Gene selection for genomic newborn screening: Moving toward consensus?

PURPOSE: Gene selection for genomic newborn screening (gNBS) underpins the validity, acceptability, and ethical application of this technology. Existing gNBS gene lists are highly variable despite being based on shared principles of gene-disease validity, treatability, and age of onset. This study aimed to curate a gNBS gene list that builds upon existing efforts and provide a core consensus list of gene-disease pairs assessed by multiple expert groups worldwide. METHODS: Our multidisciplinary expert team curated a gene list using an open platform and multiple existing curated resources. We included severe treatable disorders with age of disease onset <5 years with established gene-disease associations and reliable variant detection. We compared the final list with published lists from 5 other gNBS projects to determine consensus genes and to identify areas of discrepancy. RESULTS: We reviewed 1279 genes and 604 met our inclusion criteria. Metabolic conditions comprised the largest group (25%), followed by immunodeficiencies (21%) and endocrine disorders (15%). We identified 55 consensus genes included by all 6 gNBS research projects. Common reasons for discrepancy included variable definitions of treatability and strength of gene-disease association. CONCLUSION: We have identified a consensus gene list for gNBS that can be used as a basis for systematic harmonization efforts internationally.

Direct notification by health professionals of relatives at-risk of genetic conditions (with patient consent): views of the Australian public.

Genetic risk information for medically actionable conditions has relevance for patients' blood relatives. However, cascade testing uptake in at-risk families is <50%, and the burden of contacting relatives is a significant barrier to dissemination of risk information. Health professionals (HPs) could notify at-risk relatives directly, with patients' consent. This practice is supported by international literature, including strong public support. However, there is little exploration of the Australian public's views about this issue. We surveyed Australian adults using a consumer research company. Respondents were provided a hypothetical scenario and asked about views and preferences regarding direct contact by HPs. 1030 members of the public responded, with median age 45 y and 51% female. The majority would want to be told about genetic risk for conditions that can be prevented/treated early (85%) and contacted directly by a HP (68%). Most preferred a letter that included specific information about the genetic condition in the family (67%) and had no privacy concerns about HPs sending a letter using contact details provided by a relative (85%). A minority (< 5%) had significant privacy concerns, mostly about use of personal contact information. Concerns included ensuring information was not shared with third parties. Almost 50% would prefer that a family member contacted them before the letter was sent, while about half did not prefer this or were unsure. The Australian public supports (and prefers) direct notification of relatives at risk of medically actionable genetic conditions. Guidelines would assist with clarifying clinicians' discretion in this area.

Barriers to and Facilitators of Implementing Guidelines for Detecting Familial Hypercholesterolaemia in Australia.

BACKGROUND: Familial hypercholesterolaemia (FH) is a genetic condition that is a preventable cause of premature cardiovascular morbidity and mortality. High-level evidence and clinical practice guidelines support preventative care for people with FH. However, it is estimated that less than 10% of people at risk of FH have been detected using any approach across Australian health settings. The aim of this study was to identify the implementation barriers to and facilitators of the detection of FH in Australia. METHODS: Four, 2-hour virtual focus groups were facilitated by implementation scientists and a clinicians as part of the 2021 Australasian FH Summit. Template analysis was used to identify themes. RESULTS: There were 28 workshop attendees across four groups (n=6-8 each), yielding 13 barriers and 10 facilitators across three themes: (1) patient related, (2) provider related, and (3) system related. A "lack of care pathways" and "upskilling clinicians in identifying and diagnosing FH" were the most interconnected barriers and facilitators for the detection of FH. CONCLUSIONS: The relationships between barriers and facilitators across the patient, provider, and system themes indicates that a comprehensive implementation strategy is needed to address these different levels. Future research is underway to develop a model for implementing the Australian FH guidelines into practice.

Gene Therapy for Paediatric Homozygous Familial Hypercholesterolaemia.

