Rare Genetic Disorders Walk-through
Cohorts Walk-through: Rare Genetic Disorders
This walk-through is meant to represent a typical workflow when building and studying a cohort of rare genetic disorder cases.
Login and Create a new ICA Project
Create a new Project to track your study:
Login to the ICA
Navigate to
Projects
Create a new project using the
New Project
button.Give your project a name and click
Save
.Navigate to the ICA Cohorts module by clicking
COHORTS
in the left navigation panel then chooseCohorts
.
Create and Review a Rare Disease Cohort
Navigate to the ICA Cohorts module by clicking
Cohorts
in the left navigation panel.Click
Create Cohort
button.Enter a name for your cohort, like
Rare Disease + 1kGP
at top, left of pencil icon.From the
Public Data Sets
list select:DRAGEN-1kGP
All
Rare genetic disease cohorts
Notice that a cohort can also be created based on
Technology
,Disease Type
andTissue
.Under
Selected Conditions
in right panel, click onApply
A new page opens with your cohort in a top-level tab.
Expand
Query Details
to see the study makeup of your cohort.A set of 4
Charts
will be open by default. If they are not, clickShow Charts
.Use the gear icon in the top-right of the Charts pane to change chart settings.
The bottom section is demarcated by 8 tabs (Subjects, Marker Frequency, Genes, GWAS, PheWAS, Correlation, Molecular Breakdown, CNV).
The
Subjects
tab displays a list of exportable Subject IDs and attributes.Clicking on a
Subject ID
link pops up a Subject details page.
Analyze Your Rare Disease Cohort Data
A recent GWAS publication identified 10 risk genes for intellectual disability (ID) and autism. Our task is to evaluate them in ICA Cohorts: TTN, PKHD1, ANKRD11, ARID1B, ASXL3, SCN2A, FHL1, KMT2A, DDX3X, SYNGAP1.
First let’s
Hide charts
for more visual space.Click the
Genes
tab where you need to query a gene to see and interact with results.Type
SCN2A
into the Gene search field and select it from autocomplete dropdown options.The
Gene Summary
tab now lists information and links to public resources about SCN2A.Click on the
Variants
tab to see an interactive Legend and analysis tracks.The Needle Plot displays
gnomAD Allele Frequency
for variants in your cohort.Note that some are in SCN2A conserved protein domains.
In Legend, switch the
Plot by
option toSample Count
in your cohort.In Legend, uncheck all
Variant Types
exceptStop gained
. Now you should see 7 variants.Hover over pin heads to see pop-up information about particular variants.
The
Primate AI
track displays Scores for potential missense variants, based on polymorphisms observed in primate species. Points above the dashed line for the 75th percentile may be considered "likely pathogenic" as cross-species sequence is highly conserved; you often see high conservancy at the functional domains. Points below the 25th percentile may be considered "likely benign".The
Pathogenic variants
track displays markers from ClinVar color-coded by variant type. Hover over to see pop-ups with more information.The
Exons
track shows mRNA exon boundaries with click and zoom functionality at the ends.Below the Needle Plot and analysis tracks is a list of "Variants observed in the selected cohort"
Export Gene Variants
table icon is above the legend on right side.
Now let's click on the
Gene Expression
tab to see a Bar chart of 50 normal tissues from GTEx in transcripts per million (TPM). SCN2A is highly expressed in certain Brain tissues, indicating specificity to where good markers for intellectual disability and autism could be expected.As a final exercise in discovering good markers, click on the tab for
Genetic Burden Test
. The table here associatesPhenotypes
withMutations Observed
in each Study selected for our cohort, alongsideMutations Expected
to derive p-values. Given all considerations above, SCN2A is good marker for intellectual disability (p < 1.465 x 10 -22) and autism (p < 5.290 x 10 -9).Continue to check the other genes of interest in step 1.
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