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 @@ + + + + + +UCSC Genome Browser · Tutorial 4: Clinical case studies + + + + + + + +
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UCSC Genome Browser · Tutorial 4: Clinical case studies
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UCSC Genome Browser · Tutorial 4

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Clinical case studies

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Real diagnostic variants, worked live on the Browser

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Coding · splicing · non-coding · structural & repeat · genome.ucsc.edu

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How these case studies work

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  • Each case is a real diagnostic variant saved as a live UCSC session — open it and follow along.
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  • They are grouped by variant class: coding, splicing, non-coding/regulatory, and structural/repeat.
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  • The recurring move: pick the right Recommended Track Set, then read the evidence off the stacked tracks.
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  • Cases contributed by clinical collaborators (credited per slide); sessions are public.
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Builds on Tutorial 3 Tutorial 3 introduced the tracks and Recommended Track Sets; here we put them to work on one variant after another.
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Coding variants

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read the call — then check the transcript

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MECP2 — Rett syndrome

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NM_001110792.2(MECP2):c.538C>T p.Arg180Ter (R168X) chrX

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  • X-linked neurodevelopmental disorder; a classic loss-of-function nonsense variant.
  • You can paste the HGVS expression straight into the position box and press Enter.
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Read it off the set Load the Clinical SNVs Recommended Track Set: ClinVar, HGMD and LOVD stack the pathogenic evidence at the codon.
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Try it, ▶ open the session Paste the HGVS, then open Recommended Track Sets → Clinical SNVs.
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Session: s/Max/rett

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MECP2 Rett-syndrome nonsense variant on hg38
MECP2 nonsense variant with ClinVar / HGMD / LOVD tracks
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MAP2K2 — a small missense

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NM_030662.4(MAP2K2):c.401A>G p.Tyr134Cys

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  • A RASopathy-gene missense change — the everyday coding question.
  • The SNV Recommended Track Set is on display here.
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Lines of evidence ClinVar submitted interpretations & evidence, plus Varaico literature annotations for Y134C, sit together in one view.
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Try it, ▶ open the session Read the ClinVar interpretations and the Varaico annotation for Y134C.
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Example session (variant via Marina Di Stefano, Broad Institute)

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MAP2K2 c.401A>G missense on hg38
MAP2K2 Y134C missense with SNV Recommended Track Set
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Read the annotation carefully

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when a coding call isn't what it seems

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TCF4 — but do you trust this exon?

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p.Ser504Ter chr18:55,234,435G>T ENST00000635822.2

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  • Gene implicated in a syndromic intellectual disability; this looks like a stop-gain.
  • But the exon is coding only in one transcript, and it is not conserved across vertebrates.
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The catch If the exon is not a real coding region, the “nonsense” call collapses — the variant is most likely benign. Always check the transcript and conservation.
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Try it, ▶ open the session Compare transcripts; read the 100-vertebrate conservation over this exon.
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Case: Irina Giurgea, Hôpital Trousseau

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TCF4 variant in a non-conserved exon on hg38
TCF4 apparent stop-gain in a non-conserved, transcript-specific exon
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Splicing

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synonymous and deep-intronic variants that still break splicing

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IGHMBP2 — a new splice site deep in an intron

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NM_002180(IGHMBP2):c.712-610A>G hg38 chr11:68,914,208

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  • A variant deep in an intron, far from any coding exon — easy to dismiss.
  • But it can create a new splice site.
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Scan the predictors The Splicing Impact / SpliceAI track flags the gain; SpliceVarDB and a PubTator hit corroborate it.
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Try it, ▶ open the session Turn on Splicing Impact; inspect the SpliceAI delta scores at the variant.
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Session: s/Max/ighmbp2.712 · PMID 33189025

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IGHMBP2 deep-intronic splice variant on hg38
IGHMBP2 deep-intronic variant with SpliceAI / Splicing Impact
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KCTD7 — a synonymous variant that isn't silent

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KCTD7:c.456G>A p.Val152Val exon 3

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  • A synonymous change — no amino-acid change, so it looks harmless.
  • But it disrupts splicing.
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Synonymous ≠ silent The Splicing Impact track shows the effect; the variant is in the LOVD of a 2019 paper from the same lab.
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Try it, ▶ open the session Check the splicing predictions over this synonymous position.
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Session: s/Max/kctd7.456GA · PMC10506157

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KCTD7 c.456G>A synonymous splice-affecting variant on hg38
KCTD7 synonymous variant predicted to affect splicing
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Non-coding & regulatory

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enhancers, promoters and RNA genes

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POU1F1 — a deletion upstream of the gene

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8.7 kb deletion, ~3 kb upstream hg38 chr3:87,279,612-87,288,322