The clinical outcome for children and adolescents with homozygous familial hypercholesterolaemia (HoFH) can be devastating, and treatment options are limited in the presence of a null variant. In HoFH, atherosclerotic risk accumulates from birth. Gene therapy is an appealing treatment option as restoration of low-density lipoprotein receptor (LDLR) gene function could provide a cure for HoFH. A clinical trial using a recombinant adeno-associated vector (rAAV) to deliver LDLR DNA to adult patients with HoFH was recently completed; results have not yet been reported. However, this treatment strategy may face challenges when translating to the paediatric population. The paediatric liver undergoes substantial growth which is significant as rAAV vector DNA persists primarily as episomes (extra-chromosomal DNA) and are not replicated during cell division. Therefore, rAAV-based gene addition treatment administered in childhood would likely only have a transient effect. With over 2,000 unique variants in LDLR, a goal of genomic editing-based therapy development would be to treat most (if not all) mutations with a single set of reagents. For a robust, durable effect, LDLR must be repaired in the genome of hepatocytes, which could be achieved using genomic editing technology such as clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 and a DNA repair strategy such as homology-independent targeted integration. This review discusses this issue in the context of the paediatric patient group with severe compound heterozygous or homozygous null variants which are associated with aggressive early-onset atherosclerosis and myocardial infarction, together with the important pre-clinical studies that use genomic editing strategies to treat HoFH in place of apheresis and liver transplantation.

Abbreviated Echocardiographic Screening for Rheumatic Heart Disease by Nonexperts with and without Offsite Expert Review: A Diagnostic Accuracy Study.

BACKGROUND: Early detection of rheumatic heart disease (RHD) through echocardiographic screening can facilitate early access to effective treatment, which reduces the risk for progression. Accurate, feasible approaches to echocardiographic screening that can be incorporated into routine health services are needed. The authors hypothesized that offsite expert review could improve the diagnostic accuracy of nonexpert-obtained echocardiographic images. METHODS: This prospective cross-sectional study was performed to evaluate the diagnostic accuracy of health worker-conducted single parasternal long-axis view with a sweep of the heart using hand-carried ultrasound for the detection of RHD in high-risk populations in Timor-Leste and Australia. In the primary analysis, the presence of any mitral or aortic regurgitation met the criteria for a positive screening result. Sensitivity and specificity were calculated for a screen-and-refer approach based on nonexpert practitioner assessment (approach 1) and for an approach using offsite expert review of nonexpert practitioner-obtained images to decide onward referral (approach 2). Each participant had a reference test performed by an expert echocardiographer on the same day as the index test. Diagnosis of RHD was determined by a panel of three experts, using 2012 World Heart Federation criteria. RESULTS: The prevalence of borderline or definite RHD among 3,329 participants was 4.0% (95% CI, 3.4%-4.7%). The sensitivity of approach 1 for borderline or definite RHD was 86.5% (95% CI, 79.5%-91.8%), and the specificity was 61.4% (95% CI, 59.7%-63.1%). Approach 2 achieved similar sensitivity (88.4%; 95% CI, 81.5%-93.3%) and improved specificity (77.1%; 95% CI, 75.6%-78.6%). CONCLUSION: Nonexpert practitioner-obtained single parasternal long-axis view with a sweep of the heart images, reviewed by an offsite expert, can detect borderline and definite RHD on screening with reasonable sensitivity and specificity. Brief training of nonexpert practitioners with ongoing support could be used as an effective strategy for scaling up echocardiographic screening for RHD in high-risk settings.

Echocardiogram screening in pediatric dialysis and transplantation.

Transthoracic echocardiography is commonly used to identify structural and functional cardiac abnormalities that can be prevalent in childhood chronic kidney failure (KF). Left ventricular mass (LVM) increase is most frequently reported and may persist post-kidney transplant especially with hypertension and obesity. While systolic dysfunction is infrequently seen in childhood chronic KF, systolic strain identified by speckle tracking echocardiography has been frequently identified in dialysis and it can also persist post-transplant. Echocardiogram association with long-term outcomes has not been studied in childhood KF but there are many adult studies demonstrating associations between increased LVM, systolic dysfunction, strain, diastolic dysfunction, and cardiovascular events and mortality. There has been limited study of interventions to improve echocardiogram status. In childhood, improved blood pressure has been associated with better LVM, and conversion from hemodialysis to hemodiafiltration has been associated with better diastolic and systolic function. Whether long-term cardiac outcomes are also improved with these interventions is unclear. Echocardiography is a well-established technique, and regular use in childhood chronic KF seems justified. A case can be made to extend screening to include speckle tracking echocardiography and intradialytic studies in high-risk populations. Further longitudinal studies including these newer echocardiogram modalities, interventions, and long-term outcomes would help clarify recommendations for optimal use as a screening tool.

