Australian public perspectives on genomic newborn screening: which conditions should be included?

BACKGROUND: Implementing genomic sequencing into newborn screening programs allows for significant expansion in the number and scope of conditions detected. We sought to explore public preferences and perspectives on which conditions to include in genomic newborn screening (gNBS). METHODS: We recruited English-speaking members of the Australian public over 18 years of age, using social media, and invited them to participate in online focus groups. RESULTS: Seventy-five members of the public aged 23-72 participated in one of fifteen focus groups. Participants agreed that if prioritisation of conditions was necessary, childhood-onset conditions were more important to include than later-onset conditions. Despite the purpose of the focus groups being to elicit public preferences, participants wanted to defer to others, such as health professionals or those with a lived experience of each condition, to make decisions about which conditions to include. Many participants saw benefit in including conditions with no available treatment. Participants agreed that gNBS should be fully publicly funded. CONCLUSION: How many and which conditions are included in a gNBS program will be a complex decision requiring detailed assessment of benefits and costs alongside public and professional engagement. Our study provides support for implementing gNBS for treatable childhood-onset conditions.

Should secondary pharmacogenomic variants be actively screened and reported when diagnostic genome-wide sequencing is performed in a child?

This white paper was prepared by the Global Alliance for Genomics and Health Regulatory and Ethics Work Stream's Pediatric Task Team to review and provide perspective with respect to ethical, legal, and social issues regarding the return of secondary pharmacogenomic variants in children who have a serious disease or developmental disorder and are undergoing exome or genome sequencing to identify a genetic cause of their condition. We discuss actively searching for and reporting pharmacogenetic/genomic variants in pediatric patients, different methods of returning secondary pharmacogenomic findings to the patient/parents and/or treating clinicians, maintaining these data in the patient's health record over time, decision supports to assist using pharmacogenetic results in future treatment decisions, and sharing information in public databases to improve the clinical interpretation of pharmacogenetic variants identified in other children. We conclude by presenting a series of points to consider for clinicians and policymakers regarding whether, and under what circumstances, routine screening and return of pharmacogenomic variants unrelated to the indications for testing is appropriate in children who are undergoing genome-wide sequencing to assist in the diagnosis of a suspected genetic disease.

Human Genetics Society of Australasia Position Statement: Predictive and Presymptomatic Genetic Testing in Adults and Children.

This Position Statement provides guidelines for health professionals who work with individuals and families seeking predictive genetic testing and laboratory staff conducting the tests. It presents the major practical, psychosocial and ethical considerations associated with presymptomatic and predictive genetic testing in adults who have the capacity to make a decision, children and young people who lack capacity, and adults living with reduced or fluctuating cognitive capacity.Predictive Testing Recommendations: (1) Predictive testing in adults, young people and children should only be offered with pretest genetic counseling, and the option of post-test genetic counseling. (2) An individual considering whether to have a predictive test should be supported to make an autonomous and informed decision. Regarding Children and Young People: (1) Predictive testing should only be offered to children and young people for conditions where there is likely to be a direct medical benefit to them through surveillance, use of prevention strategies, or other medical interventions in the immediate future. (2) Where symptoms are likely to develop in childhood, in the absence of direct medical benefit from this knowledge, genetic health professionals and parents/guardians should discuss whether undertaking predictive testing is the best course of action for the child and the family as a whole. (3) Where symptoms are likely to develop in adulthood, the default position should be to postpone predictive testing until the young person achieves the capacity to make an autonomous and informed decision. This is applicable regardless of whether there is some action that can be taken in adulthood.

What's in a name? Justifying terminology for genomic findings beyond the initial test indication: A scoping review.

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.

Human Genetics Society of Australasia Position Statement: Genetic Carrier Testing for Recessive Conditions.

This Position Statement provides guidelines to assist all health professionals who receive requests for carrier testing and laboratory staff conducting the tests.In this Statement, the term 'carrier testing' refers to genetic testing in an individual to determine whether they have inherited a pathogenic variant associated with an autosomal or X-linked recessive condition previously identified in a blood relative. Carrier testing recommendations: (1) Carrier testing should only be performed with the individual's knowledge and consent; (2) An individual considering (for themselves, or on behalf of another) whether to have a carrier test should be supported to make an informed decision; (3) The mode of inheritance, the individual's personal experience with the condition, and the healthcare setting in which the test is being performed should be considered when determining whether carrier testing should be offered by a genetic health professional. Regarding children and young people: Unless there is direct medical benefit in the immediate future, the default position should be to postpone carrier testing until the child or young person can be supported to make an informed decision. There may be some specific situations where it is appropriate to facilitate carrier testing in children and young people (see section in this article). In such cases, testing should only be offered with pre- and post-test genetic counseling in which genetic health professionals and parents/guardians should explore the rationale for testing and the interests of the child and the family.

