6d4b6f98a4144956ad7029bd7c1874ffd90fdf2f mspeir Wed Jul 8 09:23:00 2026 -0700 redoing slides as embedded html slide deck, refs #37292 diff --git docs/slideDecks/tutorial4-clinical-cases/presentation/index.html docs/slideDecks/tutorial4-clinical-cases/presentation/index.html new file mode 100644 index 00000000000..d464b072015 --- /dev/null +++ docs/slideDecks/tutorial4-clinical-cases/presentation/index.html @@ -0,0 +1,335 @@ +<!DOCTYPE html> +<html lang="en"> +<head> +<meta charset="utf-8"> +<meta name="viewport" content="width=device-width, initial-scale=1.0"> +<title>UCSC Genome Browser · Tutorial 4: Clinical case studies</title> + +<link rel="stylesheet" href="https://cdn.jsdelivr.net/npm/reveal.js@5.1.0/dist/reveal.css"> +<link rel="stylesheet" href="https://cdn.jsdelivr.net/npm/reveal.js@5.1.0/dist/theme/white.css" id="theme"> + +<style> + :root{ + --ucsc-blue:#1f3a5f; + --ucsc-accent:#0b5394; + --ucsc-gold:#e6a817; + } + .reveal { font-size: 32px; } + .reveal h1,.reveal h2,.reveal h3 { color: var(--ucsc-blue); 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sessions are public.</li> + </ul> + <div class="callout demo"><span class="lbl">Builds on Tutorial 3</span> Tutorial 3 introduced the tracks and Recommended Track Sets; here we put them to work on one variant after another.</div> +</section> + +<section class="divider" data-background-color="#0b5394"> + <h1>Coding variants</h1> + <p class="timing">read the call — then check the transcript</p> +</section> + +<section> + <h2>MECP2 — Rett syndrome</h2> + <div class="split"> + <div class="txt"> + <p class="small"><span class="chip">NM_001110792.2(MECP2):c.538C>T</span> <span class="chip">p.Arg180Ter (R168X)</span> <span class="chip">chrX</span></p> + <ul class="small"><li>X-linked neurodevelopmental disorder; a classic loss-of-function <strong>nonsense</strong> variant.</li><li>You can paste the <strong>HGVS</strong> expression straight into the position box and press Enter.</li></ul> + <div class="callout demo"><span class="lbl">Read it off the set</span> Load the <strong>Clinical SNVs</strong> Recommended Track Set: ClinVar, HGMD and LOVD stack the pathogenic evidence at the codon.</div> + <div class="callout exercise"><span class="lbl">Try it, ▶ <a href="https://genome.ucsc.edu/s/Max/rett">open the session</a></span> Paste the HGVS, then open Recommended Track Sets → Clinical SNVs.</div> + <p class="small" style="color:#5b6673;margin-top:0.3em;">Session: s/Max/rett</p> + </div> + <div class="figwrap"><figure class="fig"><img class="shot" style="max-height:70vh;max-width:100%;width:auto;display:block;margin:0 auto;" src="/images/slideDecks/tutorial4-clinical-cases/mecp2_rett.png" alt="MECP2 Rett-syndrome nonsense variant on hg38"><figcaption>MECP2 nonsense variant with ClinVar / HGMD / LOVD tracks</figcaption></figure></div> + </div> + <aside class="notes">MECP2 c.538C>T (p.Arg168X/Arg180Ter) causes Rett syndrome. Demonstrates pasting HGVS directly into the search box and reading a clean pathogenic nonsense call off the Clinical SNVs set.</aside> +</section> + +<section> + <h2>MAP2K2 — a small missense</h2> + <div class="split"> + <div class="txt"> + <p class="small"><span class="chip">NM_030662.4(MAP2K2):c.401A>G</span> <span class="chip">p.Tyr134Cys</span></p> + <ul class="small"><li>A RASopathy-gene <strong>missense</strong> change — the everyday coding question.</li><li>The <strong>SNV Recommended Track Set</strong> is on display here.