Acute rheumatic fever and rheumatic heart disease in children and adolescents in Victoria, Australia.

AIM: To describe the epidemiology and clinical profile of children and adolescents with acute rheumatic fever (ARF) and rheumatic heart disease (RHD) in Victoria, Australia. METHODS: A retrospective audit was undertaken of children and adolescents with ARF and RHD attending the Royal Children's and Monash Children's Hospitals in Victoria, Australia between 2010 and 2019. Potential cases were identified by searching multiple sources for relevant ICD-10-AM codes and keywords, then reviewed manually. For confirmed cases, we collected data on patient demographics, clinical features, comorbidities and management. RESULTS: Of 179 participants included, there were 108 Victorian residents and 71 non-Victorian residents. 126 had at least one episode of ARF during the study period and 128 were diagnosed with RHD. In the Victorian resident group, the overall incidence of ARF was 0.8 per 100 000 5-14 year olds. This incidence was higher in Victorian Aboriginal and/or Torres Strait Islander (3.8 per 100 000) and Pacific Islander (32.1 per 100 000) sub-populations. Of 83 Victorian residents who had an ARF episode, 11 (13%) had a recurrence. Most Victorian residents with RHD had mixed aortic and mitral valve pathology (69.4%) and moderate to severe disease (61.9%). Most non-Victorian residents were Aboriginal and/or Torres Strait Islander people (80.3%) and were commonly transferred for tertiary or surgical management of RHD (83.1%). CONCLUSIONS: ARF and RHD continue to affect the health of significant numbers of children and adolescents living in Victoria, including severe and recurrent disease. Specialised services and a register-based control program may help to prevent complications and premature death.

Integrated guidance to enhance the care of children and adolescents with familial hypercholesterolaemia: Practical advice for the community clinician.

Familial hypercholesterolaemia (FH) is a highly penetrant monogenic disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL)-cholesterol (LDL-C) concentration and, if untreated, leads to premature atherosclerosis and coronary artery disease (CAD). At a prevalence of 1:250 individuals, with over 90% undiagnosed, recent estimates suggest that there are approximately 22 000 children and adolescents with FH in Australia and New Zealand. However, the overwhelming majority remain undetected and inadequately treated until adulthood or after their first cardiac event. The guidance in this paper aims to increase awareness about paediatric FH and provide practical advice for the diagnosis and management of FH in children and adolescents. Recommendations are given on the detection, diagnosis, assessment and management of FH in children and adolescents. Recommendations are also made on genetic testing, including counselling and the potential for universal screening programmes. Practical guidance on management includes treatment of non-cholesterol risk factors, and safe and appropriate use of LDL-C lowering therapies, including statins, ezetimibe, PCSK9 inhibitors and lipoprotein apheresis. Models of care for FH need to be adapted to local and regional health care needs and available resources. Targeting the detection of FH as a priority in children and young adults has the potential to alter the natural history of atherosclerotic cardiovascular disease and recognise the promise of early detection for improving long-term health outcomes. A comprehensive implementation strategy, informed by further research, including assessments of cost-benefit, will be required to ensure that this new guidance benefits all families with or at risk of FH.

Corrigendum to Synopsis of an integrated guidance for enhancing the care of familial hypercholesterolaemia: An Australian perspective [American Journal of Preventive Cardiology 6 (2021) 100151].

[This corrects the article DOI: 10.1016/j.ajpc.2021.100151.].

Telemedicine to Timor-Leste: implementing an international cardiac telehealth service during population dislocation, floods and COVID-19.

