Clinician s Guide to Actionable Genes and Genome Interpretation

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Clinician s Guide to Actionable Genes and Genome Interpretation Brandy Bernard PhD Senior Research Scientist Institute for Systems Biology Seattle, WA Dr.

1 Clinician s Guide to Actionable Genes and Genome Interpretation Brandy Bernard PhD Senior Research Scientist Institute for Systems Biology Seattle, WA Dr. Bernard s research interests are in cancer drug discovery and clinical genomics. He is currently a part of the ISB Genome Data Analysis Center (GDAC) within The Cancer Genome Atlas (TCGA) network. During this time, he has developed novel computational methods and analyses in support of TCGA network research and publications, and has provided scientific guidance for the data exploration tools and algorithms developed by the team. Dr. Bernard has led the group s research efforts and contributions to several TCGA Analysis Working Groups, particularly in the area of heterogeneous data integration and graph analysis. In collaboration with experts in functional genomics he has integrated TCGA and RNAi screening data to prioritize novel targets and tumor types for drug discovery and repurposing. His research in the area of cancer genomics has resulted in several proffered presentations at TCGA symposia and AACR meetings on distinct topics, a First Prize in the YarcData Graph Analytics Challenge, and a Life Science Discovery Fund grant to further the development of our cancer genomics web portals. In the area of clinical genomics, Dr. Bernard co-leads a collaboration with Inova Translational Medicine Institute (ITMI) to provide analytic support and develop scalable infrastructure for the integration of clinical data with whole genome sequences and molecular data from thousands of patients. Related to this effort, Dr. Bernard has worked with the PRE-EMPT Global Pregnancy Collaboration (CoLab) as well as the Crohn s and Colitis Foundation of America (CCFA) to advise in the study design and infrastructure of large-scale clinical genomics programs. Annual Quality Congress Breakout Session, Saturday, October 3, 2015 Clinician s Guide to Actionable Genes and Genome Interpretation Objective: Define actionable genes.

2 Disclosure Clinical Genomics: Actionable genes & Genome interpretation Sr. Research Scientist Brady Bernard does not have any financial arrangement or affiliations with a commercial entity. Brady Bernard will not be discussing the unlabeled use of a commercial product in her presentation. Discussion topics Given a genome sequence, consider: What is actionable What can or should be reported With clinical or phenotypic data, how is genomics being being utilized as a tool What is the distinction between genes and genomic variation for clinical genomics What are the approaches and challenges for analysis and interpretation Actionable How would you define it? How does this relate specifically to genomics in the clinic? *What will not be covered* Ethics, legal, or social consideration & implications Specific tools, technologies, or detailed bioinformatics methods What others have to say Actionable results and genes Actionable result : a result for which there is a specific clinical action to be taken for prevention or treatment of a medical condition. (Yu et al. AJHG 2014) Actionable genes : defined as having deleterious variant(s) whose penetrance would result in specific, defined medical recommendation(s) that are supported by evidence, the implementation of which would be expected to avoid significant morbidity and mortality (Dorschner et al. AJHG 2013, Amendola et al. Genome Research 2015) Additional considerations Different stages or trajectories of health and disease Prediction, prevention, diagnosis, intervention, and drug selection Each has value in the clinic Depending on the institution, the following examples may not be considered actionable (Berg et al. Genet Med 2013): Carrier status Pharmacogenetic associations (low probability of receiving a drug and available testing; P450 2C19) Late onset diseases Asymptomatic patients (low penetrance; NF1) Diseases that are diagnosable by standard techniques upon presentation (familial Mediterranean fever) Perinatal and Family environment Does family planning make almost anything actionable? October 3,

Actionability and genomics Simplified definition Any genomic information, supported by evidence, that may be useful to

sequence, consider: What is actionable What can or should be reported With clinical or phenotypic data, how is

genomics Approaches and challenges for analysis and interpretation Types of findings Solomon (NEJM 2014) Reporting

potential for the recognition and reporting of incidental or secondary findings unrelated to the indication for

