Discover and read the best of Twitter Threads about #GRD23
Most recents (18)
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.
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.
A few examples shown, including POLRMT, UQCRH, etc.
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 (đź‘Ť @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.
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.
Long reads also give methylation information, which is useful since TE activity is controlled via epigenetics.
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.
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.
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.
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…
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].
Figured out a way to allow serial expansion of these cells [MMP2, I believe].
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
- 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).
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…
Long-read sequencing finds 2x as many structural variants as short reads. See:
cell.com/ajhg/pdfExtend…
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.
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.
nature.com/articles/s4158…
Untreated mice live ~7.5months, but the ABE-treated mice live much longer.
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.
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.
Lidewij Henneman #GRD23: Aim of carrier screening is to find carrier couples of recessive disorders with the goal of increasing reproductive autonomy.
A big challenge of screening preconception is that it is difficult to identify and reach the target population.
A big challenge of screening preconception is that it is difficult to identify and reach the target population.
Lidewij Henneman #GRD23 also notes that screening is not the same as diagnostics. Frequently couples are low-risk, and this is for reassurance. Need to ensure equal access -- should be inexpensive, simple, and socially accepted.
Lidewij Henneman #GRD23 shows some examples of ancestry-based screening and notes high community support for many of these.
In 2020, released guidelines about preconception carrier testing for high-risk populations (e.g., founder populations).
In 2020, released guidelines about preconception carrier testing for high-risk populations (e.g., founder populations).
Zeid Kuzbari #GRD23: Tumor-only sequencing remains the most frequent approach, but that means you need to distinguish between germline and somatic variants.
Working on recommendations of when to suggest germline follow-up after tumor-only.
Working on recommendations of when to suggest germline follow-up after tumor-only.
Zeid Kuzbari #GRD23: Starting with 49k tumors, but focused on 45k with certain features [that I missed]. Of the 58 cancer susceptibility genes, separated in different actionability classes.
Zeid Kuzbari #GRD23: ~16% of the filtered variants (by MAF, consequence, etc) were from the germline. But this is highly variable. Example: BRCA1 has a much higher germline rate vs APC.
Nathalie Charmi (@Nathalie_Chami) #GRD23: There are rare forms of obesity that are monogenic (typically early onset), which are to be distinguished from syndromic obesity.
Leptin-Melanocortin pathway regulates energy balance -> disruptions in this can lead to overeating
Leptin-Melanocortin pathway regulates energy balance -> disruptions in this can lead to overeating
.@Nathalie_Chami #GRD23: Using 500k exomes from UK Biobank and focused on 1.3k rare variants in 6 monogenic obesity genes. For each variant, calculated penetrance and the odds ratio.
At least for MC4R LoF, seems like there is a correlation between penetrance and OR
At least for MC4R LoF, seems like there is a correlation between penetrance and OR
.@Nathalie_Chami #GRD23: Only 19% of rare LoF and missense variants in these 6 genes are high impact (OR >2, penetrance > 35%).
Revisiting some of these variants with family studies (from nature.com/articles/s4159…).
Revisiting some of these variants with family studies (from nature.com/articles/s4159…).
Jay Gopalakrishnan on brain organoids #GRD23: The human brain is one of the most complex tissue systems with many different cell types that have highly orchestrated interactions.
Brain organoids are self-assembling 3D structures that could be used to model neurological disorders
Brain organoids are self-assembling 3D structures that could be used to model neurological disorders
Jay Gopalakrishnan #GRD23: Brain organoids have some of the layers seen in the brain. Have been able to make organoids with two eye-like structures (are light sensitive).
Have worked out a way to make ~1000 nearly homogeneous brain organoids per batch. "Hi-Q" brain organoids.
Have worked out a way to make ~1000 nearly homogeneous brain organoids per batch. "Hi-Q" brain organoids.
Jay Gopalakrishnan #GRD23: Discovered a cilium checkpoint, which is key for growth.
Microcephaly neural progenitor cells have premature differentiation, which leads to depletion of these NPCs.
Microcephaly neural progenitor cells have premature differentiation, which leads to depletion of these NPCs.
Gabrielle Lemire up next on how genome sequecing can be more than just a fancy exome. #GRD23
Genomes are more expensive than exomes and have a higher analytical burden, but could offer additional benefit. Want to evaluate that benefit here.
Genomes are more expensive than exomes and have a higher analytical burden, but could offer additional benefit. Want to evaluate that benefit here.
Gabrielle Lemire #GRD23: 744 families with short read genome sequencing, some also have RNAseq.
Need genomes for deep intronic variants, tandem repeats, small/intronic CNVs, or coding variants in regions that weren't well covered in exome sequencing.
Need genomes for deep intronic variants, tandem repeats, small/intronic CNVs, or coding variants in regions that weren't well covered in exome sequencing.
Gabrielle Lemire #GRD23: Patients coming both from the Center for Mendelian Genomics (academic collaboration) and the Rare Genomes Project (direct to patients study).
Solve rate was 26% (196/744). Most solves in established disease genes. 57 of the solves *required* genomes.
Solve rate was 26% (196/744). Most solves in established disease genes. 57 of the solves *required* genomes.
