Download An informatics approach to analyzing the incidentalome

An informatics approach to
analyzing the incidentalome
J.Berg et al. Genetics in Medicine
Presented by
Li Changjian
Concept
• Incidentalome: Incidental findings of genetic
variants unrelated to presenting symptoms
during the genetic diagnosis using whole
genome sequencing (WGS)
Challenge on Incidentalome
• Reducing cost in WGS makes it available for
genetic diagnosis
• Vast volume of genomic findings with dubious
clinical value is generated, overwhelming of
information to physicians and patients
• A good screening/sifting method for the
genetic data is needed
Binning System
• Categories the genetic data
Subjects & Methods
• Focus: Monogenic Disorders
• OMIM genes for provisional binning (12786
genes)
• 80 genome sequences used as test
sequences, 19 from paints and 61 from
presumably healthy individuals
• Database: PostgreSQL 8.4.3, Human Gene
Mutation Database (HGMD) and NCBI build 37
• Python script used to determine the zygosity
Screening Process of OMIM genes
Provisional
Binning
Allele Frequency
cut-off (AF<5%)
Protein-altering
variants
Further Screening
• Presence in a binned gene
• <5% AF (Low Probability Mendelian Disorder)
• Either being annotated as diseasing-causing
mutation (DM) in HGMD or predicted to be
truncating
• Analyze zygosity to assign heterozygous
variants in recessive genes to determine carrier
status
• Finally, manual review to assess evidence of
pathogenicity, reclassify the binning
Summarized Results
Screening processes of the informatics algorithm
Significant reduction the number of binned genes
Example Results
High specificity for bin 1 and bin 2c variants
Sensitivity and Specificity
• Excluding synonymous variants, noncoding
variants scarifies the sensitivity for higher
specificity
• No gold standard to definitively estimate the
specificity and sensitivity
• The sensitivity and specificity ties to quality of
clinical database due to the data querying and
predictive algorithms.
Comparison with other reports
• Substantial difference resulted by different
assumptions (ignoring SNPs variants)
• Stringent requirements on genes having
clinical utility raise the thresholds results four
orders less (0-2 variants versus 2000 variants
by Cassa et al.) returned variants in bin 1.
• The specificity of current binning system is
higher
Limitations
• Only monogenic diseases is studied in this
paper
• Specificity and Sensitivity needs quantitative
estimation
• Number of variants in manual review process
in the last step is still large (~100s)
Future directions
• Extend the method the multifactorial diesease
• Subcategorize Bin 2b into disease groups
• Establish more granular criteria to determine
the novel variants selected for review
• To better understand the penetrance of a
certain variants
• To improve and maintain clinical-grade
database of known variants
Conclusion
• Proof of concept of an framework to
organizing the incidental findings during WGS
to reduce the number of variants to be hand
curated to a manageable number.