Recommendations: laboratories performing clinical sequencing should seek and report mutations of the specified classes

3 Actionability and genomics Simplified definition Any genomic information, supported by evidence, that may be useful to the patient This does not imply that reporting such information would be advisable Discussion topics Given a genome sequence, consider: What is actionable What can or should be reported With clinical or phenotypic data, how is genomics being being utilized as a tool What is the distinction between genes and genomic variation for clinical genomics Approaches and challenges for analysis and interpretation Types of findings Solomon (NEJM 2014) Reporting findings American College of Medical Genetics and Genomics (ACMG): In clinical exome and genome sequencing, there is potential for the recognition and reporting of incidental or secondary findings unrelated to the indication for ordering the sequencing but of medical value for patient care. Recommendations: laboratories performing clinical sequencing should seek and report mutations of the specified classes or types in the following genes (Green et al. Genet Med 2013) 56 genes 24 conditions How (and who) to determine known pathogenic (KP) and expected pathogenic (EP) [in a rigorous way]? October 3,

There is not one right answer 2013-56 actionable genes from NGS sequencing (ACMG) 2015-112 actionable

results (i.e., pathogenic variants in specified genes) are a matter of judgment They are decided by a

specialists But for now let s assume we have established a list of actionable genes Discussion topics

phenotypic data, how is genomics being being utilized as a tool What is the distinction between genes and

types of genetic tests Genome sequencing increasingly used as a clinical research tool Katsanis and

Katsanis and Timing of genetic tests An example of cystic fibrosis Newborn screening considerations

4 There is not one right answer actionable genes from NGS sequencing (ACMG) actionable genes (Clinical Sequencing and Exploratory Research NEXT Medicine Return of Results Committee) Actionable results (i.e., pathogenic variants in specified genes) are a matter of judgment They are decided by a (local) expert committee (MDs, medical geneticists and counselors, bioethicists, bioinformatics specialists But for now let s assume we have established a list of actionable genes Discussion topics Given a genome sequence, consider: What is actionable What can or should be reported With clinical or phenotypic data, how is genomics being being utilized as a tool What is the distinction between genes and genomic variation for clinical genomics Approaches and challenges for analysis and interpretation Many types of genetic tests Genome sequencing increasingly used as a clinical research tool Katsanis and Katsanis. (2013). Nat Rev Genet. Katsanis and Katsanis. (2013). Nat Rev Genet. Timing of genetic tests An example of cystic fibrosis Newborn screening considerations Anastasia Wise, PhD (NHGRI) Distinguish between clinical and research purposes, what is actionable, and what should be reported Bodurtha and Strauss (NEJM 2012) October 3,

5 Perinatal relevance Newborn screening 127 selected genes corresponding to all disorders currently/planned to be included in blood-based NBS (Bodian and Solomon) Note: many NBS tests are based on proteomic or other non-genetic tests What is the relationship between these genes and genome sequencing? Distinction between genes and variants LDLR - low density lipoprotein receptor (actionable ACMG gene) Mutations in the gene encoding the LDLR are known to cause familial hypercholesterolaemia (dominant mode of inheritance) Example variant: c.1171g>a (Missense p.ala391thr protein coding) Prevalence of familial hypercholesterolaemia is 0.2%, whereas allele frequency of variant is ~6% Is this pathogenic? Discussion topics Given a genome sequence, consider: What is actionable What can or should be reported With clinical or phenotypic data, how is genomics being being utilized as a tool What is the distinction between genes and genomic variation for clinical genomics Approaches and challenges for analysis and interpretation The crux The role of genes are often characterized in networks/pathways, developmental biology, disease, But which are the pathogenic variants, observed by genome sequencing, that are caused by defects in genes and lead to disease states? Genomic variation quantified How many bases? Genome versus exome Percent of genome that is coding Number of protein-coding genes Biases in what is researched (i.e., looking for coding variants in genes, but other genomic variations are important too) How many variants observed between any two individuals? Genome Exome Goal and challenge Filter from millions of tolerable natural variants to very few, if any, that are pathogenic and actionable How many pathogenic HGMD/CLINVAR annotations are there per genome? How many turn out to be pathogenic? October 3,

