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Kaitlin Samocha Profile picture
@ksamocha
Apr 26 • 8 tweets • 6 min read Twitter logo Read on Twitter
Danny Miller (@danrdanny) #GRD23: Starts with his take home points
- long-read sequencing will fundamentally change clinical genetic testing
- will reduce barriers to accessing comprehensive testing
- this will happen even if the cost of generating other types of data falls to $0
.@danrdanny #GRD23: Traditional genetic workup (mircoarray -> panel -> exome) is diagnostic in <50% of cases.

Pitches that we can use long-read sequencing as a single test that could then be analyzed in different ways (SV -> repeat expansion -> genome, etc).
.@danrdanny #GRD23: Long-reads are 1kb+ in length. Read accuracy varies (90-99%) and the cost is $500-$3k.

Long-read sequencing finds 2x as many structural variants as short reads. See:
cell.com/ajhg/pdfExtend…
@danrdanny .@danrdanny #GRD23: Quality scores of ONT R9 data are lower than for HiFi, but it outperforms Illumina for SNP calling. More details in this preprint:
biorxiv.org/content/10.110…

Time to stop talking about the technology and to switch to talking about how we can use the technology.
.@danrdanny #GRD23: Advantage of long reads: can get SNVs, indels, SVs, methylation can all be called and phased from a single data source. Shows a few examples of applications to rare disease patients.
.@danrdanny #GRD23: Improved resolution of challenging cases will improve our ability to make new diagnoses. Has emphasized that good phenotyping is critical.
@danrdanny .@danrdanny #GRD23: How quickly can long reads be used to assess risk? 2 hours 47 minutes for a case. More details here:
medrxiv.org/content/10.110…

(Also references nejm.org/doi/10.1056/NE…)
@danrdanny .@danrdanny #GRD23: Finally, notes that there is an effort to apply long read sequencing to some 1000 Genomes samples. If you are interested, he suggests reaching out or checking here:
millerlaboratory.com/1000G-ONT.html

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More from @ksamocha

Kaitlin Samocha Profile picture
Apr 26
Rob Taylor #GRD23 on multi-omic approaches to dissect mitochondrial pathology.

Clinical mitochondrial diseases collectively have a prevalence of ~1 in 4000 and have functional, molecular, clinical, and prognostic heterogeneity.
Rob Taylor #GRD23: Some of this complexity comes from the fact that cells have many copies of the mitochondrial genome. Pathogenic variants can either be homoplasmic (in all copies) or heteroplasmic (in some copies).
Rob Taylor #GRD23: High throughput sequencing has helped identify pathogenic variants + new disease genes.

A few examples shown, including POLRMT, UQCRH, etc.
Read 6 tweets
Kaitlin Samocha Profile picture
Apr 26
Kristine Bilgrav Saether #GRD23: Transposable elements jump through the genome via RNA intermediates. They make up ~50% of the genome. Multiple versions, some of which are autonomous (LINE) and some are non-autonomous (SVA).
Kristine Bilgrav Saether #GRD23: Can use methods like MELT (👍 @DrGeneUK), xTEA, etc for short reads. For long reads, look at split reads so they wrote a new one called TELLR.

Studying 1KG and SweGen samples.
Kristine Bilgrav Saether #GRD23: TELLR finds split reads and insertions, then uses DBSCAN to cluster, minmap2 --> TE calls.

Long reads also give methylation information, which is useful since TE activity is controlled via epigenetics.
Read 4 tweets
Kaitlin Samocha Profile picture
Apr 26
Kaiyue Ma #GRD23: Mutations in alpha-dystroglycan can lead to dystroglycanopathies.

Developing SMuRF (saturation mutagenesis-reinforced functional assays) to test variants in alpha-DG glycosylation enzymes like FKRP.
Kaiyue Ma #GRD23: SMuRF scores have the expected distributions for variant type (e.g. synonymous look neutral, nonsense functional). Missense mutations in the catalytic domain tend to be more disruptive (vs those in stem). Good correlation of score with ClinVar classifications.
Kaiyue Ma #GRD23: SMuRF, EVE, and REVEL all do well in AUC analysis of computational predictors. REVEL is the best, but high correlation between SMuRF scores and REVEL. Improvements to SMuRF underway.
Read 4 tweets
Kaitlin Samocha Profile picture
Apr 26
Gosia Borowiak #GRD23: The field figured out how to make progenitor cells in culture, but trying to get homogenous populations of human beta cells was a challenge.

Time an endocrine progenitor is formed matters in likelihood of developing into a alpha vs beta cell.
Gosia Borowiak #GRD23: Digging into the microenvironment that influence human endocrine development. Found that WNT5A is necessary and sufficient for beta cell in vitro induction.

nature.com/articles/s4146…
Gosia Borowiak #GRD23: Re-emphasizes a point from yesterday: need to have a "factory" to be able to make large amounts of high quality cells if you want to do disease modelling / testing.

Figured out a way to allow serial expansion of these cells [MMP2, I believe].
Read 4 tweets
Kaitlin Samocha Profile picture
Apr 25
Now on is David Liu (@davidrliu) walking through programmable nucleases. >200 patients have been treated with therapies enabled by CRISPR nucleases thus far #GRD23
.@davidrliu #GRD23: While nucleases are good for gene disruption, they aren't great for gene correction.

Developed base editing and prime editing to address this gap and have editors now that can address all single nucleotide base changes.
.@davidrliu #GRD23: Have been able to show both ex vivo and in vivo base editing. Example of in vivo base editing for progeria in mice:
nature.com/articles/s4158…

Untreated mice live ~7.5months, but the ABE-treated mice live much longer.
Read 6 tweets
Kaitlin Samocha Profile picture
Apr 25
Hannah Verdin #GRD23: Over the last few years, just started carrier screening in Belgium via BeGECS (Belgian Genetic Expanded Carrier Screening). 400 couples have been studied to date.

Recruited pre-conception, but couples have to pay 1.5keuros.
Hannah Verdin #GRD23: Couple report is generated to inform of an increased couple risk. Also generate individual reports to provide information about specific high impact variants.
Hannah Verdin #GRD23: ~6.6% of couples had an increased couple risk for an autosomal recessive disorder. 1.3% had increased couple risk for X-linked disorders.
Read 4 tweets

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