Storing paediatric genomic data for sequential interrogation across the lifespan.

Genomic sequencing (GS) is increasingly used in paediatric medicine to aid in screening, research and treatment. Some health systems are trialling GS as a first-line test in newborn screening programmes. Questions about what to do with genomic data after it has been generated are becoming more pertinent. While other research has outlined the ethical reasons for storing deidentified genomic data to be used in research, the ethical case for storing data for future clinical use has not been explicated. In this paper, we examine the ethical case for storing genomic data with the intention of using it as a lifetime health resource. In this model, genomic data would be stored with the intention of reanalysis at certain points through one's life. We argue this could benefit individuals and create an important public resource. However, several ethical challenges must first be met to achieve these benefits. We explore issues related to privacy, consent, justice and equality. We conclude by arguing that health systems should be moving towards futures that allow for the sequential interrogation of genomic data throughout the lifespan.

Going home: Clinician perspectives on decision-making in paediatric home mechanical ventilation.

AIM: Despite a recent increase in the use of ventilators in the home setting for children with chronic respiratory failure, there is currently no unified approach for clinical decision-making for children requiring long-term mechanical ventilation. The purpose of this study is to understand the clinician's perspective on decision-making around home ventilation for children, and how home-based care contributes to successful outcomes in this population. METHODS: We recruited physicians and home ventilation nurses with at least 2 years' experience working in an Australian paediatric tertiary home ventilation service using professional networks and snowball sampling. Semi-structured interviews were conducted by two researchers between February 2019 and June 2020. Interviews were audio-recorded, transcribed, and analysed using inductive content analysis. RESULTS: Twenty-five individuals participated (17 physicians and 8 home ventilation nurses). Participants viewed themselves as impartial medical advocates in the decision-making process, believing the decision to initiate or cease ventilation belonged to the child's family. While participants held the child's quality of life as the cornerstone of decision-making, quality of life was subjective and family specific. CONCLUSION: These findings provide insight into how clinicians working with children with chronic respiratory insufficiency approach the decision to introduce home-based ventilation. By understanding their role, strategies can be developed to assist them, leading to better outcomes for patients and families. Further research is needed to compare the perspectives of clinicians with the experience of ventilator-assisted children and families in Australia.

Australian healthcare professionals' perspectives on the ethical and practical issues associated with genomic newborn screening.

Newborn bloodspot screening (NBS) is a successful public health initiative that seeks to identify serious, treatable medical conditions. The increasing use of genomic sequencing (GS) in a wide range of medical settings has reignited the discussion on whether GS can and should be integrated into NBS. Yet, the perspectives of healthcare professionals (HCPs) in Australia on the ethical and practical issues associated with the implementation of genomic newborn screening (GNBS) are underexplored. To address this, we conducted semi-structured interviews with 16 Australian HCPs with clinical or policy experience in NBS and/or GS to explore their perspectives on the ethical, social, and practical issues raised by integrating GS into NBS. Interviews were analyzed using inductive content analysis. When asked whether GS should be incorporated into NBS, HCPs did not feel it was currently appropriate but there was a strong consensus it may be implemented within the next decade. However, HCPs had differing perspectives on what conditions should be included and how to best handle the volume of data generated from GNBS. Our findings have important implications for determining at what point and how genomics can be integrated into NBS. The differing views expressed amongst HCPs suggest that further research is needed to explore the reasons behind this. Importantly, our participants highlighted a potential role for genetic counselors in the implementation of GNBS on a larger scale by developing educational resources to facilitate obtaining informed consent and return of results.

Navigating the uncertainties of next-generation sequencing in the genetics clinic.

This study explores the different manifestations and navigations of uncertainty in the practice of diagnostic next-generation sequencing (NGS) testing. Drawing upon multi-sited fieldwork conducted at a large Centre for Human Genetics in Belgium, we analyse how uncertainty takes shape and is managed in the different steps of the diagnostic process: starting from the testing offer, to the analysis in the lab, the multidisciplinary team meetings (MDTs) and ending with the consultation with the patient. Building on interviews with genetic healthcare professionals and their patients and observations in consultations and MDTs, our empirical work underlines the duality of uncertainty as both burdensome and productive. Building on the existing literature on uncertainty in medicine and NGS, our analysis shows the ontological politics at play in the everyday uncertainty work in this CHG. We show how the, at times, contrasting ways of dealing with uncertainty lead to friction but also result in constructive negotiation and collaboration between actors, making use of multiple types of evidence and expertise. By not only minimising but also sustaining or inviting uncertainty, genetic healthcare professionals are able to advance the practices around NGS in a way that matches their multidisciplinary understandings, considerations and more normative stances.

