Disease: Von Willebrand Disease (VWD) Type 2A

Patient: 31 yo, Female

Variant1: VWF NC_000012.12: c.875-5T>Gdel, p.(Ser292_Glu333delinsLys) Causes complete exon 8 skipping

Variant2: VWF NM_000552.5: c.813C>G, p.(Tyr271*)

Phenotypes: History of bleeding (epistaxis, uncontrollable by conventional hemostatic treatment), Easy bruising, gum bleeding, excessive menstrual bleeding, mild decrease in plasma VWF:Ag, severe impairment in VWF function, VWF:Ab/VWF:Ag ratio decreased, VWF:CB/VWF:Ag ratio decreased, FVIII:C lvs slighly below normal range

Family: Son had bleeding diathesis and spontaneous epistaxis (less severe than proband), normal parents

In silico data available: SpliceAI delta score of 0.51 for loss of splice acceptor caused by variant 1

Alamut showed small to moderate effects of the variant on normal splicing of VWF

NetGene2 showed weak strength of 3' splice sites in exon 8

SpliceAid2 showed TIA-1 and TIAL 1, which bind to U-rich motifs and facilitate 5' splice site recognition where destroyed in the mutated sequence

Disease: Von-Willebrand Disorder

Patient 2 Variant(s):

VWF NM_000552.5: c.4135C>T p.(Arg1379Cys) Exon 28 VWF NM_000552.5: c.4130C>T p.(Ala1377Val) Exon 28 VWF NM_000552.5: c.3797C>T p.(Pro1266Leu) Exon 28 VWF NM_000552.5: c.3835G>A p.(Val1279Ile) Exon 28

Note: Pro1266Leu and Val1279Ile are in trans with Ala1377Val and Arg1379Cys

Note2: MAF of Ala1377Val is present in Exome Variant Server (<0.01) and 1000 Genomes database (<0.02), designated as rare variant, typically found in indiv with African ethnicity

Family: Relatives molecular analysis showed Arg1379 and Ala1377Val variants mentioned above were in cis

Patient 2 Phenotype: Mild bleeding symptom Nearly normal VWF:Ag value, reduced VWF:RCo value slight loss of HMWM with smear decreased/slightly decreased proteolysis Slightly reduced RIPA VWFpp/VWF:Ag ratio shows increased VWF clearance VWF platelet levels reduced reduced rBpIba binding in VWF plasma VWF:GPIbM values slightly increased

Note: Treated with desmopressin in case of minor surgeries or delivery

Note 2: Slightly decreased RIPA may be explained by presence of 2B New York Variant (Pro1266Leu) that mitigates RIPA assay in 2M phenotype.

In silico analysis available:

I-Mutant 3.0 states decrease in A1 domain stability for both mutations (Ala1377Val = -0.91, Arg1379Cys = -1.36)

PYMOL predicts Ala1377Val does not alter formation of hydrogen bonds with Arg1374 residue and water. Predicts substitution of ARG 1379 with a cysteine results in the loss of hydrogen bonds with Lys1407 and Lys1408, predicted change in secondary structure of A1 domain

Ala1377Val was previously reported in 3 other patients Publications:

Millar CM, Riddel AF, Mellors G, Yee TT. The spectrum of VWD type 2 phenotypes associated with A1 domain mutations posters. J Thromb Haemost 2009; 7: 531–2.

Logsdon BA, Dai JY, Auer PL et al. A variational Bayes discrete mixture test for rare variant association. Genet Epidemiol 2014; 38: 21–30.

Final note: Authors suggest patients' 2M phenotype is due to the presence of Ala1377Val and Arg1379Cys together to create synergistic effect. Though difficult to discern with this specific patient having two other variants in addition to the two mentioned above.

In at least one other published version the first two items on this list are not peacock fans and Japanese screens but “ormolu garden gates, handleless cups”. The Oxford Book of Victorian Ghost Stories, ed. Michael Cox and R.A. Gilbert

Ormolu is the gilding technique of applying finely ground, high-carat gold–mercury amalgam to an object of bronze, and for objects finished in this way. The mercury is driven off in a kiln leaving behind a gold coating. The French refer to this technique as "bronze doré"; in English, it is known as "gilt bronze". https://en.wikipedia.org/wiki/Ormolu?wprov=sfti1

In at least one other published version the first two items on this list are not peacock fans and Japanese screens but “ormolu garden gates, handleless cups”. The Oxford Book of Victorian Ghost Stories, ed. Michael Cox and R.A. Gilbert

Ormolu is the gilding technique of applying finely ground, high-carat gold–mercury amalgam to an object of bronze, and for objects finished in this way. The mercury is driven off in a kiln leaving behind a gold coating. The French refer to this technique as "bronze doré"; in English, it is known as "gilt bronze". https://en.wikipedia.org/wiki/Ormolu?wprov=sfti1

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Sandra Ciesek. (2021, December 8). Unsere ersten Daten zur Neutralisation von Omicron versus Delta sind fertig: 2x Biontech, 2x Moderna, 1xAZ/1x Biontech nach 6 Monaten 0% Neutralisation bei Omicron, auch 3x Biontech 3 Monate nach Booster nur 25% NT versus 95% bei Delta. Bis zu 37fache Reduktion Delta vs. Omicron https://t.co/w0gHww26sg [Tweet]. @CiesekSandra. https://twitter.com/CiesekSandra/status/1468465347519041539

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Meng, B., Abdullahi, A., Ferreira, I. A. T. M., Goonawardane, N., Saito, A., Kimura, I., Yamasoba, D., