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Expanded carrier screening (ECS) for recessive monogenic diseases requires prior knowledge of genomic variation, including DNA variants that cause disease. The composition of pathogenic variants differs greatly among human populations, but historically, research about monogenic diseases has focused mainly on people with European ancestry. By comparison, less is known about pathogenic DNA variants in people from other parts of the world. Consequently, inclusion of currently underrepresented Indigenous and other minority population groups in genomic research is essential to enable equitable outcomes in ECS and other areas of genomic medicine. Here, we discuss this issue in relation to the implementation of ECS in Australia, which is currently being evaluated as part of the national Government’s Genomics Health Futures Mission. We argue that significant effort is required to build an evidence base and genomic reference data so that ECS can bring significant clinical benefit for many Aboriginal and/or Torres Strait Islander Australians. These efforts are essential steps to achieving the Australian Government’s objectives and its commitment “to leveraging the benefits of genomics in the health system for all Australians.” They require culturally safe, community-led research and community involvement embedded within national health and medical genomics programs to ensure that new knowledge is integrated into medicine and health services in ways that address the specific and articulated cultural and health needs of Indigenous people. Until this occurs, people who do not have European ancestry are at risk of being, in relative terms, further disadvantaged.

Population health research is increasingly focused on the genetic determinants of healthy ageing, but there is no public resource of whole genome sequences and phenotype data from healthy elderly individuals. Here we describe the first release of the Medical Genome Reference Bank (MGRB), comprising whole genome sequence and phenotype of 2570 elderly Australians depleted for cancer, cardiovascular disease, and dementia. We analyse the MGRB for single-nucleotide, indel and structural variation in the nuclear and mitochondrial genomes. MGRB individuals have fewer disease-associated common and rare germline variants, relative to both cancer cases and the gnomAD and UK Biobank cohorts, consistent with risk depletion. Age-related somatic changes are correlated with grip strength in men, suggesting blood-derived whole genomes may also provide a biologic measure of age-related functional deterioration. The MGRB provides a broadly applicable reference cohort for clinical genetics and genomic association studies, and for understanding the genetics of healthy ageing.

Background: New approaches are required to address the needs of complex undiagnosed diseases patients. These approaches include clinical genomic diagnostic pipelines, utilizing intra- and multi-disciplinary platforms, as well as specialty-specific genomic clinics. Both are advancing diagnostic rates. However, complementary cross-disciplinary approaches are also critical to address those patients with multisystem disorders who traverse the bounds of multiple specialties and remain undiagnosed despite existing intra-specialty and genomic-focused approaches. The diagnostic possibilities of undiagnosed diseases include genetic and non-genetic conditions. The focus on genetic diseases addresses some of these disorders, however a cross-disciplinary approach is needed that also simultaneously addresses other disorder types. Herein, we describe the initiation and summary outcomes of a public health system approach for complex undiagnosed patients- the Undiagnosed Diseases Program-Western Australia (UDP-WA). Results: Briefly the UDP-WA is: i) one of a complementary suite of approaches that is being delivered within health service, and with community engagement, to address the needs of those with severe undiagnosed diseases; ii) delivered within a public health system to support equitable access to health care, including for those from remote and regional areas; iii) providing diagnoses and improved patient care; iv) delivering a platform for in-service and real time genomic and phenomic education for clinicians that traverses a diverse range of specialties; v) retaining and recapturing clinical expertise; vi) supporting the education of junior and more senior medical staff; vii) designed to integrate with clinical translational research; and viii) is supporting greater connectedness for patients, families and medical staff. Conclusion: The UDP-WA has been initiated in the public health system to complement existing clinical genomic approaches; it has been targeted to those w

Public health relies on technologies to produce and analyse data, as well as effectively develop and implement policies and practices. An example is the public health practice of epidemiology, which relies on computational technology to monitor the health status of populations, identify disadvantaged or at risk population groups and thereby inform health policy and priority setting. Critical to achieving health improvements for the underserved population of people living with rare diseases is early diagnosis and best care. In the rare diseases field, the vast majority of diseases are caused by destructive but previously difficult to identify protein-coding gene mutations. The reduction in cost of genetic testing and advances in the clinical use of genome sequencing, data science and imaging are converging to provide more precise understandings of the ‘person-time-place’ triad. That is: who is affected (people); when the disease is occurring (time); and where the disease is occurring (place). Consequently we are witnessing a paradigm shift in public health policy and practice towards ‘precision public health’. Patient and stakeholder engagement has informed the need for a national public health policy framework for rare diseases. The engagement approach in different countries has produced highly comparable outcomes and objectives. Knowledge and experience sharing across the international rare diseases networks and partnerships has informed the development of the Western Australian Rare Diseases Strategic Framework 2015–2018 (RD Framework) and Australian government health briefings on the need for a National plan. The RD Framework is guiding the translation of genomic and other technologies into the Western Australian health system, leading to greater precision in diagnostic pathways and care, and is an example of how a precision public health framework can improve health outcomes for the rare diseases population. Five vignettes are used to illustrate how policy decis