The patient with 41 reports: Analysis of laboratory exome sequencing reporting of a "virtual patient".

PURPOSE: Few studies have systematically analyzed the structure and content of laboratory exome sequencing reports from the same patient. METHODS: We merged 8 variants from patients into "normal" exomes to create virtual patient-parent trios. We provided laboratories worldwide with the data and patient phenotype information (developmental delay, dysmorphic features, and cardiac hypertrophy). Laboratories analyzed the data and issued a diagnostic exome report. Reports were scored using a coding matrix developed from existing guidelines. RESULTS: In total, 41 laboratories representing 17 countries issued reports. Reporting of quality control statistics and technical information was poor (46.3%). Although 75.6% of the reports clearly stated the classification of all reported variants, few reports listed extensive evidence supporting variant classification. Only 53.1% of laboratories that reported unsolicited or secondary findings gave advice regarding health-related follow-up and 20.5% gave advice regarding cascade testing for relatives. Of the 147 variants reported, 105 (71.4%) were classified in agreement with classifications based on American College of Medical Genetics and Genomics/Association for Molecular Pathology and Association for Clinical Genomic Science guidelines. Concordance was higher for known pathogenic variants (86.3%) than for novel unpublished variants (56.8%). CONCLUSION: The considerable variability identified in the components that laboratories included in their reports and their classification of variants suggests that existing guidelines are not being used consistently with significant implications for patient care.

Genetic testing for psychiatric illness in children: ethical issues.

PURPOSE OF REVIEW: Genetic and genomic technologies are showing great potential in the field of psychiatry. Genetic testing for psychiatric conditions poses a range of ethical challenges, many of which are likely to be exacerbated for paediatric populations. As a large proportion of psychiatric conditions present in late adolescence and early adulthood, testing in childhood may be considered in some circumstances. Synthesis of issues specific to psychiatric genetic testing in paediatric populations has been limited. RECENT FINDINGS: Balancing the autonomy of the child and parents requires consideration and judging capacity may be complicated by the presence of psychiatric illness in the child and their family. Health professionals' limited understanding of psychiatric genetics may inhibit delivery of effective psychiatric care. Risk of stigma and discrimination associated with genetic diagnosis and psychiatric illness is compounded for children, who inherently cannot make their own decisions and for whom the impact of a genetic diagnosis is likely to be longest lasting. SUMMARY: Although the current evidence base suggests genetic testing may not be appropriate for clinical use in psychiatric populations right now, when it is, appropriate pre-test counselling and informed decision making will be essential to support and protect children's developing and future autonomy.

A framework for reporting secondary and incidental findings in prenatal sequencing: When and for whom?

As the use of genomic sequencing (GS) in the prenatal setting becomes more widespread, laboratories and clinicians will be tasked with making decisions about whether to offer incidental and secondary findings to expectant parents and, if so, which ones. Unfortunately, few guidelines or position statements issued by professional bodies address the return of secondary findings specifically in the context of prenatal GS, nor do they offer clear guidance on whether, and which types of incidental findings should be reported. Laboratories and clinicians will also need to navigate other challenges, such as how to obtain sufficiently informed consent, workload burdens for both laboratories and clinicians, and funding. Here we discuss these, and other challenges associated with offering incidental and secondary findings in the context of prenatal GS. We outline existing guidelines for return of these findings, prenatally and in children. We review the existing literature on stakeholder perspectives on return of incidental and secondary findings and discuss the main practical and ethical challenges that require consideration. We then propose a framework to help guide decision-making, suggesting a baseline routine analysis, with additional layers of analysis that could be offered, according to local laboratory policy, with additional opt-in consent from the parents.

Moving from 'fully' to 'appropriately' informed consent in genomics: The PROMICE framework.