</li></ul> + <div class="callout demo"><span class="lbl">Lines of evidence</span> ClinVar submitted interpretations & evidence, plus <strong>Varaico</strong> literature annotations for Y134C, sit together in one view.</div> + <div class="callout exercise"><span class="lbl">Try it, ▶ <a href="https://genome.ucsc.edu/s/Lou/clinGenMissenseExample">open the session</a></span> Read the ClinVar interpretations and the Varaico annotation for Y134C.</div> + <p class="small" style="color:#5b6673;margin-top:0.3em;">Example session (variant via Marina Di Stefano, Broad Institute)</p> + </div> + <div class="figwrap"><figure class="fig"><img class="shot" style="max-height:70vh;max-width:100%;width:auto;display:block;margin:0 auto;" src="/images/slideDecks/tutorial4-clinical-cases/map2k2_missense.png" alt="MAP2K2 c.401A>G missense on hg38"><figcaption>MAP2K2 Y134C missense with SNV Recommended Track Set</figcaption></figure></div> + </div> + <aside class="notes">MAP2K2 p.Tyr134Cys, a small missense shown with the SNV Recommended Track Set: ClinVar submitted interpretations plus Varaico paper annotations.</aside> +</section> + +<section class="divider" data-background-color="#0b5394"> + <h1>Read the annotation carefully</h1> + <p class="timing">when a coding call isn't what it seems</p> +</section> + +<section> + <h2>TCF4 — but do you trust this exon?</h2> + <div class="split"> + <div class="txt"> + <p class="small"><span class="chip">p.Ser504Ter</span> <span class="chip">chr18:55,234,435G>T</span> <span class="chip">ENST00000635822.2</span></p> + <ul class="small"><li>Gene implicated in a syndromic intellectual disability; this looks like a <strong>stop-gain</strong>.</li><li>But the exon is coding <strong>only in one transcript</strong>, and it is <strong>not conserved</strong> across vertebrates.</li></ul> + <div class="callout demo"><span class="lbl">The catch</span> If the exon is not a real coding region, the “nonsense” call collapses — the variant is most likely <strong>benign</strong>. Always check the transcript and conservation.</div> + <div class="callout exercise"><span class="lbl">Try it, ▶ <a href="https://genome.ucsc.edu/s/Max/tcf">open the session</a></span> Compare transcripts; read the 100-vertebrate conservation over this exon.</div> + <p class="small" style="color:#5b6673;margin-top:0.3em;">Case: Irina Giurgea, Hôpital Trousseau</p> + </div> + <div class="figwrap"><figure class="fig"><img class="shot" style="max-height:70vh;max-width:100%;width:auto;display:block;margin:0 auto;" src="/images/slideDecks/tutorial4-clinical-cases/tcf4_exon.png" alt="TCF4 variant in a non-conserved exon on hg38"><figcaption>TCF4 apparent stop-gain in a non-conserved, transcript-specific exon</figcaption></figure></div> + </div> + <aside class="notes">A cautionary case: p.Ser504Ter looks pathogenic, but the exon is coding only in ENST00000635822.2 and is not conserved in vertebrates, arguing the variant is benign. Reinforces transcript choice and conservation.</aside> +</section> + +<section class="divider" data-background-color="#0b5394"> + <h1>Splicing</h1> + <p class="timing">synonymous and deep-intronic variants that still break splicing</p> +</section> + +<section> + <h2>IGHMBP2 — a new splice site deep in an intron</h2> + <div class="split"> + <div class="txt"> + <p class="small"><span class="chip">NM_002180(IGHMBP2):c.712-610A>G</span> <span class="chip">hg38 chr11:68,914,208</span></p> + <ul class="small"><li>A variant <strong>deep in an intron</strong>, far from any coding exon — easy to dismiss.</li><li>But it can create a <strong>new splice site</strong>.