Opportunities and Challenges for Genome Sequencing in the Clinic

Cavalleri, Gianpiero L.; Delanty, Norman

doi:10.1016/b978-0-12-394287-6.00003-3

Cited by 9 publications

(8 citation statements)

References 77 publications

(75 reference statements)

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“…The classic epilepsy genes (ion channel genes/regulatory genes, neurotransmitter genes/receptor genes/regulatory genes, genes that disrupt cortical circuits, and genes that lower the convulsion stimuli) rarely present in genomic data from sequencing studies. This may be because the classical epilepsy mutations are Mendelian, whereas exome sequencing likely targets more polygenic cases, noting that only 1% of epilepsy disorders are inherited in a Mendelian manner (Cavalleri and Delanty, 2012). …”

Section: Discussionmentioning

confidence: 99%

SDS, a structural disruption score for assessment of missense variant deleteriousness

Preeprem

Gibson

2014

Front. Genet.

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We have developed a novel structure-based evaluation for missense variants that explicitly models protein structure and amino acid properties to predict the likelihood that a variant disrupts protein function. A structural disruption score (SDS) is introduced as a measure to depict the likelihood that a case variant is functional. The score is constructed using characteristics that distinguish between causal and neutral variants within a group of proteins. The SDS score is correlated with standard sequence-based deleteriousness, but shows promise for improving discrimination between neutral and causal variants at less conserved sites. The prediction was performed on 3-dimentional structures of 57 gene products whose homozygous SNPs were identified as case-exclusive variants in an exome sequencing study of epilepsy disorders. We contrasted the candidate epilepsy variants with scores for likely benign variants found in the EVS database, and for positive control variants in the same genes that are suspected to promote a range of diseases. To derive a characteristic profile of damaging SNPs, we transformed continuous scores into categorical variables based on the score distribution of each measurement, collected from all possible SNPs in this protein set, where extreme measures were assumed to be deleterious. A second epilepsy dataset was used to replicate the findings. Causal variants tend to receive higher sequence-based deleterious scores, induce larger physico-chemical changes between amino acid pairs, locate in protein domains, buried sites or on conserved protein surface clusters, and cause protein destabilization, relative to negative controls. These measures were agglomerated for each variant. A list of nine high-priority putative functional variants for epilepsy was generated. Our newly developed SDS protocol facilitates SNP prioritization for experimental validation.

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Section: Discussionmentioning

confidence: 99%

SDS, a structural disruption score for assessment of missense variant deleteriousness

Preeprem

Gibson

2014

Front. Genet.

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“…Advances in our understanding of the genetics of the epilepsies is increasing apace, and much of previously unexplained epilepsy is now known to be due to underlying individually rare but collectively common pathogenic mutations across the human genome . These exciting advances in our understanding of the epilepsies are posing opportunities but also challenges for treating clinicians, and for patients and families . The potential to understand at a molecular level the reason for a particular patient's epilepsy, and to use this information to inform on precision therapy will become a significant advance in the way we practice clinical epileptology .…”

Section: Introductionmentioning

confidence: 99%

“…1,2 These exciting advances in our understanding of the epilepsies are posing opportunities but also challenges for treating clinicians, and for patients and families. 3 The potential to understand at a molecular level the reason for a particular patient's epilepsy, and to use this information to inform on precision therapy will become a significant advance in the way we practice clinical epileptology. 4 In parallel, the cost of next-generation sequencing (NGS) is dropping and becoming cost-effective in the clinic, and routine early diagnostic sequencing may soon accompany magnetic resonance imaging (MRI) and electroencephalography (EEG) as standard of care for many of our patients.…”

Section: Introductionmentioning

confidence: 99%

Development of a genomics module within an epilepsy‐specific electronic health record: Toward genomic medicine in epilepsy care

et al. 2019

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Objectives Both clinical genomics and e‐Health technology are changing the way medicine is being practiced. Although the basic clinical methodology of good medical care will remain unchanged, the combined power of genomics and electronic health records has the capability of enhancing, and in some cases transforming, the practice of medicine. This is particularly true in the care of patients with complex long‐term medical conditions such as chronic refractory epilepsy, especially in those with related complex comorbidities including intellectual disability and psychiatric disease. Methods Herein we outline the development and integration of an epilepsy genomics module into a preexisting epilepsy electronic patient record (EPR) system. Results We describe how this EPR infrastructure is used to facilitate discussion at multidisciplinary clinical meetings around molecular diagnosis and resulting changes in management. Significance This work illustrates the role of eHealth technology in embedding genomics into the clinical pathway.

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“…In contrast to the limited diagnostic value available from large-scale common variant genome-wide association studies [8], next-generation sequencing technologies have achieved high rates of molecular diagnoses for individuals living with epilepsy [9]. Among the rare paediatric epilepsies, for example, more than 30% of individuals with an epileptic encephalopathy obtain a molecular diagnosis on the basis of a single dominant-acting de novo mutation in a known epilepsy gene [10].…”

Section: Next-generation Sequencing In Epilepsy: Accurate Diagnosis Amentioning

confidence: 99%

“…The epilepsy research community is starting to think beyond the traditional approach of using “blunderbuss” seizure-suppressing drugs (e.g., sodium channel blockers) and look at other compounds (both novel and re-purposed chemical entities) that may tackle the fundamental molecular defect of an individual's epilepsy [9]. …”

Section: The Emergence Of Precision Therapeutics In Rare Epilepsy Synmentioning

confidence: 99%

eHealth as a Facilitator of Precision Medicine in Epilepsy

Cavalleri¹,

Petrovski²,

Fitzsimons³

et al. 2017

Biomed Hub

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Epilepsy is a chronic neurological condition that affects approximately 50 million people worldwide. Current treatments are inadequate and around a third of patients continue to experience uncontrolled seizures. The genetic architecture of many of the epilepsies makes them amenable to next-generation sequencing technologies, enabling a molecular diagnosis in an increasing proportion of patients. As a result, rare but remarkable examples of precision therapeutics in epilepsy are emerging. Coordinated research efforts are required to increase the diagnostic yield of sequencing and translate diagnosis to improved prognosis. This review explores the potential of eHealth technologies in facilitating and accelerating precision therapeutics in epilepsy. We describe the state of the art in precision diagnostics and therapeutics in epilepsy and identify opportunities for eHealth to accelerate the realisation of precision therapeutics via patient registries, research-enabled electronic health records, and connected health solutions.

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Opportunities and Challenges for Genome Sequencing in the Clinic

Cited by 9 publications

References 77 publications

SDS, a structural disruption score for assessment of missense variant deleteriousness

SDS, a structural disruption score for assessment of missense variant deleteriousness

Development of a genomics module within an epilepsy‐specific electronic health record: Toward genomic medicine in epilepsy care

eHealth as a Facilitator of Precision Medicine in Epilepsy

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