BACKGROUND: The East Timor Hearts Fund has provided cardiac services in Timor-Leste since 2010, conducting three clinics yearly. AIM: To develop collaborative telehealth services between Australia and Timor-Leste in the context of international border closures due to the COVID-19 pandemic. METHODS: Scoping discussions identified major challenges (structural, patient related and medical system related). At two pilot clinics, patient history, investigation and management were collated. Clinic metrics were compared with an index face-to-face clinic in February 2019. Post-clinic discussions identified areas of success and shortfall in the conduct of the telehealth clinics. RESULTS: Twenty-three patients were reviewed at the online telehealth clinics held onsite at Timorese medical facilities. Compared with an index 2019 clinic, there were markedly lower numbers of new referrals (2 vs 190 patients; 8.7% vs 59.4%). Patients seen at the online clinic were predominantly female (17/23; 73.9%) and Dili based (18/23; 78.3%), with a mean age of 25.9 ± 7.2 years. The majority (12/23; 52.2%) had isolated rheumatic mitral valve disease. Investigations including electrocardiography, pathology, echocardiography and 6-min walk tests were conducted in select patients. Medication advice was provided for 10 (43.5%) patients. Eleven (47.8%) patients were deemed to require urgent intervention. Post-clinic discussions indicated general satisfaction with telehealth clinics, although frustration at the current inability to provide interventional services was highlighted. CONCLUSION: Our pilot telehealth clinics indicate that capacity-building telemedicine can be rapidly implemented in an emergency setting internationally. Clinic design benefits from careful identification and resolution of challenges to optimise flow. Cardiac patients in Timor-Leste have a significant burden of disease amenable to intervention.

Ethylmalonic encephalopathy masquerading as meningococcemia.

Ethylmalonic encephalopathy (MIM #602473) is a rare autosomal recessive metabolic condition caused by biallelic variants in ETHE1 (MIM #608451), characterized by global developmental delay, infantile hypotonia, seizures, and microvascular damage. The microvascular changes result in a pattern of relapsing spontaneous diffuse petechiae and purpura, positional acrocyanosis, and pedal edema, hemorrhagic suffusions of mucous membranes, and chronic diarrhea. Here, we describe an instructive case in which ethylmalonic encephalopathy masqueraded as meningococcal septicemia and shock. Ultrarapid whole-genome testing (time to result 60 h) and prompt biochemical analysis facilitated accurate diagnosis and counseling with rapid implementation of precision treatment for the metabolic crisis related to this condition. This case provides a timely reminder to consider rare genetic diagnoses when atypical features of more common conditions are present, with an early referral to ensure prompt biochemical and genomic diagnosis.

Standardized practices for RNA diagnostics using clinically accessible specimens reclassifies 75% of putative splicing variants.

PURPOSE: Genetic variants causing aberrant premessenger RNA splicing are increasingly being recognized as causal variants in genetic disorders. In this study, we devise standardized practices for polymerase chain reaction (PCR)-based RNA diagnostics using clinically accessible specimens (blood, fibroblasts, urothelia, biopsy). METHODS: A total of 74 families with diverse monogenic conditions (31% prenatal-congenital onset, 47% early childhood, and 22% teenage-adult onset) were triaged into PCR-based RNA testing, with comparative RNA sequencing for 19 cases. RESULTS: Informative RNA assay data were obtained for 96% of cases, enabling variant reclassification for 75% variants that can be used for genetic counseling (71%), to inform clinical care (32%) and prenatal counseling (41%). Variant-associated mis-splicing was highly reproducible for 28 cases with samples from ≥2 affected individuals or heterozygotes and 10 cases with ≥2 biospecimens. PCR amplicons encompassing another segregated heterozygous variant was vital for clinical interpretation of 22 of 79 variants to phase RNA splicing events and discern complete from partial mis-splicing. CONCLUSION: RNA diagnostics enabled provision of a genetic diagnosis for 64% of recruited cases. PCR-based RNA diagnostics has capacity to analyze 81.3% of clinically significant genes, with long amplicons providing an advantage over RNA sequencing to phase RNA splicing events. The Australasian Consortium for RNA Diagnostics (SpliceACORD) provide clinically-endorsed, standardized protocols and recommendations for interpreting RNA assay data.

Single-View Echocardiography by Nonexpert Practitioners to Detect Rheumatic Heart Disease: A Prospective Study of Diagnostic Accuracy.

