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Understanding the impact of splicing and nonsense variants on RNA is crucial for the resolution of variant classification as well as their suitability for precision medicine interventions. This is primarily enabled through RNA studies involving transcriptomics followed by targeted assays using RNA isolated from clinically accessible tissues (CATs) such as blood or skin of affected individuals. Insufficient disease gene expression in CATs does however pose a major barrier to RNA based investigations, which we show is relevant to 1,436 Mendelian disease genes. We term these "silent" Mendelian genes (SMGs), the largest portion (36%) of which are associated with neurological disorders. We developed two approaches to induce SMG expression in human dermal fibroblasts (HDFs) to overcome this limitation, including CRISPR-activation-based gene transactivation and fibroblast-to-neuron transdifferentiation. Initial transactivation screens involving 40 SMGs stimulated our development of a highly multiplexed transactivation system culminating in the 6- to 90,000-fold induction of expression of 20/20 (100%) SMGs tested in HDFs. Transdifferentiation of HDFs directly to neurons led to expression of 193/516 (37.4%) of SMGs implicated in neurological disease. The magnitude and isoform diversity of SMG expression following either transactivation or transdifferentiation was comparable to clinically relevant tissues. We apply transdifferentiation and/or gene transactivation combined with short- and long-read RNA sequencing to investigate the impact that variants in USH2A, SCN1A, DMD, and PAK3 have on RNA using HDFs derived from affected individuals. Transactivation and transdifferentiation represent rapid, scalable functional genomic solutions to investigate variants impacting SMGs in the patient cell and genomic context.

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INTRODUCTION: Direct-to-patient telegenetics, which uses video conferencing to connect health professionals directly to patients' devices, has been widely adopted during the pandemic. However, limited evidence currently supports its use in cancer genetic counselling. METHODS: Before the pandemic, we conducted a two-arm partially randomised patient-preference pilot trial to evaluate direct-to-patient telegenetics for patients and genetic counsellors. Patients were randomised to a standard care (telephone/in-person) or direct-to-patient telegenetics appointment. Patients completed questionnaires before, during and after appointments measuring: psychological distress, perceived genetic counsellor empathy, telegenetics satisfaction and technical challenges. Genetic counsellor-reported outcomes -measured using purpose-designed questionnaires- included telegenetics satisfaction, therapeutic alliance and time for assessment. Open-ended patient and genetic counsellor questionnaire responses were synthesised using content analysis. RESULTS: Fifty-six patients and seven genetic counsellors participated. Thirteen patients switched appointment type. No significant differences in distress (P = 0.84) were identified between direct-to-patient telegenetics and standard care. Perceived genetic counsellor empathy was high for all appointment types. There was no evidence of differences in reported maximum empathy scores between direct-to-patient telegenetics and standard care [telephone (P = 0.57); in-person (P = 0.44)]. Patients reported high direct-to-patient telegenetics satisfaction despite technical challenges in most appointments (65%). Genetic counsellors were satisfied with direct-to-patient telegenetics and perceived high therapeutic alliance irrespective of appointment type. No significant differences in genetic counsellor time were identified between direct-to-patient telegenetics and standard care [telephone (P > 0.90); in-person (P = 0.35)]. DISCUSSION: Our results suggest that direct-to-patient telegenetics is a satisfactory service delivery model that does not appear to compromise patient-genetic counsellor relationships or increase patient distress. These findings support direct-to-patient telegenetics use in cancer genetic counselling, although larger trials are needed.

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In Australia, individuals of Aboriginal and Torres Strait Islander descent (Indigenous Australians) have poorer health outcomes than the general population, including higher incidence of cancer and reduced life expectancy up to 14 years compared to non-Indigenous Australians. Although differences in engagement with healthcare and beliefs about disease/cancer exist between Indigenous communities, a number of common barriers have been identified hindering attendance at mainstream health services. To inform exploration of barriers that may impact access to a cancer genetic counseling service, consultations with Aboriginal stakeholders were undertaken. Ethical principles for studies that engage Indigenous communities were followed throughout the research endeavor. Using a stakeholder-endorsed focus group approach, the views of an Aboriginal Elders group (n = 9) were sought with additional semi-structured interviews with social science and genetics researchers working with Indigenous communities in Australia (n = 7). Thematic analysis of the results identified three themes: explanatory models of illness, barriers to keeping well and attending services, and recommendations for improvements to access/attendance. Barriers common to accessing both mainstream health services and clinical genetic services were identified, including attributions of illness and cancer. Specific genetic counseling barriers included the cultural inclusivity and accessibility of services, and a lack of awareness of genetic counseling both in the community and by clinicians unfamiliar with genetics. Recommendations included developing flexible service delivery models and culturally appropriate resources for Indigenous patients. These findings may inform future studies to improve Indigenous health outcomes and promote a more accessible, culturally appropriate approach to provision of cancer genetics services for Australia's First Peoples.

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