Genomic sequencing technologies (GS) pose novel challenges not seen in older genetic technologies, making traditional standards for fully informed consent difficult or impossible to meet. This is due to factors including the complexity of the test and the broad range of results it may identify. Meaningful informed consent is even more challenging to secure in contexts involving significant time constraints and emotional distress, such as when rapid genomic testing (RGS) is performed in neonatal intensive care units. In this article, we propose that informed consent matters not for its own sake, but because obtaining it furthers a range of morally important goals, such as promoting autonomy, well-being, and trust in medicine. These goals form the basis of a new framework [PROmoting Morally Important Consent Ends (PROMICE)] for assessing the ethical appropriateness of various informed consent models. We illustrate this framework with two examples: (a) a tiered and layered consent model for obtaining consent for GS, and (b) consent for RGS in critically ill newborns. We conclude that appropriately-rather than fully-informed consent provides the correct standard for genomic medicine and research.

Raw Genomic Data: Storage, Access, and Sharing.

Patients are increasingly being encouraged and supported to access and control their own medical and genomic data. We argue that well-established and transparent raw genomic data retention and returning policies are imperative to enable patients to practice their rights to access and control raw data.

Disclosure of genetic information to family members: a systematic review of normative documents.

PURPOSE: Findings from genomic sequencing can have important implications for patients and family members. Yet, when a patient does not consent to the disclosure of genetic information to relatives, it is unclear how health-care professionals (HCPs) should balance their responsibilities toward patients and their family members and whether breaches in confidentiality are warranted. METHODS: We conducted a systematic review of normative documents to understand how HCPs should discuss and facilitate family disclosure, and what should be done in cases where the patient does not consent to disclosure. RESULTS: We analyzed 35 documents from advisory committees at the national, European, and international level. We identified discrepancies regarding the recommended role of HCPs in disclosure. While almost all normative documents supported the disclosure of genetic information without patient consent in limited conditions, the conditions for disclosure were often not well defined. Documents provided varying degrees of information regarding what actions HCPs must take in such situations. CONCLUSION: Our findings present concerns regarding the ability of these normative documents to guide HCPs' decision making around the disclosure of genetic information to family members. Clearer guidance outlining the responsibilities and acceptability of disclosure is necessary to facilitate disclosure of genetic information to family members.

Analysis of laboratory reporting practices using a quality assessment of a virtual patient.

PURPOSE: Existing research suggests that while some laboratories report variants of uncertain significance, unsolicited findings (UF), and/or secondary findings (SF) when performing exome sequencing, others do not. METHODS: To investigate reporting differences, we created virtual patient-parent trio data by merging variants from patients into "normal" exomes. We invited laboratories worldwide to analyze the data along with patient phenotype information (developmental delay, dysmorphic features, and cardiac hypertrophy). Laboratories issued a diagnostic exome report and completed questionnaires to explain their rationale for reporting (or not reporting) each of the eight variants integrated. RESULTS: Of the 39 laboratories that completed the questionnaire, 30 reported the HDAC8 variant, which was a partial cause of the patient's primary phenotype, and 26 reported the BICD2 variant, which explained another phenotypic component. Lack of reporting was often due to using a filter or a targeted gene panel that excluded the variant, or because they did not consider the variant to be responsible for the phenotype. There was considerable variation in reporting variants associated with the cardiac phenotype (MYBPC3 and PLN) and reporting UF/SF also varied widely. CONCLUSION: This high degree of variability has significant impact on whether causative variants are identified, with important implications for patient care.

Genetics experience impacts attitudes towards germline gene editing: a survey of over 1500 members of the public.

CRISPR-Cas9 has revolutionised genome engineering and has the potential to radically change our approach to genetic disease. However, the potential for genetic modification of embryos has raised significant and complex ethical and social concerns. The scientific community have called for ongoing stakeholder consultation about Germline Gene Editing (GGE), in particular lay publics, to help guide policy, education, research and regulatory priorities. In response, we conducted a survey to gauge public support for GGE and describe the demographic, experiential and contextual factors that influence individual attitudes. Respondent support was measured across nine hypothetical medical and enhancement GGE applications. We received responses from 1537 participants across 67 countries. Respondents were generally supportive of GGE, particularly for medical applications. While the most opposition observed was among religious respondents, those with work experience in genetics or genomics also reported greater resistance to GGE. Personal or family-related experience with genetics or genomics, identifying as female and tertiary education were also associated with less support for GGE. Further research needs to explore a diverse range of community and group attitudes towards GGE; the reasons underlying demographic and experiential differences; and to determine where the public and genetics professionals draw the line on ethical implementation respectively.

Kufs disease due to mutation of CLN6: clinical, pathological and molecular genetic features.

