions (NASRHP) while the profession of genetic counseling in New Zealand is utilizing this framework to establish their regulation pathway. Regulation has a number of implications for genetic counselors, their employers, and the wider community, with the primary purpose of regulation being protection of the public from harm. This paper details the process of formalizing self-regulation for genetic counselors in Australasia, by defining professional regulation; outlining the purpose of regulation and the status of regulation for genetic counselors in Australasia and internationally, as well as health professionals more broadly; exploring the challenges of establishing regulation in Australasia; and the next steps for regulation in Australasia. Through detailing this process, the intention is to provide a framework to support genetic counseling colleagues internationally as well as other health professions in Australasia to explore and achieve regulation through their respective jurisdiction.

Exome sequencing (WES) enhances the diagnostic rate of perinatal autopsy: A prospective clinical utility trial with implications for prenatal diagnosis. Objective(s): (1) To determine the utility of WES in perinatal post mortem for congenital anomalies. (2) To model the outcome of WES as a prenatal test. Method(s): Probands with congenital anomalies were referred by pathologists. They were enrolled for sequencing if their microarray was negative and their anomalies were considered to have a monogenic cause. WES was performed as an adjunct to routine perinatal autopsy and the diagnostic outcomes were compared. A geneticist reviewed the probands' antenatal imaging findings and recommended a gene list to model the clinical utility of prenatal WES. Result(s): The referred cohort numbered 131. Forty-nine (37%) were unsuitable for inclusion. The parents of 5 (4%) declined enrolment and 10 (8%) could not be consented. Sixty-seven probands (52%) were enrolled. Results are available for 65 probands (32 singletons and 33 trios). Autopsy identified specific diagnoses in 11 cases (17%). WES identified specific diagnoses ('pathogenic'or 'likely pathogenic'variants) in 23 cases - a diagnostic rate of 35%. The combined diagnostic was 38%. VUS were reported in 13 cases (20%). The rate of diagnostic or suspicious variants was 42%. Genomic diagnoses were obtained from 34% of singleton exomes and 36% of trio exomes. Antenatal sequencing in this cohort would have identified a diagnosis in 18 of 23 cases diagnosed by sequencing (78%). Conclusion(s): WES doubles the diagnostic rate of autopsy for congenital anomalies and supports the prenatal use of genomic sequencing.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM-/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.Copyright © 2019, The Author(s).

Background: Exome sequencing has the potential to be used in newborn screening and international research is investigating the feasibility of this approach. It is not yet clear how parents will respond to the genomic newborn screening in their children. Aim(s): To explore parents' interest in genomic testing and what factors influence decision making about the scope of results received. Method(s): Families that consented for WES to identify the cause of hearing loss in their child were eligible. They could choose additional analysis of selected childhood onset genetic conditions unrelated to hearing loss. Families were provided with a decision aid and a genetic counseling session over two sites. Participants could choose to receive results for childhood onset genetic conditions with a known treatment or intervention pathway (Choice B), or all conditions, some of which do not have a known treatment or intervention pathway (Choice C). The families' completed evaluation surveys regarding their decision making post recruitment and at return of results. Result(s): Of the 107 patients who consented for WES, 64% opted to receive additional findings. Of those, 42% selected Choice B and 58% Choice C. Decisional conflict was lower among those who chose additional findings. The rate of uptake is significantly different between the two recruitment sites. Discussion(s): A majority of parents are requesting additional information. Analysis of genetic counseling notes and patient demographics will provide insight into parents' decision making. Conclusion(s): The results of this project illustrate the importance of providing choice around additional findings in genomic testing.

Genomics has the potential to be a powerful newborn screening tool, this is being investigated internationally. Genomic tests are increasingly available in Australia and additional findings can be analyzed and inform future health. This study aimed to explore parents' interest in receiving additional findings from genomic testing and determine factors influencing decision-making about the scope of results desired. Families that consented for exome sequencing to investigate deafness in their child were eligible. They were provided with a decision aid and a genetic counseling session. Participants could choose (A) no additional results; (B) additional results for childhood onset genetic conditions with a known treatment; or (C) additional results for childhood onset conditions with or without a known treatment. All families completed surveys about their decision-making at recruitment and after return of results. One hundred and six families participated, of which 72 (68%) chose to receive additional findings: 29 (27%) opted for choice B and 43 (41%) opted for choice C. Decisional conflict and anxiety levels were lower in those who chose to receive additional findings but similar between groups B and C. Intolerance of uncertainty was highest in the choice A group. Eighty percent of participants used the decision aid and 74% made a decision before their appointment however 23% consented to a different option post genetic counseling. Four participants had additional results returned, of which two required further management. This study highlights the interest in additional findings from genomic sequencing and emphasizes the importance of choice as families desire different levels of information.