Evaluating genetic and genomic tests for heritable conditions in Australia: lessons learnt from health technology assessments

AbstractThe Medical Services Advisory Committee (MSAC) is an independent non-statutory committee established by the Australian government to provide recommendations on public reimbursement of technologies and services, other than pharmaceuticals. MSAC has established approaches for undertaking health technology assessment (HTA) of investigative services and codependent technologies. In 2016, MSAC published its clinical utility card (CUC) Proforma, an additional tool to guide assessments of genetic testing for heritable conditions. We undertook a review and narrative synthesis of information extracted from all MSAC assessments of genetic testing for heritable conditions completed since 2016, regardless of the HTA approach taken. Ten assessments met our inclusion criteria, covering a range of testing methods (from gene panels to whole-exome sequencing) and purposes (including molecular diagnosis, genetic risk assessment, identification of congenital anomaly syndromes, and carrier screening). This analysis identified a range of methodological and policy challenges such as how to incorporate patient and societal preferences for the health and non-health outcomes of genomic testing, how best to capture the concept of co-production of utility, and how to engage clinicians as referrers for genomics tests whilst at the same time ensuring equity of access to a geographically dispersed population. A further challenge related to how qualitative assessments of patient and community needs influenced the evidence thresholds against which decisions were made. These concepts should be considered for incorporation within the value assessment frameworks used by HTA agencies around the world.

Download Full-text

P.057 Solely neonatal hypoxic ischemic encephalopathy or more? A study examining genetic predisposition towards a clinical picture of HIE

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2019.157 ◽

2019 ◽

Vol 46 (s1) ◽

pp. S29

Author(s):

KE Woodward ◽

P Murthy ◽

A Mineyko ◽

K Mohammad ◽

M Esser

Keyword(s):

Risk Factors ◽

Genetic Testing ◽

Significant Risk ◽

Hypoxic Ischemic Encephalopathy ◽

Whole Exome ◽

Clinical Phenomenon ◽

Preliminary Study ◽

Or Gene ◽

Gene Panels ◽

Ischemic Encephalopathy

Background: Neonatal hypoxic ischemic encephalopathy (HIE) is a clinical phenomenon, that often results from pre or perinatal reduced cerebral blood flow and/or hypoxemia. However, in some cases, neonates present with HIE without significant risk factors or have an unusual clinical course. With the advent of advanced genetic testing, we aimed to explore if such infants had genetic risk factors predisposing them to an HIE-phenotype. Methods: We reviewed 206 charts of infants meeting local protocol criteria for moderate to severe HIE at Level III NICU’s in Calgary, Alberta. Of these, 27 patients had genetic testing such as microarray, whole exome sequencing, or gene panels. Results: Six/twenty-seven patients had genetic mutations; two CDKL5 mutations (protein kinase), one CFTR mutation (cystic fibrosis), one PDH deficiency, one CYP21A2 mutation (congenital adrenal hyperplasia), and one ISY1 (VUS; pre-mRNA splicing). Two patients had noted difficult deliveries and four had minor complications, but all were out of keeping with the severity of presumed HIE. Conclusions: This preliminary study demonstrates a possible association between genetic co-morbidities and predisposition towards HIE in the context of a relatively uneventful pre/perinatal course. Earlier identification of genetic etiology, recognized by a discrepancy between risk factors and clinical presentation, could aid in treatment decisions and outcome prognostication.

Download Full-text

Challenges and Controversies in the Genetic Diagnosis of Hereditary Spastic Paraplegia

Current Neurology and Neuroscience Reports ◽

10.1007/s11910-021-01099-x ◽

2021 ◽

Vol 21 (4) ◽

Author(s):

Lydia Saputra ◽

Kishore Raj Kumar

Keyword(s):