Dana Marafi (@Danamarafi) #GRD23: Founder effect is a loss of genetic variation due to a population being established by a small group of individuals (due to a bottleneck or geographical/cultural isolation).
See allele frequency differences to originating population.
See allele frequency differences to originating population.
.@Danamarafi #GRD23: These leads to founder mutations, some of which can contribute to disease. Can identify these founder mutations via haplotype analysis, genealogical investigation, or minor allele frequency in a matched genetic ancestry group.
@Danamarafi .@Danamarafi #GRD23 walks through a few disease associated founder mutations in e.g, India, Finland, and North America.
Claudia Gonzaga-Jauregui (@cgonzagaj) starts off this morning describing rare disordes in Latin America. Variable definitions between countries. #GRD23
@cgonzagaj .@cgonzagaj #GRD23: Barriers for implementation of molecular diagnostics in Latin America:
- limited testing coverage by healthcare/insurance
- high cost/low availability
- lack of awareness from PCPs
- low testing demands
- few trained professionals
-> etc
- limited testing coverage by healthcare/insurance
- high cost/low availability
- lack of awareness from PCPs
- low testing demands
- few trained professionals
-> etc
.@cgonzagaj #GRD23: REMEXER project to start a rare disease registry in Mexico. Can start to understand the number of patients, the challenges/needs, and the diagnoses.
144 patients registered in the first year.
144 patients registered in the first year.
Alexandre Reymond #GRD23: Found out a few years ago that CNV carriers in the general population tend to be at the mild end of the phenotypic spectrum, see:
jamanetwork.com/journals/jama/…
With larger database/biobanks, can do a CNV-GWAS to find CNVs as phenotypic modifiers.
jamanetwork.com/journals/jama/…
With larger database/biobanks, can do a CNV-GWAS to find CNVs as phenotypic modifiers.
Alexandre Reymond #GRD23: In a CNV-GWAS, found 131 signals across 47 phenotypes in:
pubmed.ncbi.nlm.nih.gov/35240056/
Found a few new associations, including a novel gene association for MARF1 in female reproduction time.
pubmed.ncbi.nlm.nih.gov/35240056/
Found a few new associations, including a novel gene association for MARF1 in female reproduction time.
Alexandre Reymond #GRD23: 16p11.2 is known to have mirror phenotypes in a number of realms. Highlights that this is also see for age of menarche in both humans and mice.
More details:
biorxiv.org/content/10.110…
More details:
biorxiv.org/content/10.110…
Nechama Wieder (@NechamaWieder) #GRD23 starts by reminding us of how critical 5'UTRs are.
Start codons within the 5'UTRs (uAUGs) can decrease translation of the downstream coding sequence.
Start-stop: "minimum ORF" impedes ribosome scanning without peptide production of uORFs.
Start codons within the 5'UTRs (uAUGs) can decrease translation of the downstream coding sequence.
Start-stop: "minimum ORF" impedes ribosome scanning without peptide production of uORFs.
.@NechamaWieder #GRD23: Start-stop contribute to ribosome pausing and decreasing downstream translation.
~5% of all MANE Select transcripts have these start-stops and most of them only have one.
~5% of all MANE Select transcripts have these start-stops and most of them only have one.
.@NechamaWieder #GRD23: Start-stops are enriched in genes intolerant to LoF (via LOEUF deciles)... but those genes are also longer and have different GC content.
Used a shuffling algorithm to determine observed/expected per hexamer to show that the start-stops are enriched.
Used a shuffling algorithm to determine observed/expected per hexamer to show that the start-stops are enriched.
Peter Robinson #GRD23 on splicing-impacting variants.
Diagnostic rates have improved over time, but still are low. Where are the other diagnoses?
Notes that bioinformatics can help increase efficiency by improving variant prioritization and interpretation.
Diagnostic rates have improved over time, but still are low. Where are the other diagnoses?
Notes that bioinformatics can help increase efficiency by improving variant prioritization and interpretation.
Peter Robinson #GRD23: Field is slowly moving to focus on prioritizing noncoding variants (vs missense).
For splice sites, know about the importance of the canonical sites (e.g., donor +1/+2), but variants that fall outside of those regions are harder to interpret.
For splice sites, know about the importance of the canonical sites (e.g., donor +1/+2), but variants that fall outside of those regions are harder to interpret.
Peter Robinson #GRD23: SQUIRLS
Super QUick Information content Random-forest Learning of Splice variants
Paper on it:
pubmed.ncbi.nlm.nih.gov/34289339/
Super QUick Information content Random-forest Learning of Splice variants
Paper on it:
pubmed.ncbi.nlm.nih.gov/34289339/
Morton #LupskiLecture #GRD23: Walking through a specific case with a balanced rearrangement (an inversion) that disrupted HMGA2.
Described more here:
sciencedirect.com/science/articl…
Described more here:
sciencedirect.com/science/articl…
Morton #LupskiLecture #GRD23: Reminds the room that 97% of the genome does not code for proteins and highlights that there are >15k lncRNAs in the human genome. See more lncRNAs in mice, meaning that we may be missing some in humans.
Morton #LupskiLecture #GRD23: For more information on lncRNAs, strongly suggests reading:
nature.com/articles/s4158…
"I think they [lncRNAs] do everything"
nature.com/articles/s4158…
"I think they [lncRNAs] do everything"
