Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.
The IGM N-of-One Diagnostic
Interpretation for Genetic Disorders
Prepared by: Slavé Petrovski and David B. Goldstein
Insti...
The IGM trio framework is divided into Tier 1 and Tier 2:
Tier 1: takes the philosophy that it's unlikely that we will fin...
N-of-One Clinical Sequencing for Genetic Disorders
Trio exome sequencing
Identify qualifying genotypes
Genetic diagnosis G...
Making A Genetic Diagnosis
• Based on known gene-disease associations in human
1. Known human disease gene (OMIM)
2. Disea...
Bioinformatics Signatures
Rank FLAG DNMs HEMIZ HOMOZ CMPDHET
High KnownVar Yes Yes Yes Yes
High Indel KnownVar Yes Yes Yes...
Additional Screens (Periodically assessed)
1. Non-trio interpretation.
2. Regenerate qualifying genotypes and bioinformati...
Upcoming SlideShare
Loading in …5
×

The IGM N-of-One Diagnostic Interpretation for Genetic Disorders

3,498 views

Published on

The IGM N-of-One Diagnostic Interpretation for Genetic Disorders.

Published in: Healthcare
  • I have always found it hard to meet the requirements of being a student. Ever since my years of high school, I really have no idea what professors are looking for to give good grades. After some google searching, I found this service ⇒ www.WritePaper.info ⇐ who helped me write my research paper. The final result was amazing, and I highly recommend ⇒ www.WritePaper.info ⇐ to anyone in the same mindset as me.
       Reply 
    Are you sure you want to  Yes  No
    Your message goes here

The IGM N-of-One Diagnostic Interpretation for Genetic Disorders

  1. 1. The IGM N-of-One Diagnostic Interpretation for Genetic Disorders Prepared by: Slavé Petrovski and David B. Goldstein Institute for Genomic Medicine (IGM), Columbia University sp3347@cumc.columbia.edu
  2. 2. The IGM trio framework is divided into Tier 1 and Tier 2: Tier 1: takes the philosophy that it's unlikely that we will find individiuals among the general population that share the same pathogenic genotype(s) as a proband with a severe undiagnosed genetic disorder. Tier 2: accepts that above can infrequently happen due to various biological and artifactual reasons and helps identify such events. Tier 2 is similarly more permissive to coverage and quality metrics. The IGM internal controls of convenience for diagnostic sequencing are selected on the basis of NOT being ascertained for neurodev., neuropsych., immunological, dysmorphic, early onset, or severe Mendelian disorders. The IGM places a strong emphasis on support from population genetic data and does develop bioinformatics signatures to aid interpretation of genetic variation. This is where our philosophy can slightly differ to other Centers.
  3. 3. N-of-One Clinical Sequencing for Genetic Disorders Trio exome sequencing Identify qualifying genotypes Genetic diagnosis Genetic candidate (GUS) Tier 1: Conservative (↑specificity) • Absent among parents & controls • Non-synonymous CCDS only • Highest QC (coverage, etc.). Tier 2: Liberal (↑sensitivity) •Low Genotype frequency in controls •Include IEB & non-CCDS transcripts •Reduce Coverage and QC thresholds Generally only done for: Previously reported variants or LoF variants in known HI genes. Research N-of-One Candidate • Follow Literature • Gene Matchmaking • Functional Work? 1) Visually Inspect 2) Sanger Validate Bioinformatics Signature GUS
  4. 4. Making A Genetic Diagnosis • Based on known gene-disease associations in human 1. Known human disease gene (OMIM) 2. Disease phenotype overlaps with the patient’s clinical features 3. Genetic model is consistent with known genotype-phenotype relationship 4. Qualifying mutation has been reported or is of the same class as those that have been reported (e.g., loss-of-function mutation in a haploinsufficient gene) 5. Has to be agreement between genetics team and treating clinician(s) 6. Independent Sanger validation (CLIA) • Richards S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in Medicine (2015) • MacArthur DG, et al. Guidelines for investigating causality of sequence variants in human disease. Nature (2014)
  5. 5. Bioinformatics Signatures Rank FLAG DNMs HEMIZ HOMOZ CMPDHET High KnownVar Yes Yes Yes Yes High Indel KnownVar Yes Yes Yes Yes High LoF_inLoFClinVar/Gene Yes Yes Yes Yes High HotZone CCDS Essential Yes Yes Yes Double High Non-Syn in MGI Seizure Ortholog Yes Yes Yes Yes High Exceptional recessive LoF genotype - - Yes Double Moderate 2bp +/- KnownVar Yes Yes Yes Yes Moderate HotZone CCDS Yes Yes Yes Double Moderate LoF_inLoFintol [FDR<0.01] Yes Yes Yes Yes Moderate Non-Syn in Intolerant, Essential, Constrain gene Yes Yes Yes Double Moderate Exceptional recessive LoF genotype; 1 LoF allele - - Yes Yes Low Non-Syn with Global Intolerance score <50%tile Yes Yes Yes Double Low Variant in OMIM disease-associated gene Yes Yes Yes Yes Low Recessive Non-Syn genotype in a Carrier Gene - Yes Yes Double
  6. 6. Additional Screens (Periodically assessed) 1. Non-trio interpretation. 2. Regenerate qualifying genotypes and bioinformatics signatures based on most recent literature and knowledge. 3. Relink to most recent instances of pathogenic variant databases. 4. Relink to most recent OMIM gene-disease associations. 5. Run a Parental Mosaic inheritance screen. 6. Generate an incomplete penetrance screen (permitted to be present in unaffected parent).

×