</li></ul> + <div class="callout demo"><span class="lbl">Scan the predictors</span> The <strong>Splicing Impact</strong> / SpliceAI track flags the gain; SpliceVarDB and a PubTator hit corroborate it.</div> + <div class="callout exercise"><span class="lbl">Try it, ▶ <a href="https://genome.ucsc.edu/s/Max/ighmbp2.712">open the session</a></span> Turn on Splicing Impact; inspect the SpliceAI delta scores at the variant.</div> + <p class="small" style="color:#5b6673;margin-top:0.3em;">Session: s/Max/ighmbp2.712 · PMID 33189025</p> + </div> + <div class="figwrap"><figure class="fig"><img class="shot" style="max-height:70vh;max-width:100%;width:auto;display:block;margin:0 auto;" src="/images/slideDecks/tutorial4-clinical-cases/ighmbp2_splice.png" alt="IGHMBP2 deep-intronic splice variant on hg38"><figcaption>IGHMBP2 deep-intronic variant with SpliceAI / Splicing Impact</figcaption></figure></div> + </div> + <aside class="notes">IGHMBP2 c.712-610A>G is a deep-intronic variant that creates a new splice site, caught by SpliceAI / the Splicing Impact super-track and corroborated by SpliceVarDB and literature.</aside> +</section> + +<section> + <h2>KCTD7 — a synonymous variant that isn't silent</h2> + <div class="split"> + <div class="txt"> + <p class="small"><span class="chip">KCTD7:c.456G>A</span> <span class="chip">p.Val152Val</span> <span class="chip">exon 3</span></p> + <ul class="small"><li>A <strong>synonymous</strong> change — no amino-acid change, so it looks harmless.</li><li>But it disrupts <strong>splicing</strong>.</li></ul> + <div class="callout demo"><span class="lbl">Synonymous ≠ silent</span> The <strong>Splicing Impact</strong> track shows the effect; the variant is in the LOVD of a 2019 paper from the same lab.</div> + <div class="callout exercise"><span class="lbl">Try it, ▶ <a href="https://genome.ucsc.edu/s/Max/kctd7.456GA">open the session</a></span> Check the splicing predictions over this synonymous position.</div> + <p class="small" style="color:#5b6673;margin-top:0.3em;">Session: s/Max/kctd7.456GA · PMC10506157</p> + </div> + <div class="figwrap"><figure class="fig"><img class="shot" style="max-height:70vh;max-width:100%;width:auto;display:block;margin:0 auto;" src="/images/slideDecks/tutorial4-clinical-cases/kctd7_synsplice.png" alt="KCTD7 c.456G>A synonymous splice-affecting variant on hg38"><figcaption>KCTD7 synonymous variant predicted to affect splicing</figcaption></figure></div> + </div> + <aside class="notes">KCTD7 c.456G>A (p.Val152Val) is synonymous yet splice-altering; the Splicing Impact track reveals the effect. Teaching point: synonymous is not the same as silent.</aside> +</section> + +<section class="divider" data-background-color="#0b5394"> + <h1>Non-coding & regulatory</h1> + <p class="timing">enhancers, promoters and RNA genes</p> +</section> + +<section> + <h2>POU1F1 — a deletion upstream of the gene</h2> + <div class="split"> + <div class="txt"> + <p class="small"><span class="chip">8.7 kb deletion, ~3 kb upstream</span> <span class="chip">hg38 chr3:87,279,612-87,288,322</span></p> + <ul class="small"><li>Homozygous deletion upstream of <strong>POU1F1</strong>, a pituitary transcription factor (pituitary hormone deficiency).</li><li>No coding sequence is touched — the evidence is <strong>regulatory</strong>.</li></ul> + <div class="callout demo"><span class="lbl">Read the regulation</span> The deletion removes an ENCODE <strong>cCRE</strong> with a distal-enhancer signature; <strong>conservation</strong> and <strong>GTEx</strong> (pituitary +++) support its role.