BACKGROUND: Echocardiographic screening can detect asymptomatic cases of rheumatic heart disease (RHD), facilitating access to treatment. Barriers to implementation of echocardiographic screening include the requirement for expensive equipment and expert practitioners. We aimed to evaluate the diagnostic accuracy of an abbreviated echocardiographic screening protocol (single parasternal-long-axis view with a sweep of the heart) performed by briefly trained, nonexpert practitioners using handheld ultrasound devices. METHODS: Participants aged 5 to 20 years in Timor-Leste and the Northern Territory of Australia had 2 echocardiograms: one performed by an expert echocardiographer using a GE Vivid I or Vivid Q portable ultrasound device (reference test), and one performed by a nonexpert practitioner using a GE Vscan handheld ultrasound device (index test). The accuracy of the index test, compared with the reference test, for identifying cases with definite or borderline RHD was determined. RESULTS: There were 3111 enrolled participants; 2573 had both an index test and reference test. Median age was 12 years (interquartile range, 10-15); 58.2% were female. Proportion with definite or borderline RHD was 5.52% (95% CI, 4.70-6.47); proportion with definite RHD was 3.23% (95% CI, 2.61-3.98). Compared with the reference test, sensitivity of the index test for definite or borderline RHD was 70.4% (95% CI, 62.2-77.8), specificity was 78.1% (95% CI, 76.4-79.8). CONCLUSIONS: Nonexpert practitioners can be trained to perform single parasternal-long-axis view with a sweep of the heart echocardiography. However, the specificity and sensitivity are inadequate for echocardiographic screening. Improved training for nonexpert practitioners should be investigated.

Synopsis of an integrated guidance for enhancing the care of familial hypercholesterolaemia: an Australian perspective.

INTRODUCTION: Familial hypercholesterolaemia (FH) is a common, heritable and preventable cause of premature coronary artery disease, with significant potential for positive impact on public health and healthcare savings. New clinical practice recommendations are presented in an abridged guidance to assist practitioners in enhancing the care of all patients with FH. MAIN RECOMMENDATIONS: Core recommendations are made on the detection, diagnosis, assessment and management of adults, children and adolescents with FH. There is a key role for general practitioners (GPs) working in collaboration with specialists with expertise in lipidology. Advice is given on genetic and cholesterol testing and risk notification of biological relatives undergoing cascade testing for FH; all healthcare professionals should develop skills in genomic medicine. Management is under-pinned by the precepts of risk stratification, adherence to healthy lifestyles, treatment of non-cholesterol risk factors, and appropriate use of low-density lipoprotein (LDL)-cholesterol lowering therapies, including statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Recommendations on service design are provided in the full guidance. POTENTIAL IMPACT ON CARE OF FH: These recommendations need to be utilised using judicious clinical judgement and shared decision making with patients and families. Models of care need to be adapted to both local and regional needs and resources. In Australia new government funded schemes for genetic testing and use of PCSK9 inhibitors, as well as the National Health Genomics Policy Framework, will enable adoption of these recommendations. A broad implementation science strategy is, however, required to ensure that the guidance translates into benefit for all families with FH.

Essentials of a new clinical practice guidance on familial hypercholesterolaemia for physicians.

Familial hypercholesterolaemia (FH) is a common, heritable and preventable cause of premature coronary artery disease. New clinical practice recommendations are presented to assist practitioners in enhancing the care of all patients with FH. Core recommendations are made on the detection, diagnosis, assessment and management of adults, children and adolescents with FH. Management is under-pinned by the precepts of risk stratification, adherence to healthy lifestyles, treatment of non-cholesterol risk factors and appropriate use of low-density lipoprotein (LDL)-cholesterol-lowering therapies including statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. The recommendations need to be utilised using judicious clinical judgement and shared decision-making with patients and families. New government-funded schemes for genetic testing and use of PCSK9 inhibitors, as well as the National Health Genomics Policy Framework, will enable adoption of the recommendations. However, a comprehensive implementation science and practice strategy is required to ensure that the guidance translates into benefit for all families with FH.

Morbidity and mortality of rheumatic heart disease and acute rheumatic fever in the inpatient setting in Timor-Leste.

