Experience of the first adult-focussed undiagnosed disease program in Australia (AHA-UDP): solving rare and puzzling genetic disorders is ageless.

BACKGROUND: Significant recent efforts have facilitated increased access to clinical genetics assessment and genomic sequencing for children with rare diseases in many centres, but there remains a service gap for adults. The Austin Health Adult Undiagnosed Disease Program (AHA-UDP) was designed to complement existing UDP programs that focus on paediatric rare diseases and address an area of unmet diagnostic need for adults with undiagnosed rare conditions in Victoria, Australia. It was conducted at a large Victorian hospital to demonstrate the benefits of bringing genomic techniques currently used predominantly in a research setting into hospital clinical practice, and identify the benefits of enrolling adults with undiagnosed rare diseases into a UDP program. The main objectives were to identify the causal mutation for a variety of diseases of individuals and families enrolled, and to discover novel disease genes. METHODS: Unsolved patients in whom standard genomic diagnostic techniques such as targeted gene panel, exome-wide next generation sequencing, and/or chromosomal microarray, had already been performed were recruited. Genome sequencing and enhanced genomic analysis from the research setting were applied to aid novel gene discovery. RESULTS: In total, 16/50 (32%) families/cases were solved. One or more candidate variants of uncertain significance were detected in 18/50 (36%) families. No candidate variants were identified in 16/50 (32%) families. Two novel disease genes (TOP3B, PRKACB) and two novel genotype-phenotype correlations (NARS, and KMT2C genes) were identified. Three out of eight patients with suspected mosaic tuberous sclerosis complex had their diagnosis confirmed which provided reproductive options for two patients. The utility of confirming diagnoses for patients with mosaic conditions (using high read depth sequencing and ddPCR) was not specifically envisaged at the onset of the project, but the flexibility to offer recruitment and analyses on an as-needed basis proved to be a strength of the AHA-UDP. CONCLUSION: AHA-UDP demonstrates the utility of a UDP approach applying genome sequencing approaches in diagnosing adults with rare diseases who have had uninformative conventional genetic analysis, informing clinical management, recurrence risk, and recommendations for relatives.

Recurrent pneumothorax in a case of tenascin-X deficient Ehlers-Danlos syndrome: Broadening the phenotypic spectrum.

The genomic region surrounding the Tenascin-XB gene (TNXB) is a complex and duplicated region, with several pseudogenes that predispose to high rates of homologous recombination. Classical-like Ehlers-Danlos syndrome (clEDS) is the result of tenascin-X deficiency due to biallelic loss of function variants in the TNXB gene. Here we present a patient with clEDS and spontaneous pneumothorax, a feature not previously reported to be associated with this condition. Two inherited pathogenic/likely pathogenic variants were identified; a previously reported deletion resulting in a TNXA/TNXB chimeric gene and a novel frameshift variant. The Tenascin-XB gene is well described in the literature to be associated with collagen metabolism, stabilization of the fibrillar-collagen matrix and is expressed abundantly in the extracellular matrix. We propose that tenascin-X deficiency is directly related to pneumothorax predisposition. This case expands the phenotypic spectrum of clEDS and highlights the challenges with molecular analysis and diagnosis.

Case fatality rates of invasive meningococcal disease by serogroup and age: A systematic review and meta-analysis.

INTRODUCTION: Invasive meningococcal disease (IMD) is uncommon but still causes considerable public health burden due to its high mortality and morbidity. This review aims to quantitatively synthesise all published evidence pertinent to mortality caused by IMD and assess the effect of age and serogroup on case fatality rates (CFRs). METHODS: The PubMed and Embase databases, and the Cochrane Library were searched. Articles reporting national CFRs and published in English between January 2000 and May 2018 were eligible. The studies reporting mortality resulting from a specific symptom of IMD (e.g. meningococcal meningitis) were excluded. Mixed-effects logistic regression with a restricted cubic spline was used to analyse CFRs as a function of age. Random-effects meta-analyses were performed to estimate an overall CFR and CFRs by serogroup. RESULTS: Among 48 eligible studies reporting national CFRs, 40 studies were included in meta-analyses representing 163,758 IMD patients. CFRs ranged from 4.1% to 20.0% with the pooled overall CFR of 8.3% (95% confidence interval (CI): 7.5-9.1%). Serogroup B was associated with a lower pooled CFR (6.9% (95%CI: 6.0-7.8%)) than other serogroups (W: 12.8% (95%CI: 10.7-15.0%); C: 12.0% (95%CI: 10.5-13.5%); Y: 10.8% (95%CI: 8.2-13.4%)). The meta-analysis was not performed for serogroup A (MenA) cases due to a small number of MenA patients who were enrolled in eligible studies. For laboratory confirmed IMD cases, the predicted CFR was 9.0% in infants, gradually decreased to 7.0% in 7-year olds, subsequently increased to 15.0% in young adults aged 28 years, stabilised between 15 and 20% in mid-aged adults and reached a high in elderly people. CONCLUSIONS: Our findings can provide useful information for better understanding the mortality risks, and quantifying the burden associated with IMD mortality.

Costs of Invasive Meningococcal Disease: A Global Systematic Review.

BACKGROUND: Invasive meningococcal disease remains a public health concern because of its rapid onset and significant risk of death and long-term disability. New meningococcal serogroup B and combination serogroup ACWY vaccines are being considered for publicly funded immunization programs in many countries. Contemporary costing data associated with invasive meningococcal disease are required to inform cost-effectiveness analyses. OBJECTIVE: The objective of this study was to estimate costs and resource utilization associated with acute infection and the long-term care of invasive meningococcal disease. DATA SOURCES AND METHODS: PubMed, EMBASE, The Cochrane Library, health economic databases, and electronically available conference abstracts were searched. Studies reporting any costs associated with acute infection and long-term sequelae of invasive meningococcal disease in English were included. All costs were converted into purchasing power parity-adjusted estimates [international dollars (I$)] using the Campbell and Cochrane Economics Methods Group and the Evidence for Policy and Practice Information and Coordinating Centre cost converter. RESULTS: Fourteen studies met our eligibility criteria and were included. The mean costs of acute admission ranged from I$1629 to I$50,796, with an incremental cost of I$16,378. The mean length of hospital stay was reported to be 6-18 days in multiple studies. The average costs reported for readmissions ranged from I$7905 to I$15,908. Key variables such as the presence of sequelae were associated with higher hospitalization costs and longer inpatient stay. No studies estimated direct non-healthcare costs and productivity loss. Ten studies reported only unadjusted mean values without using appropriate statistical methods for adjustment. CONCLUSIONS: Invasive meningococcal disease can result in substantial costs to healthcare systems. However, costing data on long-term follow-up and indirect costs used to populate health economic models are lacking.