</div> + <div class="callout exercise"><span class="lbl">Try it, ▶ <a href="https://genome.ucsc.edu/s/Max/pou1f1">open the session</a></span> Turn on ENCODE cCREs, 100-vertebrate conservation, and GTEx over the deleted region.</div> + <p class="small" style="color:#5b6673;margin-top:0.3em;">Case: Amselem & Legendre labs, Hôpital Trousseau</p> + </div> + <div class="figwrap"><figure class="fig"><img class="shot" style="max-height:70vh;max-width:100%;width:auto;display:block;margin:0 auto;" src="/images/slideDecks/tutorial4-clinical-cases/pou1f1_upstream.png" alt="POU1F1 upstream regulatory deletion on hg38"><figcaption>POU1F1 upstream deletion overlapping a distal-enhancer cCRE</figcaption></figure></div> + </div> + <aside class="notes">An 8.7 kb homozygous deletion ~3 kb upstream of POU1F1 removes a distal-enhancer-like cCRE; conservation and pituitary-specific GTEx expression support a regulatory mechanism for pituitary deficiency.</aside> +</section> + +<section> + <h2>SHH / ZRS — a limb enhancer in an intron of LMBR1</h2> + <div class="split"> + <div class="txt"> + <p class="small"><span class="chip">Patient chr7:156,791,472C>T</span> <span class="chip">intron 5 of LMBR1 (the ZRS)</span></p> + <ul class="small"><li>The <strong>ZRS</strong> is a classic long-range enhancer of <strong>SHH</strong>; variants in it cause limb malformations.</li><li>In snakes, a 17 bp ZRS deletion contributed to <strong>limb loss</strong> (Kvon et al.).</li></ul> + <div class="callout demo"><span class="lbl">Motif in an enhancer</span> BLAT the snake sequence and Short Match the <strong>ETS1</strong> motif; the patient variant sits in a conserved ETS motif inside a distal-enhancer cCRE, with other OMIM-allele patients nearby.</div> + <div class="callout exercise"><span class="lbl">Try it, ▶ <a href="https://genome.ucsc.edu/s/Max/lrmb1">open the session</a></span> Use BLAT / Short Match for the ETS motif; read the cCRE, conservation and OMIM alleles.</div> + <p class="small" style="color:#5b6673;margin-top:0.3em;">Cases: Wieczorek et al. 2009; snake example: Kvon et al.</p> + </div> + <div class="figwrap"><figure class="fig"><img class="shot" style="max-height:70vh;max-width:100%;width:auto;display:block;margin:0 auto;" src="/images/slideDecks/tutorial4-clinical-cases/shh_zrs.png" alt="SHH ZRS enhancer variant in LMBR1 intron 5 on hg38"><figcaption>The ZRS limb enhancer with ETS motif, cCRE and conservation</figcaption></figure></div> + </div> + <aside class="notes">The ZRS (in LMBR1 intron 5) is a long-range SHH limb enhancer. Ties together BLAT / Short Match (ETS1 motif), conservation, ENCODE cCREs and OMIM alleles for a non-coding enhancer variant.</aside> +</section> + +<section> + <h2>RNU4-2 — a variant in a non-coding RNA gene</h2> + <div class="split"> + <div class="txt"> + <p class="small"><span class="chip">hg38 chr12:120,291,858 C>T</span> <span class="chip">RNU4-2 (NR_003137.3):n.46G>A</span></p> + <ul class="small"><li><strong>RNU4-2</strong> encodes the U4 spliceosomal snRNA — a non-coding RNA gene, not a protein.</li><li>Recently (2024) shown to cause one of the most common monogenic neurodevelopmental disorders (ReNU syndrome).</li></ul> + <div class="callout demo"><span class="lbl">No protein here</span> There is no coding consequence to read; you reason from the <strong>RNA gene</strong> itself and the recent literature.</div> + <div class="callout exercise"><span class="lbl">Try it, ▶ <a href="https://genome.ucsc.edu/s/Max/rnu42.c46ga">open the session</a></span> View the variant within the RNU4-2 gene body; a second hotspot sits at n.129G>A.