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Silver-Russell syndrome (SRS OMIM 180860) is a rare, albeit well-recognized disorder characterized by severe intrauterine and postnatal growth retardation. It remains a clinical diagnosis with a molecular cause identifiable in approximately 60%–70% of patients. We report a 4-year-old Australian Aboriginal girl who was born at 32 weeks gestation with features strongly suggestive of SRS, after extensive investigation she was referred to our undiagnosed disease program (UDP). Genomic sequencing was performed which identified a heterozygous splice site variant in IGF2 which is predicted to be pathogenic by in-silico studies, paternal allelic origin, de novo status, and RNA studies on fibroblasts. We compare clinical findings with reported patients to add to the knowledge base on IGF2 variants and to promote the engagement of other Australian Aboriginal families in genomic medicine.

© 2017 The Author(s). 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 be

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

© Springer International Publishing AG 2017. 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 vign

Background The Rare and Undiagnosed Diseases Diagnostic Service (RUDDS) refers to a genomic diagnostic platform operating within the Western Australian Government clinical services delivered through Genetic Services of Western Australia (GSWA). GSWA has provided a state-wide service for clinical genetic care for 28 years and it serves a population of 2.5 million people across a geographical area of 2.5milion Km2. Within this context, GSWA has established a clinically integrated genomic diagnostic platform in partnership with other public health system managers and service providers, including but not limited to the Office of Population Health Genomics, Diagnostic Genomics (PathWest Laboratories) and with executive level support from the Department of Health. Herein we describe report presents the components of this service that are most relevant to the heterogeneity of paediatric clinical genetic care. Results Briefly the platform : i) offers multiple options including non-genetic testing; monogenic and genomic (targeted in silico filtered and whole exome) analysis; and matchmaking; ii) is delivered in a patient-centric manner that is resonant with the patient journey, it has multiple points for entry, exit and re-entry to allow people access to information they can use, when they want to receive it; iii) is synchronous with precision phenotyping methods; iv) captures new knowledge, including multiple expert review; v) is integrated with current translational genomic research activities and best practice; and vi) is designed for flexibility for interactive generation of, and integration with, clinical research for diagnostics, community engagement, policy and models of care. Conclusion The RUDDS has been established as part of routine clinical genetic services and is thus sustainable, equitably managed and seeks to translate new knowledge into efficient diagnostics and improved health for the whole community.

The Rare and Undiagnosed Diseases Diagnostic Service (RUDDS) is a Clinical Genomic Diagnostic Pipeline operating within the clinical service at Genetic Services of Western Australia (GSWA). GSWA has provided a state-wide service for clinical genetic care for more than 25 years and it serves a population of 2.5 million people. It includes paediatric, adult, prenatal and familial cancer services in metropolitan and regional WA. Within this framework, and in partnership with the Office of Population Health Genomics, Diagnostic Genomics at PathWest and others, it is delivering a clinically integrated pipeline. This service is aligned to the WA Rare Diseases Strategic Framework 2015-2018 to address the unmet need of the diagnostic odyssey of those living with rare and undiagnosed diseases. It is: (I) delivered in a patient-centric manner that is resonant with the patient journey; (II) offers multiple options including non-genetic testing; monogenic and genomic (targeted and whole exome) analysis, and matchmaking; (III) is synchronous with precision phenotyping methods, including 3D facial analysis, and phenotype-enabled decision support; (IV) captures new knowledge, including multiple expert review; (V) has multiple points for entry, exit and re-entry to allow people access to information they can use, when they want to receive it; (VI) draws on the clarity gained from the extremity of rare diseases to provide insights for more common diseases; (VII) is integrated with current translational genomic research activities; and (VIII) is designed for flexibility for integrative generation of, and integration with, further clinical research including for diagnostics, community engagement, policy and models of care.

Background The genetic mutation resulting in osteogenesis imperfecta (OI) type V was recently characterised as a single point mutation (c.-14C > T) in the 5’ untranslated region (UTR) of IFITM5, a gene encoding a transmembrane protein with expression restricted to skeletal tissue. This mutation creates an alternative start codon and has been shown in a eukaryotic cell line to result in a longer variant of IFITM5, but its expression has not previously been demonstrated in bone from a patient with OI type V. Methods Sanger sequencing of the IFITM5 5’ UTR was performed in our cohort of subjects with a clinical diagnosis of OI type V. Clinical data was collated from referring clinicians. RNA was extracted from a bone sample from one patient and Sanger sequenced to determine expression of wild-type and mutant IFITM5. Results All nine subjects with OI type V were heterozygous for the c.-14C > T IFITM5 mutation. Clinically, there was heterogeneity in phenotype, particularly in the manifestation of bone fragility amongst subjects. Both wild-type and mutant IFITM5 mRNA transcripts were present in bone. Conclusions The c.-14C > T IFITM5 mutation does not result in an RNA-null allele but is expressed in bone. Individuals with identical mutations in IFITM5 have highly variable phenotypic expression, even within the same family.