Offering complex genomic screening in acute pediatric settings: Family decision-making and outcomes.

Purpose: Families of children in pediatric acute care who are offered ultrarapid genomic sequencing are making complex decisions during a high-stress period. To reduce complexity for families and clinicians, we offered genomic screening for the child and parents after the completion of diagnostic testing. We evaluated uptake, understanding, and service delivery preferences.

A national education program for rapid genomics in pediatric acute care: Building workforce confidence, competence, and capability.

Purpose: To develop and evaluate a scalable national program to build confidence, competence and capability in the use of rapid genomic testing (rGT) in the acute pediatric setting.

Methods: We used theory-informed approaches to design a modular, adaptive program of blended learning aimed at diverse professional groups involved in acute pediatric care. The program comprised 4 online learning modules and an online workshop and was centered on case-based learning.

Secondary use of genomic data: patients' decisions at point of testing and perspectives to inform international data sharing.

International sharing of genomic data files arising from clinical testing of patients is essential to further improve genomic medicine. Whilst the general public are reluctant to donate DNA for research, the choices patients actually make about sharing their clinical genomic data for future re-use (research or clinical) are unknown. We ascertained the data-sharing choices of 1515 patients having genomic testing for inherited conditions or cancer treatment from clinical consent forms.

Two-step offer and return of multiple types of additional genomic findings to families after ultrarapid trio genomic testing in the acute care setting: a study protocol.

Introduction: As routine genomic testing expands, so too does the opportunity to look for additional health information unrelated to the original reason for testing, termed additional findings (AF). Analysis for many different types of AF may be available, particularly to families undergoing trio genomic testing. The optimal model for service delivery remains to be determined, especially when the original test occurs in the acute care setting.

Making community voices heard in a research-health service alliance, the evolving role of the Community Advisory Group: a case study from the members' perspective.

Background: The Melbourne Genomics Health Alliance (the Alliance) is a collaboration of leading hospitals, research and academic organisations, supported by its member organisations and the Victorian Government. The Alliance was set up by its members in 2013 to steer the translation of genomics, making it an integral part of health care in Victoria, Australia. The Community Advisory Group (CAG) was formed soon after, to give input and advice across the program.

"It's something I've committed to longer term": The impact of an immersion program for physicians on adoption of genomic medicine.

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.

Methods: Program design and delivery was informed by implementation science, behavior change and experiential learning theories.

Evaluating the resource implications of different service delivery models for offering additional genomic findings.

Purpose: To evaluate the resource implications of different delivery models for the provision of additional findings (AF) in genomics from a health-care purchaser perspective.

Methods: Data from the Additional Findings study were used to develop and validate a discrete event simulation model that represented the pathway of delivering AF. Resource implications were estimated by microcosting the consultations, sample verifications, bioinformatics, curation, and multidisciplinary case review meetings.

Clinical impact of genomic testing in patients with suspected monogenic kidney disease.

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.

Utility of clinical comprehensive genomic characterization for diagnostic categorization in patients presenting with hypocellular bone marrow failure syndromes.

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).

Exome sequencing in newborns with congenital deafness as a model for genomic newborn screening: the Baby Beyond Hearing project.

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.

Prospective Evaluation of the Utility of Whole Exome Sequencing in Dilated Cardiomyopathy.

Background Dilated cardiomyopathy may be heritable but shows extensive genetic heterogeneity. The utility of whole exome sequencing as a first-line genetic test for patients with dilated cardiomyopathy in a contemporary "real-world" setting has not been specifically established. Using whole exome sequencing with rigorous, evidence-based variant interpretation, we aimed to identify the prevalence of a molecular diagnosis in patients with dilated cardiomyopathy in a clinical setting.

Exome sequencing in infants with congenital hearing impairment: a population-based cohort study.

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.

A novel approach to offering additional genomic findings-A protocol to test a two-step approach in the healthcare system.

Internationally, the practice of offering additional findings (AFs) when undertaking a clinically indicated genomic test differs. In the USA, the recommendation is to include analysis for AFs alongside diagnostic analysis, unless a patient opts-out, whereas European and Canadian guidelines recommend opt-in models. These guidelines all consider the offer of AFs as an activity concurrent with the offer of diagnostic testing.

A protocol for whole-exome sequencing in newborns with congenital deafness: a prospective population-based cohort.

Introduction: The aetiology of congenital hearing loss is heterogeneous, and in many infants a genetic cause is suspected. Parents face a diagnostic odyssey when searching for a cause of their infant's hearing loss. Through the Melbourne Genomics Health Alliance, a prospective cohort of infants will be offered whole-exome sequencing (WES) with targeted analysis in conjunction with chromosome microarray to determine the genetic causes of congenital hearing loss.

Genetic Counseling in the Era of Genomics: What's all the Fuss about?

As genomic sequencing becomes more widely available in clinical settings for diagnostic purposes, a number of genetic counseling issues are gaining precedence. The ability to manage these issues will be paramount as genetic and non-genetic healthcare professionals navigate the complexities of using genomic technologies to facilitate diagnosis and inform patient management. Counseling issues arising when counseling for diagnostic genomic sequencing were identified by four genetic counselors with 10 years of collective experience providing genetic counseling in this setting.

Ownership of uncertainty: healthcare professionals counseling and treating women from hereditary breast and ovarian cancer families who receive an inconclusive BRCA1/2 genetic test result.

Aim: The aim of this study was to understand more fully how healthcare professionals deal with the uncertainty intrinsic in counseling and treating women from hereditary breast/ovarian cancer families who receive inconclusive BRCA1/2 genetic test results (genetic tests that do not find a mutation to account for the family history).

Methods: We conducted a small, qualitative, exploratory study using open-ended semistructured interviews of 12 geneticists, genetic counselor/nurses, oncologists, gynecologists, and breast surgeons at a major UK cancer center. We asked questions about how these professionals dealt with the large amount of uncertainty raised by an inconclusive result, how they communicated the uncertainty involved, their feelings about presenting medical management options based on information fraught with uncertainty, the role of the media, differences in perspectives by specialty, and personal feelings about the uncertainty.

Is no news good news? Inconclusive genetic test results in BRCA1 and BRCA2 from patients and professionals' perspectives.

Background: Women from families with a high risk of breast or ovarian cancer in which genetic testing for mutations in the BRCA1/2 genes is inconclusive are a vulnerable and understudied group. Furthermore, there are no studies of the professional specialists who treat them - geneticists, genetic counsellors/nurses, oncologists, gynaecologists and breast surgeons.

Methods: We conducted a small qualitative study that investigated women who had developed breast cancer under the age of 45 and who had an inconclusive BRCA1/2 genetic diagnostic test (where no mutations or unclassified variants were identified).

Biallelic PMS2 mutations and a distinctive childhood cancer syndrome.

Biallelic mutations in PMS2, a gene usually associated in heterozygous form with hereditary nonpolyposis colorectal cancer (HNPCC), results in a recently described childhood cancer syndrome. The tumor spectrum encompasses atypical brain cancers, hematologic malignancies, and colonic polyposis and cancer. Cutaneous stigmata resembling café-au-lait macules with more diffuse margins are frequently seen.

Predictive testing of eighteen year olds: counseling challenges.

Genetic counseling of teenagers is challenging and complex. The ability to think abstractly, a sense of self and independence from family all develop during adolescence. Predictive genetic testing counseling protocols presuppose that these qualities exist, requiring the at-risk individual to consider the short and long term consequences of testing as well as their motivations.