</div> + <p class="small" style="color:#5b6673;margin-top:0.3em;">Case: Jon Bernstein · medRxiv 2025</p> + </div> + <div class="figwrap"><figure class="fig"><img class="shot" style="max-height:70vh;max-width:100%;width:auto;display:block;margin:0 auto;" src="/images/slideDecks/tutorial4-clinical-cases/rnu42.png" alt="RNU4-2 snRNA-gene variant on hg38"><figcaption>RNU4-2 non-coding RNA-gene variant on hg38</figcaption></figure></div> + </div> + <aside class="notes">RNU4-2 n.46G>A (and n.129G>A) in the U4 snRNA gene cause ReNU syndrome, a recently described common neurodevelopmental disorder. A non-coding RNA-gene case: no protein consequence, reason from the gene and literature.</aside> +</section> + +<section class="divider" data-background-color="#0b5394"> + <h1>Structural & repeat</h1> + <p class="timing">CNVs and repeat expansions</p> +</section> + +<section> + <h2>A 2.22 Mb duplication on chromosome 22</h2> + <div class="split"> + <div class="txt"> + <p class="small"><span class="chip">chr22:g.18,895,798-21,111,753dup</span> <span class="chip">GRCh38</span> <span class="chip">2.22 Mb</span></p> + <ul class="small"><li>A large copy-number gain at <strong>22q11.2</strong> — a different interpretation problem from SNVs.</li><li>Load the <strong>CNV Recommended Track Set</strong>.</li></ul> + <div class="callout demo"><span class="lbl">CNV-specific evidence</span> <strong>ClinGen Dosage</strong> (triplosensitivity), <strong>ClinVar CNVs</strong>, <strong>DECIPHER</strong> and <strong>PanelApp</strong> CNV regions — each filterable.</div> + <div class="callout exercise"><span class="lbl">Try it, ▶ <a href="https://genome.ucsc.edu/s/Lou/clinGenCNVsDupExample">open the session</a></span> Load the CNV RTS; compare the duplication against ClinGen Dosage and DECIPHER.</div> + <p class="small" style="color:#5b6673;margin-top:0.3em;">Example session</p> + </div> + <div class="figwrap"><figure class="fig"><img class="shot" style="max-height:70vh;max-width:100%;width:auto;display:block;margin:0 auto;" src="/images/slideDecks/tutorial4-clinical-cases/chr22_cnvdup.png" alt="chr22 2.22 Mb duplication on hg38"><figcaption>A 2.22 Mb duplication with ClinGen Dosage, ClinVar CNVs, DECIPHER and PanelApp</figcaption></figure></div> + </div> + <aside class="notes">A 2.22 Mb 22q11.2 duplication interpreted with the CNV Recommended Track Set: ClinGen Dosage triplosensitivity, ClinVar CNVs, DECIPHER CNVs and PanelApp CNV regions.</aside> +</section> + +<section> + <h2>FGF14 — a GAA repeat expansion</h2> + <div class="split"> + <div class="txt"> + <p class="small"><span class="chip">FGF14 intron 1</span> <span class="chip">hg38 chr13:102,161,567</span> <span class="chip">~270-300 GAA repeats</span></p> + <ul class="small"><li>Late-onset cerebellar ataxia (SCA27B) caused by an intronic <strong>repeat expansion</strong> — not an SNV or CNV.</li><li>A distinct class of variant with its own resources.</li></ul> + <div class="callout demo"><span class="lbl">A third variant class</span> View the intron-1 GAA locus in the Browser, then cross-check dedicated tandem-repeat resources (<strong>WebSTR</strong>, <strong>TRatlas</strong>).</div> + <div class="callout exercise"><span class="lbl">Try it, ▶ <a href="https://genome.ucsc.edu/s/Max/fgf14">open the session</a></span> Navigate to the intron-1 repeat; compare against the tandem-repeat tracks/resources.