Genetic Diagnosis ◽

Spastic Paraplegia ◽

Limb Weakness ◽

Hereditary Spastic Paraplegias ◽

Gene Testing ◽

Testing Strategies ◽

Whole Exome ◽

The Right ◽

Gene Panels ◽

High Degree

Abstract Purpose of Review The hereditary spastic paraplegias (HSPs) are a group of disorders characterised by progressive lower limb weakness and spasticity. We address the challenges and controversies involved in the genetic diagnosis of HSP. Recent Findings There is a large and rapidly expanding list of genes implicated in HSP, making it difficult to keep gene testing panels updated. There is also a high degree of phenotypic overlap between HSP and other disorders, leading to problems in choosing the right panel to analyse. We discuss genetic testing strategies for overcoming these diagnostic hurdles, including the use of targeted sequencing gene panels, whole-exome sequencing and whole-genome sequencing. Personalised treatments for HSP are on the horizon, and a genetic diagnosis may hold the key to access these treatments. Summary Developing strategies to overcome the challenges and controversies in HSP may hold the key to a rapid and accurate genetic diagnosis.

Download Full-text

Abstract 16468: Results of Research Genetic Testing in Pediatric Cardiomyopathy Patients Justify Broader Clinical Genetic Testing

Circulation ◽

10.1161/circ.132.suppl_3.16468 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Stephanie M Ware ◽

Steven E Lipshultz ◽

Steven D Colan ◽

Ling Shi ◽

Charles E Canter ◽

...

Keyword(s):

Genetic Testing ◽

Family History ◽

Risk Stratification ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Clinical Genetic ◽

Clinical Genetic Testing ◽

Whole Exome ◽

Pediatric Cardiomyopathy ◽

History Of

Introduction: Pediatric cardiomyopathies are genetically heterogeneous diseases with high risk of death or cardiac transplant. Despite progress in identifying causes, the majority of cases remain idiopathic. Currrently, genetic testing is not performed in all children with cardiomyopathy. Gene identification leads to better individual risk stratification and has the potential to stimulate the development of therapies based on the underlying mutation. The aim of this study is to identify genetic mutations in pediatric cardiomyopathy patients using whole exome sequencing. Hypothesis: Sarcomeric mutations are under-diagnosed causes of all forms of cardiomyopathy in children. Methods: Probands with cardiomyopathy were recruited from 11 institutions. Results of clinical genetic testing prior to enrollment were collected. Whole exome sequencing was performed and mutations were identified in 35 genes currently available on clinical genetic testing panels. Results: The initial 154 probands subjected to exome included 78 patients with DCM, 43 with HCM, 14 with RCM, and 19 with LVNC, mixed, or unknown types. Familial disease was present in 38% and the remainder were idiopathic. Twenty-seven percent had positive clinical genetic testing prior to enrollment. Exome testing identified mutations in 38 subjects who had not had clinical testing, increasing the cohort positive testing rate to 55% (DCM, 34.6%; HCM, 74.4%; RCM, 71.4%). Forty-five percent of subjects with no family history of disease had an identifiable mutation. Conclusions: Pediatric cardiomyopathy patients have a high incidence of mutations that can be identified by clinically available genetic testing. Lack of a family history of cardiomyopathy was not predictive of normal genetic testing. These results support the broader use of genetic testing in pediatric patients with all functional phenotypes of cardiomyopathy to identify disease causation allowing better family risk stratification.

Download Full-text

Fundoscopy-directed genetic testing to re-evaluate negative whole exome sequencing results

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-020-1312-1 ◽

2020 ◽

Vol 15 (1) ◽

Cited By ~ 1

Author(s):

Ahra Cho ◽

Jose Ronaldo Lima de Carvalho ◽

Akemi J. Tanaka ◽

Ruben Jauregui ◽

Sarah R. Levi ◽

...

Keyword(s):

Genetic Testing ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Whole Exome

Download Full-text

Analysis of tumor mutational burden: correlation of five large gene panels with whole exome sequencing

Scientific Reports ◽

10.1038/s41598-020-68394-4 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Carina Heydt ◽

Jan Rehker ◽

Roberto Pappesch ◽

Theresa Buhl ◽

Markus Ball ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Large Gene ◽

Mutational Burden ◽

Whole Exome ◽

Tumor Mutational Burden ◽

Gene Panels

Download Full-text

P0066KIDNEYCODE: A GENETIC TESTING PROGRAM FOR PATIENTS WITH CHRONIC KIDNEY DISEASE

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0066 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Prasad Devarajan ◽

Geoffrey Block ◽

Keisha Gibson ◽

Jim McKay ◽

Colin Meyer ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Genetic Testing ◽