AIM: To describe the clinical features, treatment and outcomes of acute rheumatic fever (ARF) and rheumatic heart disease (RHD) in children admitted to the national referral hospital in Dili, Timor-Leste. METHODS: This prospective study documented cases of ARF and RHD in children aged 14 years and under who were admitted between June 2017 and May 2019. ARF was diagnosed using an adapted version of the 2015 Jones criteria and presumed (rather than proven) exposure to group A Streptococcus. Clinical and echocardiographic findings, comorbidities and discharge outcomes are reported. RESULTS: A total of 63 patients were admitted with ARF or RHD; 54 were diagnosed with RHD for the first time. Median age was 11 years (range 3-14); 48% were female. Of those with echocardiograms, 56/58 had RHD, 55/56 (98%) had mitral regurgitation (37/55 (67%) severe), 11/56 (20%) had mitral stenosis and 43/56 (77%) had aortic regurgitation. Left ventricular dysfunction (55%), pulmonary hypertension (64%) and cardiac failure (78%) were common. Four (6%) patients died in hospital, and 30/59 (51%) of surviving patients were lost to follow up. CONCLUSIONS: Community echocardiography screening has reported a high prevalence of undetected mild to moderate cases of RHD in Timor-Leste, whereas this hospital study documents mostly severe disease among hospitalised patients with a high case fatality rate and loss to follow up. RHD is a significant health problem in Timor-Leste and improved recognition and diagnosis, as well as effective delivery of treatment and follow-up are imperative.

Integrated Guidance for Enhancing the Care of Familial Hypercholesterolaemia in Australia.

Familial hypercholesterolaemia (FH) is a dominant and highly penetrant monogenic disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL)-cholesterol concentration and, if untreated, leads to premature atherosclerosis and coronary artery disease (CAD). There are approximately 100,000 people with FH in Australia. However, an overwhelming majority of those affected remain undetected and inadequately treated, consistent with FH being a leading challenge for public health genomics. To further address the unmet need, we provide an updated guidance, presented as a series of systematically collated recommendations, on the care of patients and families with FH. These recommendations have been informed by an exponential growth in published works and new evidence over the last 5 years and are compatible with a contemporary global call to action on FH. Recommendations are given on the detection, diagnosis, assessment and management of FH in adults and children. Recommendations are also made on genetic testing and risk notification of biological relatives who should undergo cascade testing for FH. Guidance on management is based on the concepts of risk re-stratification, adherence to heart healthy lifestyles, treatment of non-cholesterol risk factors, and safe and appropriate use of LDL-cholesterol lowering therapies, including statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors and lipoprotein apheresis. Broad recommendations are also provided for the organisation and development of health care services. Recommendations on best practice need to be underpinned by good clinical judgment and shared decision making with patients and families. Models of care for FH need to be adapted to local and regional health care needs and available resources. A comprehensive and realistic implementation strategy, informed by further research, including assessments of cost-benefit, will be required to ensure that this new guidance benefits all Australian families with or at risk of FH.

Hyperendemic rheumatic heart disease in a remote Australian town identified by echocardiographic screening.

OBJECTIVES: Using echocardiographic screening, to estimate the prevalence of rheumatic heart disease (RHD) in a remote Northern Territory town. DESIGN: Prospective, cross-sectional echocardiographic screening study; results compared with data from the NT rheumatic heart disease register. SETTING, PARTICIPANTS: People aged 5-20 years living in Maningrida, West Arnhem Land (population, 2610, including 2366 Indigenous Australians), March 2018 and November 2018. INTERVENTION: Echocardiographic screening for RHD by an expert cardiologist or cardiac sonographer. MAIN OUTCOME MEASURES: Definite or borderline RHD, based on World Heart Federation criteria; history of acute rheumatic fever (ARF), based on Australian guidelines for diagnosing ARF. RESULTS: The screening participation rate was 72%. The median age of the 613 participants was 11 years (interquartile range, 8-14 years); 298 (49%) were girls or women, and 592 (97%) were Aboriginal Australians. Definite RHD was detected in 32 screened participants (5.2%), including 20 not previously diagnosed with RHD; in five new cases, RHD was classified as severe, and three of the participants involved required cardiac surgery. Borderline RHD was diagnosed in 17 participants (2.8%). According to NT RHD register data at the end of the study period, 88 of 849 people in Maningrida and the surrounding homelands aged 5-20 years (10%) were receiving secondary prophylaxis following diagnoses of definite RHD or definite or probable ARF. CONCLUSION: Passive case finding for ARF and RHD is inadequate in some remote Australian communities with a very high burden of RHD, placing children and young people with undetected RHD at great risk of poor health outcomes. Active case finding by regular echocardiographic screening is required in such areas.