The clinical utility of exome sequencing and extended bioinformatic analyses in adolescents and adults with a broad range of neurological phenotypes: an Australian perspective.

Currently there is no secured ongoing funding in Australia for next generation sequencing (NGS) such as exome sequencing (ES) for adult neurological disorders. Studies have focused on paediatric populations in research or highly specialised settings, utilised standard NGS pipelines focusing only on small insertions, deletions and single nucleotide variants, and not explored impacts on management in detail. This prospective multi-site study performed ES and an extended bioinformatics repeat expansion analysis pipeline, on patients with broad phenotypes (ataxia, dementia, dystonia, spastic paraparesis, motor neuron disease, Parkinson's disease and complex/not-otherwise-specified), with symptom onset between 2 and 60 years. Genomic data analysis was phenotype-driven, using virtual gene panels, reported according to American College of Medical Genetics and Genomics guidelines. One-hundred-and-sixty patients (51% female) were included, median age 52 years (range 14-79) and median 9 years of symptoms. 34/160 (21%) patients received a genetic diagnosis. Highest diagnostic rates were in spastic paraparesis (10/25, 40%), complex/not-otherwise-specified (10/38, 26%) and ataxia (7/28, 25%) groups. Findings were considered 'possible/uncertain' in 21/160 patients. Repeat expansion detection identified an unexpected diagnosis of Huntington disease in an ataxic patient with negative ES. Impacts on management, such as more precise and tailored care, were seen in most diagnosed patients (23/34, 68%). ES and a novel bioinformatics analysis pipepline had a substantial diagnostic yield (21%) and management impacts for most diagnosed patients, in heterogeneous, complex, mainly adult-onset neurological disorders in real-world settings in Australia, providing evidence for NGS and complementary multiple, new technologies as valuable diagnostic tools.

A cost-effectiveness analysis of genomic sequencing in a prospective versus historical cohort of complex pediatric patients.

PURPOSE: Cost-effectiveness evaluations of first-line genomic sequencing (GS) in the diagnosis of children with genetic conditions are limited by the lack of well-defined comparative cohorts. We sought to evaluate the cost-effectiveness of early GS in pediatric patients with complex monogenic conditions compared with a matched historical cohort. METHODS: Data, including investigation costs, were collected in a prospective cohort of 92 pediatric patients undergoing singleton GS over an 18-month period (2016-2017) with two of the following: a condition with high mortality, multisystem disease involving three or more organs, or severe limitation of daily function. Comparative data were collected in a matched historical cohort who underwent traditional investigations in the years 2012-2013. RESULTS: GS yielded a diagnosis in 42% while traditional investigations yielded a diagnosis in 23% (p = 0.003). A change in management was experienced by 74% of patients diagnosed following GS, compared with 32% diagnosed following traditional investigations. Singleton GS at a cost of AU$3100 resulted in a mean saving per person of AU$3602 (95% confidence interval [CI] AU$2520-4685). Cost savings occurred across all investigation subtypes and were only minimally offset by clinical management costs. CONCLUSION: GS in complex pediatric patients saves significant costs and doubles the diagnostic yield of traditional approaches.

Development of a communication aid for explaining hypertrophic cardiomyopathy genetic test results.

BACKGROUND: Large gene panels are now commonplace for hypertrophic cardiomyopathy (HCM), increasing the yield of uncertain genetic findings. Few resources exist which aim to facilitate communication of HCM genetic test results. We sought to develop, pilot, and refine a communication aid for probands receiving HCM genetic test results. METHODS: Development was a multi-step process involving expertise of a multidisciplinary team, literature review, and empirical experience. The aid went through an iterative revision process throughout the piloting phase to incorporate feedback. HCM probands attending a specialized multidisciplinary HCM clinic, aged ≥ 18 years and genetic test results available for disclosure between May and August 2016, or recently received their gene results (January-April 2015) were eligible. A purposive sampling strategy was employed, recruiting those attending clinic during the study period or those who could attend without difficulty. RESULTS: We developed and pilot tested a genetic counsellor-led communication aid. Based on clinical expertise, the aid addresses (a) what genetic testing is, (b) implications for the patient, (c) reasoning for variant classification, and (d) implications for the family. Pilot data were sought to assess knowledge, feasibility, and acceptability using a self-report survey 2 weeks post-intervention. Twelve of 13 participants completed the follow-up questionnaire. Participants valued the individualised nature of the aid, recommended use of the aid, and indicated genetic knowledge, and family communication was better facilitated. Iterative modification of images helped to more simply depict important genetic concepts. CONCLUSIONS: We have developed a tool that is feasible, acceptable, and helpful to patients receiving genetic results. This is an important first step, and trial of the aid to assess effectiveness compared to usual care will follow.