Kidney Disease ◽

Exome Sequencing ◽

Polycystic Kidney Disease ◽

Whole Exome Sequencing ◽

Alport Syndrome ◽

Polycystic Kidney ◽

Accuracy And Precision ◽

Whole Exome

Abstract Background and Aims Knowledge about genetic causes of chronic kidney disease (CKD) is one of the key gaps in global kidney research and recent International Society of Nephrology recommendations encourage the adoption of genetic testing to enable a goal of providing precision medicine based on individual risk (1). A recent whole-exome sequencing study showed that genetic inheritance may be responsible for up to 10% of CKD diagnoses, many of which may be previously undiagnosed or mis-diagnosed (2). Continued advances in DNA sequencing technology have made genetic testing, even whole-exome sequencing, applicable to routine clinical diagnoses. In order to test the hypothesis that genetic testing can provide valuable information to increase the accuracy and precision of diagnosis in CKD, we designed a gene panel to prospectively provide genetic testing in a subset of patients with CKD defined by a specific set of inclusion criteria. Method Reata Pharmaceuticals is partnering with Invitae on a program called KidneyCode, which provides no-charge genetic testing to enable diagnosis of three specific rare monogenic causes of CKD: Alport syndrome (AS), autosomal dominant polycystic kidney disease (ADPKD) due to PKD2 mutations, and focal segmental glomerulosclerosis (FSGS), as well as detection of variants in one of the autosomal recessive polycystic kidney disease gene, PKHD1. Invitae’s renal disease panel includes 17 genes (ACTN4, ANLN, CD2AP, COL4A3, COL4A4, COL4A5, CRB2, HNF1A, INF2, LMX1B, MYO1E, NPHS1, NPHS2, PAX2, PKD2, PKHD1, and TRPC6), and its assay includes both full-gene sequencing and intragenic deletion/duplication analysis using next-generation sequencing (NGS). The assay targets the coding exons and flanking 10bp of intronic sequences. Invitae’s method of variant classification uses a systematic process for assessing evidence based on guidelines published by the American College of Medical Genetics (3). Patients in the US at risk for hereditary CKD (eGFR ≤ 90 mL/min/1.73m2 plus hematuria or a family history of CKD) or with a known diagnosis of AS or FSGS are eligible. Family members of those with suspected or known AS or FSGS are also eligible. All participants in the KidneyCode program have access to genetic counseling follow-up at no additional charge. Results In the first five months of the KidneyCode program, 152 genetic tests have been completed. A genetic variant was reported in 87 patients. Of those 87 patients, 67 patients had 75 variants in COL4A3, 4, or 5 genes (34 Pathogenic/Likely Pathogenic (P/LP), 41 Variants of Uncertain Significance (VUS)), 20 patients had 24 variants in genes associated with FSGS (3 P/LP, 21 VUS), 15 patients had 20 variants in PKHD1 (1 P/LP, 19 VUS), and 2 patients had variants in PKD2 (1 P/LP, 1 VUS). Of the 34 patients with Pathogenic or Likely Pathogenic COL4A variants, 19 reported a previous diagnosis of Alport syndrome. Other diagnoses in patients with COL4A mutations included FSGS, thin basement membrane disease, and familial hematuria. Extra-renal manifestations such as hearing loss and eye disease were reported in 7 of the 34 patients with COL4A variants. Conclusion Initial results with the KidneyCode panel demonstrate the utility of NGS and support the hypothesis that combining genetic testing with clinical presentation and medical history can significantly improve accuracy and precision of diagnosis in patients with hereditary CKD.