Kufs disease is the major adult form of neuronal ceroid lipofuscinosis, but is rare and difficult to diagnose. Diagnosis was traditionally dependent on the demonstration of characteristic storage material, but distinction from normal age-related accumulation of lipofuscin can be challenging. Mutation of CLN6 has emerged as the most important cause of recessive Kufs disease but, remarkably, is also responsible for variant late infantile ceroid lipofuscinosis. Here we provide a detailed description of Kufs disease due to CLN6 pathogenic variants. We studied 20 cases of Kufs disease with CLN6 pathogenic variants from 13 unrelated families. Mean age of onset was 28 years (range 12-51) with bimodal peaks in teenage and early adult life. The typical presentation was of progressive myoclonus epilepsy with debilitating myoclonic seizures and relatively infrequent tonic-clonic seizures. Patients became wheelchair-bound with a mean 12 years post-onset. Ataxia was the most prominent motor feature. Dementia appeared to be an invariable accompaniment, although it could take a number of years to manifest and occasionally cognitive impairment preceded myoclonic seizures. Patients were usually highly photosensitive on EEG. MRI showed progressive cerebral and cerebellar atrophy. The median survival time was 26 years from disease onset. Ultrastructural examination of the pathology revealed fingerprint profiles as the characteristic inclusions, but they were not reliably seen in tissues other than brain. Curvilinear profiles, which are seen in the late infantile form, were not a feature. Of the 13 unrelated families we observed homozygous CLN6 pathogenic variants in four and compound heterozygous variants in nine. Compared to the variant late infantile form, there was a lower proportion of variants that predicted protein truncation. Certain heterozygous missense variants in the same amino acid position were found in both variant late infantile and Kufs disease. There was a predominance of cases from Italy and surrounding regions; this was partially explained by the discovery of three founder pathogenic variants. Clinical distinction of type A (progressive myoclonus epilepsy) and type B (dementia with motor disturbance) Kufs disease was supported by molecular diagnoses. Type A is usually caused by recessive pathogenic variants in CLN6 or dominant variants in DNAJC5. Type B Kufs is usually associated with recessive CTSF pathogenic variants. The diagnosis of Kufs remains challenging but, with the availability of genetic diagnosis, this will largely supersede the use of diagnostic biopsies, particularly as biopsies of peripheral tissues has unsatisfactory sensitivity and specificity.

Human Genetics Society of Australasia Position Statement: Predictive and Presymptomatic Genetic Testing in Adults and Children.

In 2020, the Human Genetics Society of Australasia released its Position Statement on Predictive and Presymptomatic Genetic Testing in Adults and Children. This Position Statement synthesizes the major practical, psychosocial and ethical considerations associated with presymptomatic and predictive genetic testing in adults who have the capacity to make a decision, children and young people who lack capacity and adults living with reduced or fluctuating capacity. Recommendations include that predictive testing in adults, young people and children should only be offered with pretest genetic counseling and the option of posttest genetic counseling. An individual considering (for themselves or on behalf of another) whether to have a predictive test should also be supported to allow them to make an autonomous and informed decision. Predictive testing should only be offered to children and young people for conditions where there is likely to be a direct medical benefit to them through surveillance, use of prevention strategies or other medical interventions in the immediate future. Where symptoms are likely to develop in childhood, in the absence of options to implement surveillance or risk reduction measures, genetic health professionals and parents/guardians should discuss whether undertaking predictive testing is the best course of action for the child and the family as a whole. Where symptoms are likely to develop in adulthood, the default position should be to postpone predictive testing until the young person achieves the capacity to make their own autonomous and informed decision.

Genetic health professionals' experiences returning results from diagnostic genomic sequencing to patients.

Despite widespread use of genomic sequencing (GS) in clinical care, there has been little exploration of actual experiences of genetic health professionals (GHPs) using GS in clinical practice worldwide. To address this, semi-structured interviews were conducted with 31 clinical geneticists and genetic counselors across Europe, Australia, and Canada to explore their experiences with returning results from GS to patients. GHPs remarked that patients' reactions to receiving causative results vary; some patients are relieved or appreciative at identification of a genetic cause, while others express frustration that finding an answer does not lead to a treatment. GHPs discussed the importance of managing expectations in pre-test counseling to minimize disappointment. Although some patients experience mild distress, they generally cope well receiving unsolicited findings and appreciate being informed of their increased risk. While many GHPs felt patients understand what a variant of uncertain significance (VUS) means, a proportion found VUS quite difficult to convey and had concerns for patients' level of understanding. A proportion mentioned concerns regarding potential negative repercussions of non-genetic clinicians misinterpreting the significance of VUS. These results provide important insights into the challenges GHPs can experience returning GS results to patients, highlighting a need for additional training for GHPs and non-genetic clinicians.