Background: Sertoli cell tight junctions (TJs) are gonadotropin-dependent components of the blood-testis barrier (BTB) that sequesters adluminal meiotic and post-meiotic germ cells from the testicular vasculature. In normal adult rodents and men, the key TJ transmembrane protein, claudin-11, is localized to the TJ at the BTB. In rodents following gonadotropin suppression and associated germ cell loss, claudin-11 is spatially disrupted, and TJ function is lost. The potential for the human TJ to be gonadotropin-dependent has not been elucidated. Aim(s): To investigate the localization of claudin-11 at the human TJ following chronic gonadotropin suppression. Method(s): Claudin-11 was assessed by immunohistochemistry in archived testis tissue from men following 8 weeks of gonadotropin suppression and for whom meiotic and post-meiotic germ cell numbers were available. Suppression regimens were i) testosterone enanthate (TE) plus the GnRH antagonist acyline (A); ii) T + progestin, levonorgestrel (LNG); iii) TE+LNG+A or iv) TE+LNG+ 5alpha-reductase inhibitor, dutasteride. Result(s): Claudin-11 formed a continuous staining pattern at the BTB in control men. Regardless of treatment, claudin-11 localization was markedly disrupted and was broadly associated with the extent of meiotic/post meiotic germ cell suppression; claudin-11 staining was punctate when the average numbers of adluminal germ cells were <15% of control, and fragmented or continuous when 15%-25% or >40% of control, respectively. Conclusion(s): We show for the first time that claudin-11 localization is disrupted in gonadotropin-suppressed men. This result is consistent with its known importance in rodent spermatogenesis, and identifies the human Sertoli cell TJ as a potential site of male hormonal contraception.

STUDY QUESTION Are Sertoli cell tight junctions (TJs) disrupted in men undergoing hormonal contraception? SUMMARY ANSWER Localization of the key Sertoli cell TJ protein, claudin-11, was markedly disrupted by 8 weeks of gonadotropin suppression, the degree of which was related to the extent of adluminal germ cell suppression. WHAT IS KNOWN ALREADY Sertoli cell TJs are vital components of the blood-testis barrier (BTB) that sequester developing adluminal meiotic germ cells and spermatids from the vascular compartment. Claudin-11 knockout mice are infertile; additionally claudin-11 is spatially disrupted in chronically gonadotropin-suppressed rats coincident with a loss of BTB function, and claudin-11 is disorganized in various human testicular disorders. These data support the Sertoli cell TJ as a potential site of hormonal contraceptive action. STUDY DESIGN, SIZE, DURATION BTB proteins were assessed by immunohistochemistry (n = 16 samples) and mRNA (n = 18 samples) expression levels in available archived testis tissue from a previous study of 22 men who had undergone 8 weeks of gonadotropin suppression and for whom meiotic and post-meiotic germ cell numbers were available. The gonadotropin suppression regimens were (i) testosterone enanthate (TE) plus the GnRH antagonist, acyline (A); (ii) TE + the progestin, levonorgestrel, (LNG); (iii) TE + LNG + A or (iv) TE + LNG + the 5alpha-reductase inhibitor, dutasteride (D). A control group consisted of seven additional men, with three archived samples available for this study. PARTICIPANTS/MATERIALS, SETTINGS, METHODS Immunohistochemical localization of claudin-11 (TJ) and other junctional type markers [ZO-1 (cytoplasmic plaque), beta-catenin (adherens junction), connexin-43 (gap junction), vinculin (ectoplasmic specialization) and beta-actin (cytoskeleton)] and quantitative PCR was conducted using matched frozen testis tissue. MAIN RESULTS AND THE ROLE OF CHANCE Claudin-11 formed a continuous staining pattern at the BTB in