Download Full-text

Új módszertani lehetőségek és ezek alkalmazása a hormonális rendszer daganatainak genetikai kivizsgálásában

Orvosi Hetilap ◽

10.1556/650.2015.30316 ◽

2015 ◽

Vol 156 (51) ◽

pp. 2063-2069

Author(s):

Attila Patócs ◽

István Likó ◽

Henriett Butz ◽

Kornélia Baghy ◽

Károly Rácz

Keyword(s):

Genetic Testing ◽

Ethical Issues ◽

Genetic Alterations ◽

Clinical Genetic ◽

Patients With Cancer ◽

Clinical Genetic Testing ◽

Technical Developments ◽

Whole Exome ◽

Genetically Determined ◽

Genome Scale

The technical developments leading to revolution in clinical genetic testing offer new approaches for patients with cancer. From one mutation or one gene approach the scale of genetic testing moved to whole exome or whole genome scale. It is well known that many tumours are genetically determined ans they are part of familial tumour syndromes. In addition, some mutations indicate specific molecular targeted therapies. Although sampling and sample preparation are different for testing germline and somatic mutations, the technical background of the analysis is the same. The aim of clinical genetic testing is to identify patients who are carriers of disease-causing mutations or to test tumour tissue for the presence of genetic alterations which may be targets for therapeutic approaches. In this review the authors summarize novel possibilities offered by next-generation sequencing in clinical genetic testing of patients with endocrine tumours. In addition, the authors review recent guidelines on technical and ethical issues related to these novel methods. Orv. Hetil., 2015, 156(51), 2063–2069.

Download Full-text

Genetic counselling

10.1093/med/9780198784906.003.0145 ◽

2018 ◽

Author(s):

Jodie Ingles ◽

Charlotte Burns ◽

Laura Yeates

Keyword(s):

Genetic Testing ◽

Genetic Counselling ◽

Psychosocial Care ◽

Clinical Psychologist ◽

Master's Level ◽

Large Panels ◽

Sequencing Technologies ◽

Whole Exome ◽

Genetic Test Results ◽

Post Test

Cardiac genetic counselling is an emerging but important subspecialty. The qualifications of cardiac genetic counsellors depend on the country of practice, but at a minimum they are Master’s-level trained health professionals with expertise in genetics, and are integral members of the multidisciplinary inherited cardiovascular disease clinic. Though the framework is diverse in different countries, key roles include investigation and confirmation of family history details, discussion of inheritance risks and facilitation of cardiac genetic testing, communication with at-risk relatives, and increasingly, curation of genetic test results. The use of next-generation sequencing technologies has seen a recent shift in the uptake of genetic testing, due to greater availability and lowered costs. As these gene tests become more comprehensive, including large panels of genes and even whole exome or whole genome sequencing, the need for cardiac genetic counsellors to provide informed consent, appropriate pre- and post-test genetic counselling, and ongoing curation of the variants identified is evident. Finally, given the improved understanding of the psychological implications of living with a cardiovascular genetic disease, cardiac genetic counsellors are integral in delivering psychosocial care and identifying patients requiring intervention with a clinical psychologist.

Download Full-text

Practical guide to genetic screening for inherited eye diseases

Therapeutic Advances in Ophthalmology ◽

10.1177/2515841420954592 ◽

2020 ◽

Vol 12 ◽

pp. 251584142095459

Author(s):

Cécile Méjécase ◽

Samantha Malka ◽

Zeyu Guan ◽

Amy Slater ◽

Gavin Arno ◽

...

Keyword(s):

Genetic Screening ◽

Treatment Options ◽

Genomic Medicine ◽

Genetic Diagnosis ◽

Eye Diseases ◽

Practical Guide ◽

Whole Exome ◽

Post Test ◽

Pros And Cons ◽

Gene Panels

Genetic eye diseases affect around one in 1000 people worldwide for which the molecular aetiology remains unknown in the majority. The identification of disease-causing gene variant(s) allows a better understanding of the disorder and its inheritance. There is now an approved retinal gene therapy for autosomal recessive RPE65-retinopathy, and numerous ocular gene/mutation-targeted clinical trials underway, highlighting the importance of establishing a genetic diagnosis so patients can fully access the latest research developments and treatment options. In this review, we will provide a practical guide to managing patients with these conditions including an overview of inheritance patterns, required pre- and post-test genetic counselling, different types of cytogenetic and genetic testing available, with a focus on next generation sequencing using targeted gene panels, whole exome and genome sequencing. We will expand on the pros and cons of each modality, variant interpretation and options for family planning for the patient and their family. With the advent of genomic medicine, genetic screening will soon become mainstream within all ophthalmology subspecialties for prevention of disease and provision of precision therapeutics.

Download Full-text