Genetic testing and genetic counseling for amyotrophic lateral sclerosis: an update for clinicians

Roggenbuck, Jennifer; Quick, Adam; Kolb, Stephen J.

doi:10.1038/gim.2016.107

Cited by 69 publications

(91 citation statements)

References 74 publications

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“…Any human population sample, whether an ALS cohort (Cirulli et al 2015;Ozoguz et al 2015) or other disease cohort (Lek et al 2016), carry many rare genetic variants. If not efficiently examined, this heterogeneity can increase the difficulty and cost of genetic diagnosis, which remains a key barrier for implementation in the clinical setting (Roggenbuck et al 2016). The use of single variant tests in clinical diagnostic laboratories is limited for ALS given the breadth of diseasecausing variants that have been identified.…”

Section: Discussionmentioning

confidence: 99%

Whole exome sequencing and DNA methylation analysis in a clinical amyotrophic lateral sclerosis cohort

Garton

Benyamin

Zhao

et al. 2017

Molec Gen & Gen Med

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BackgroundGene discovery has provided remarkable biological insights into amyotrophic lateral sclerosis (ALS). One challenge for clinical application of genetic testing is critical evaluation of the significance of reported variants.MethodsWe use whole exome sequencing (WES) to develop a clinically relevant approach to identify a subset of ALS patients harboring likely pathogenic mutations. In parallel, we assess if DNA methylation can be used to screen for pathogenicity of novel variants since a methylation signature has been shown to associate with the pathogenic C9orf72 expansion, but has not been explored for other ALS mutations. Australian patients identified with ALS‐relevant variants were cross‐checked with population databases and case reports to critically assess whether they were “likely causal,” “uncertain significance,” or “unlikely causal.”ResultsPublished ALS variants were identified in >10% of patients; however, in only 3% of patients (4/120) could these be confidently considered pathogenic (in SOD1 and TARDBP). We found no evidence for a differential DNA methylation signature in these mutation carriers.ConclusionsThe use of WES in a typical ALS clinic demonstrates a critical approach to variant assessment with the capability to combine cohorts to enhance the largely unknown genetic basis of ALS.

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Section: Discussionmentioning

confidence: 99%

Whole exome sequencing and DNA methylation analysis in a clinical amyotrophic lateral sclerosis cohort

Garton

Benyamin

Zhao

et al. 2017

Molec Gen & Gen Med

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“…The identification of multiple novel genes in ALS and the newly recognized link between ALS and frontotemporal dementia have resulted in the need to incorporate genetic counseling into multidisciplinary ALS care 16,90,91…”

Section: Introductionmentioning

confidence: 99%

Amyotrophic lateral sclerosis: improving care with a multidisciplinary approach

Hogden¹,

Foley²,

Henderson³

et al. 2017

JMDH

131

107

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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease, leading to death within an average of 2–3 years. A cure is yet to be found, and a single disease-modifying treatment has had a modest effect in slowing disease progression. Specialized multidisciplinary ALS care has been shown to extend survival and improve patients’ quality of life, by providing coordinated interprofessional care that seeks to address the complex needs of this patient group. This review examines the nature of specialized multidisciplinary care in ALS and draws on a broad range of evidence that has shaped current practice. The authors explain how multidisciplinary ALS care is delivered. The existing models of care, the role of palliative care within multidisciplinary ALS care, and the costs of formal and informal care are examined. Critical issues of ALS care are then discussed in the context of the support rendered by multidisciplinary-based care. The authors situate the patient and family as key stakeholders and decision makers in the multidisciplinary care network. Finally, the current challenges to the delivery of coordinated interprofessional care in ALS are explored, and the future of coordinated interprofessional care for people with ALS and their family caregivers is considered.

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“…The C9orf72 repeat expansion is the most common genetic cause of MND. This is reported to account for about 40% of familial and about 7% of sporadic disease, 31 , 32 but the exact frequency of MND‐related genes varies between different populations and specific data on prevalence in Australia are still limited. Preliminary national studies identified C9ORF72 mutation in 38.5% of familial cases and 3.5% of sporadic cases 33 .…”

Section: Genetics: New Insightsmentioning

confidence: 99%

“…Preliminary national studies identified C9ORF72 mutation in 38.5% of familial cases and 3.5% of sporadic cases 33 . There are also some shared clinical traits in these patients, who are typically of northern European descent and who clinically often have neuropsychiatric symptoms, including frank FTD 32 , 33 . There is also a suggestion of higher frequency of bulbar‐onset disease, earlier age of symptom onset, and more rapid disease progression 26 , 32 …”

Section: Genetics: New Insightsmentioning

confidence: 99%

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Motor neurone disease: progress and challenges

Dharmadasa

Henderson

Talman

et al. 2017

Medical Journal of Australia

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Major progress has been made over the past decade in the understanding of motor neurone disease (MND), changing the landscape of this complex disease. Through identifying positive prognostic factors, new evidence-based standards of care have been established that improve patient survival, reduce burden of disease for patients and their carers, and enhance quality of life. These factors include early management of respiratory dysfunction with non-invasive ventilation, maintenance of weight and nutritional status, as well as instigation of a multidisciplinary team including neurologists, general practitioners and allied health professionals. Advances in technology have enhanced our understanding of the genetic architecture of MND considerably, with implications for patients, their families and clinicians. Recognition of extra-motor involvement, particularly cognitive dysfunction, has identified a spectrum of disease from MND through to frontotemporal dementia. Although riluzole remains the only disease-modifying medication available in clinical practice in Australia, several new therapies are undergoing clinical trials nationally and globally, representing a shift in treatment paradigms. Successful translation of this clinical research through growth in community funding, awareness and national MND research organisations has laid the foundation for closing the research-practice gap on this debilitating disease. In this review, we highlight these recent developments, which have transformed treatment, augmented novel therapeutic platforms, and established a nexus between research and the MND community. This era of change is of significant relevance to both specialists and general practitioners who remain integral to the care of patients with MND.

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Genetic testing and genetic counseling for amyotrophic lateral sclerosis: an update for clinicians

Cited by 69 publications

References 74 publications

Whole exome sequencing and DNA methylation analysis in a clinical amyotrophic lateral sclerosis cohort

Whole exome sequencing and DNA methylation analysis in a clinical amyotrophic lateral sclerosis cohort

Amyotrophic lateral sclerosis: improving care with a multidisciplinary approach

Motor neurone disease: progress and challenges

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