6 Given a genome, what to do? Primary finding of candidate variants or reportable incidental findings How can the intended analysis and interpretation utilize prior knowledge? Pre-symptomatic New or indeterminate diagnosis Family history of disorder Finding candidate variants Generally relies on prior literature, annotations, and inheritance Transcript definitions Machine learning classification Quantitative trait loci Genome wide association studies Regulatory and epigenomics Family pedigree segregation analysis Etc. Family-based genomic study design Family genomics: reducing candidate number Utilize family history to find candidate variants Segregating pedigrees of increasing size allow for the identification of fewer candidate variants that match the pattern of inheritance Recessive disorders (including compound heterozygosity) more accurately identified Association testing: Transmission disequilibrium Identify variants that are transmitted to effected offspring more frequently than expected by chance Accounts for population stratification Roach et al. (2010). Science Family genomics: phasing and recessive candidates Challenges with finding candidate variants Penetrance fraction of individuals with variant exhibiting phenotype Mode of inheritance Not always consistent or well defined Annotation quality/accuracy Sensitivity and specificity of pathogenic annotations Genomic heterogeneity of disease Locus (different genes) and Allelic (different locations in gene) heterogeneity Disease prevalence Rare case incidence makes statistical tests irrelevant Roach et al. (2010). Science Age of onset variability Environment, genetics, and epigenetics Etc., etc., October 3,

7 Actionable, Pathogenic Incidental Findings in 1,000 Participants Exomes Among the 1,000 participants, 585 instances of 239 unique variants were identified as disease causing in the Human Gene Mutation Database (HGMD). The primary literature supporting the variants pathogenicity was reviewed. Of the identified incidental findings, only 16 unique autosomal-dominant variants in 17 individuals were assessed to be pathogenic or likely pathogenic, and one participant had two pathogenic variants for an autosomal-recessive disease. Newborn screening 127 selected genes corresponding to all disorders currently/planned to be included in blood-based NBS (Bodian and Solomon) What is the relationship between these genes and genome sequencing? In 702 newborns, there were 2,216 distinct variants in the 127 genes, 229 annotated in HGMD as disease mutations and 128 as pathogenic in ClinVar. Other than hemoglobinopathies, no infants with abnormal standard NBS had a confirmed NBS disorder, concurrent with WGS results. So complex Genome sequencing as an advanced clinical diagnostic and research tool What then is the current role for genome sequencing in the clinic? Katsanis and Katsanis. (2013). Nat Rev Genet. Genomics in the clinic Many existing clinical tests return ambiguous results or are not able to diagnose complex/unprecedented cases Whole genome or exome sequencing, with accompanying annotations, can augment numerous clinical assays with a single test Annotations will continue to improve, finding pathogenic and actionable variants will become more accurate Practical note: research -vs- clinical grade sequencing Differences with cost and process, also Sanger or other CLIA validation strategies Vision and future opportunities 1. Relate clinical data elements (e.g., EMR, surveys) through standardized ontologies to disorders, 2. Combine with large collections of genome sequences, and 3. Learn probabilities of pathogenicity to create a refined knowledgebase of pathogenic variants in clinically actionable genes October 3,

8 2bnh: alpha beta horseshoe 1hv9: left handed beta helix 1m30: SH3 like barrel October 3,

Comments on Use of Databases for Establishing the Clinical Relevance of Human Genetic Variants

Comments on Use of Databases for Establishing the Clinical Relevance of Human Genetic Variants Division of Dockets Management (HFA-305) Food and Drug Administration 5630 Fishers Lane, Rm. 1061 Rockville, MD 20852 The American Society of Human Genetics 9650 Rockville Pike Bethesda, MD 20814 24 December