Neurologist Comfort in the Use of Next-Generation Sequencing Diagnostics

Helman, Guy; Bonkowsky, Joshua L.; Vanderver, Adeline

doi:10.1001/jamaneurol.2016.0168

Cited by 8 publications

(8 citation statements)

References 6 publications

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“…20 Next-generation sequencing is rapidly being implemented into routine clinical practice, improving the diagnostic rate for patients with neuromuscular diseases. [21][22][23] Almost all NGS screenings reveal many rare and private titin variants and their clinical interpretation is particularly challenging. 5,19,[24][25][26] By using MotorPlex (Agilent Technologies), a targeted NGS panel, we screened TTN and the other muscle disease genes in 504 patients with skeletal muscle disorders.…”

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confidence: 99%

Interpreting Genetic Variants in Titin in Patients With Muscle Disorders

Savarese

Maggi²,

Vihola

et al. 2018

JAMA Neurol

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IMPORTANCE Mutations in the titin gene (TTN) cause a wide spectrum of genetic diseases. The interpretation of the numerous rare variants identified in TTN is a difficult challenge given its large size. OBJECTIVE To identify genetic variants in titin in a cohort of patients with muscle disorders. DESIGN, SETTING, AND PARTICIPANTS In this case series, 9 patients with titinopathy and 4 other patients with possibly disease-causing variants in TTN were identified. Titin mutations were detected through targeted resequencing performed on DNA from 504 patients with muscular dystrophy, congenital myopathy, or other skeletal muscle disorders. Patients were enrolled from 10 clinical centers in April 2012 to December 2013. All of them had not received a diagnosis after undergoing an extensive investigation, including Sanger sequencing of candidate genes. The data analysis was performed between September 2013 and January 2017. Sequencing data were analyzed using an internal custom bioinformatics pipeline. MAIN OUTCOMES AND MEASURES The identification of novel mutations in the TTN gene and novel patients with titinopathy. We performed an evaluation of putative causative variants in the TTN gene, combining genetic, clinical, and imaging data with messenger RNA and/or protein studies. RESULTS Of the 9 novel patients with titinopathy, 5 (55.5%) were men and the mean (SD) age at onset was 25 (15.8) years (range, 0-46 years). Of the 4 other patients (3 men and 1 woman) with possibly disease-causing TTN variants, 2 (50%) had a congenital myopathy and 2 (50%) had a slowly progressive distal myopathy with onset in the second decade. Most of the identified mutations were previously unreported. However, all the variants, even the already described mutations, require careful clinical and molecular evaluation of probands and relatives. Heterozygous truncating variants or unique missense changes are not sufficient to make a diagnosis of titinopathy. CONCLUSIONS AND RELEVANCE The interpretation of TTN variants often requires further analyses, including a comprehensive evaluation of the clinical phenotype (deep phenotyping) as well as messenger RNA and protein studies. We propose a specific workflow for the clinical interpretation of genetic findings in titin.

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confidence: 99%

Interpreting Genetic Variants in Titin in Patients With Muscle Disorders

Savarese

Maggi²,

Vihola

et al. 2018

JAMA Neurol

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“…Of the limited studies conducted to date, concerns raised included genomic test access and cost (Helman et al, 2016; Chow-White et al, 2017; Jaitovich Groisman et al, 2017), lack of evidence and clinical guidelines (Bonter et al, 2011; Stanek et al, 2012; Amara et al, 2018), and the potential for genomic tests to cause psychological harm or impede insurance access (Johnson et al, 2017; Deininger et al, 2019; Knapp et al, 2019). These concerns linger from the genetics era, with additional worries arising from the complexity, volume, and uncertain nature of the data generated (Miller et al, 2014; Christensen et al, 2016; Gray et al, 2016; Knapp et al, 2019).…”

Section: Genetics Genomics and Medical Specialists: A Complex Relatmentioning

confidence: 99%

Preparing Medical Specialists to Practice Genomic Medicine: Education an Essential Part of a Broader Strategy

et al. 2019

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Developing a competent workforce will be crucial to realizing the promise of genomic medicine. The preparedness of medical specialists without specific genetic qualifications to play a role in this workforce has long been questioned, prompting widespread calls for education across the spectrum of medical training. Adult learning theory indicates that for education to be effective, a perceived need to learn must first be established. Medical specialists have to perceive genomic medicine as relevant to their clinical practice. Here, we review what is currently known about medical specialists’ perceptions of genomics, compare these findings to those from the genetics era, and identify areas for future research. Previous studies reveal that medical specialists’ views on the clinical utility of genomic medicine are mixed and are often tempered by several concerns. Specialists generally perceive their confidence and understanding to be lacking; subsequently, they welcome additional educational support, although specific needs are rarely detailed. Similar findings from the genetics era suggest that these challenges are not necessarily new but on a different scale and relevant to more specialties as genomic applications expand. While existing strategies developed for genetic education and training may be suitable for genomic education and training, investigating the educational needs of a wider range of specialties is critically necessary to determine if tailored approaches are needed and, if so, to facilitate these. Other interventions are also required to address some of the additional challenges identified in this review, and we encourage readers to see education as part of a broader implementation strategy.

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“…Some focus on genetic concepts (e.g., taking family history) and tests (Jenkins et al, 2010;Calzone et al, 2012) and others are specific to local context (i.e. specialty/discipline or health service) (Bonter et al, 2011;Haga et al, 2012;Stanek et al, 2012;Marzuillo et al, 2013;Helman et al, 2016;Chow-White et al, 2017;Groisman et al, 2017;Johnson et al, 2017;McCauley et al, 2017). For example, Chow-White et al (2017) surveyed oncologists' attitudes towards genomics and McCauley et al (2017) focused only on physician training in genomics.…”

Section: Introductionmentioning

confidence: 99%