</div> + <p class="small" style="color:#5b6673;margin-top:0.3em;">Session: s/Max/fgf14</p> + </div> + <div class="figwrap"><figure class="fig"><img class="shot" style="max-height:70vh;max-width:100%;width:auto;display:block;margin:0 auto;" src="/images/slideDecks/tutorial4-clinical-cases/fgf14_repeat.png" alt="FGF14 GAA repeat-expansion locus on hg38"><figcaption>FGF14 intron-1 GAA repeat locus on hg38</figcaption></figure></div> + </div> + <aside class="notes">FGF14 intron-1 GAA repeat expansion (~270-300 repeats) causes SCA27B. Introduces repeat expansions as a distinct variant class and the WebSTR / TRatlas tandem-repeat resources.</aside> +</section> + +<section class="divider" data-background-color="#0b5394"> + <h1>More cases</h1> + <p class="timing">a gallery of de novo neurodevelopmental variants</p> +</section> + +<section> + <h2>More cases: de novo neurodevelopmental variants</h2> + <p class="small">A gallery of further worked cases (GSS series) — each opens as a live session:</p> + <ul class="small"> + <li><strong>LRRC8A</strong> <span class="chip">c.730T>C</span> p.Phe244Leu — multisystem disorder, de novo heterozygous. <a href="https://genome.ucsc.edu/s/Max/lrrc8a">session</a></li> + <li><strong>KPNA4</strong> <span class="chip">c.557G>A</span> p.Gly186Asp <span class="chip">chr3:160,526,107C>T</span> — seizures, developmental delay, autism. <a href="https://genome.ucsc.edu/s/Max/kpn4a">session</a></li> + <li><strong>ERCC8</strong> <span class="chip">c.550+2T>C</span> splice + a complex maternal SV — compound heterozygous, Cockayne-spectrum. <a href="https://genome.ucsc.edu/s/Max/ercc8">session</a></li> + <li><strong>RNU4ATAC</strong> <span class="chip">n.12C>T</span> + <span class="chip">n.120T>G</span> — minor-spliceosome snRNA, compound heterozygous, multisystem.</li> + </ul> + <div class="callout demo"><span class="lbl">Same recipe</span> Different genes and mechanisms, one workflow: open the session, load the right track set, read the evidence.</div> +</section> + +<section> + <h2>What these cases show</h2> + <ul class="small"> + <li><strong>Coding</strong> variants can be read almost off the tracks — but always check the <em>transcript</em> and <em>conservation</em> (TCF4).</li> + <li><strong>Synonymous</strong> and <strong>deep-intronic</strong> variants can still break splicing — scan the splicing predictors.</li> + <li><strong>Non-coding</strong> variants are interpreted from regulatory context: cCREs, conservation, expression, TF motifs.</li> + <li><strong>CNVs</strong> and <strong>repeat expansions</strong> are their own classes, each with dedicated tracks and resources.</li> + </ul> + <div class="callout demo"><span class="lbl">The habit</span> Turn every variant into a set of questions, then let the right track answer each one.</div> +</section> + +<section class="divider" data-background-color="#1f3a5f"> + <h1 style="color:#fff;margin-bottom:0.12em;">Thank you!</h1> + <p style="color:#fff;font-size:0.72em;margin:0.05em 0;">Questions? · genome@soe.ucsc.edu</p> + <p style="color:#cdd9e8;font-size:0.55em;margin:0.05em 0 0.45em;">UCSC Genome Browser · genome.ucsc.edu</p> + <figure class="fig" style="margin:0 auto;"><img src="/images/slideDecks/tutorial4-clinical-cases/gb_team.jpg" alt="UCSC Genome Browser team" style="max-height:360px;width:auto;border-radius:8px;"></figure> +</section> + +</div> +</div> + +<script src="https://cdn.jsdelivr.net/npm/reveal.js@5.1.0/dist/reveal.js"></script> +<script src="https://cdn.jsdelivr.net/npm/reveal.js@5.1.0/plugin/notes/notes.js"></script> +<script> + Reveal.initialize({ + hash: true, + slideNumber: 'c/t', + transition: 'fade', + width: 1280, + height: 800, + margin: 0.06, + plugins: [ RevealNotes ] + }); +</script> +</body> +</html>