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  • Homozygous deletion upstream of POU1F1, a pituitary transcription factor (pituitary hormone deficiency).
  • No coding sequence is touched — the evidence is regulatory.
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Read the regulation The deletion removes an ENCODE cCRE with a distal-enhancer signature; conservation and GTEx (pituitary +++) support its role.
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Try it, ▶ open the session Turn on ENCODE cCREs, 100-vertebrate conservation, and GTEx over the deleted region.
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Case: Amselem & Legendre labs, Hôpital Trousseau

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POU1F1 upstream regulatory deletion on hg38
POU1F1 upstream deletion overlapping a distal-enhancer cCRE
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SHH / ZRS — a limb enhancer in an intron of LMBR1

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Patient chr7:156,791,472C>T intron 5 of LMBR1 (the ZRS)

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  • The ZRS is a classic long-range enhancer of SHH; variants in it cause limb malformations.
  • In snakes, a 17 bp ZRS deletion contributed to limb loss (Kvon et al.).
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Motif in an enhancer BLAT the snake sequence and Short Match the ETS1 motif; the patient variant sits in a conserved ETS motif inside a distal-enhancer cCRE, with other OMIM-allele patients nearby.
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Try it, ▶ open the session Use BLAT / Short Match for the ETS motif; read the cCRE, conservation and OMIM alleles.
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Cases: Wieczorek et al. 2009; snake example: Kvon et al.

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SHH ZRS enhancer variant in LMBR1 intron 5 on hg38
The ZRS limb enhancer with ETS motif, cCRE and conservation
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RNU4-2 — a variant in a non-coding RNA gene

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hg38 chr12:120,291,858 C>T RNU4-2 (NR_003137.3):n.46G>A

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  • RNU4-2 encodes the U4 spliceosomal snRNA — a non-coding RNA gene, not a protein.
  • Recently (2024) shown to cause one of the most common monogenic neurodevelopmental disorders (ReNU syndrome).
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No protein here There is no coding consequence to read; you reason from the RNA gene itself and the recent literature.
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Try it, ▶ open the session View the variant within the RNU4-2 gene body; a second hotspot sits at n.129G>A.
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Case: Jon Bernstein · medRxiv 2025

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RNU4-2 snRNA-gene variant on hg38
RNU4-2 non-coding RNA-gene variant on hg38
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Structural & repeat

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CNVs and repeat expansions

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A 2.22 Mb duplication on chromosome 22

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chr22:g.18,895,798-21,111,753dup GRCh38 2.22 Mb

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  • A large copy-number gain at 22q11.2 — a different interpretation problem from SNVs.
  • Load the CNV Recommended Track Set.
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CNV-specific evidence ClinGen Dosage (triplosensitivity), ClinVar CNVs, DECIPHER and PanelApp CNV regions — each filterable.
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Try it, ▶ open the session Load the CNV RTS; compare the duplication against ClinGen Dosage and DECIPHER.
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Example session

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chr22 2.22 Mb duplication on hg38
A 2.22 Mb duplication with ClinGen Dosage, ClinVar CNVs, DECIPHER and PanelApp
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FGF14 — a GAA repeat expansion

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FGF14 intron 1 hg38 chr13:102,161,567 ~270-300 GAA repeats

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  • Late-onset cerebellar ataxia (SCA27B) caused by an intronic repeat expansion — not an SNV or CNV.
  • A distinct class of variant with its own resources.
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A third variant class View the intron-1 GAA locus in the Browser, then cross-check dedicated tandem-repeat resources (WebSTR, TRatlas).
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Try it, ▶ open the session Navigate to the intron-1 repeat; compare against the tandem-repeat tracks/resources.
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Session: s/Max/fgf14

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FGF14 GAA repeat-expansion locus on hg38
FGF14 intron-1 GAA repeat locus on hg38
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More cases

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a gallery of de novo neurodevelopmental variants

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More cases: de novo neurodevelopmental variants

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A gallery of further worked cases (GSS series) — each opens as a live session:

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  • LRRC8A c.730T>C p.Phe244Leu — multisystem disorder, de novo heterozygous. session
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  • KPNA4 c.557G>A p.Gly186Asp chr3:160,526,107C>T — seizures, developmental delay, autism. session
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  • ERCC8 c.550+2T>C splice + a complex maternal SV — compound heterozygous, Cockayne-spectrum. session
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  • RNU4ATAC n.12C>T + n.120T>G — minor-spliceosome snRNA, compound heterozygous, multisystem.
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Same recipe Different genes and mechanisms, one workflow: open the session, load the right track set, read the evidence.
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What these cases show

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  • Coding variants can be read almost off the tracks — but always check the transcript and conservation (TCF4).
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  • Synonymous and deep-intronic variants can still break splicing — scan the splicing predictors.
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  • Non-coding variants are interpreted from regulatory context: cCREs, conservation, expression, TF motifs.
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  • CNVs and repeat expansions are their own classes, each with dedicated tracks and resources.
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The habit Turn every variant into a set of questions, then let the right track answer each one.
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Thank you!

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Questions? · genome@soe.ucsc.edu

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UCSC Genome Browser · genome.ucsc.edu

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UCSC Genome Browser team
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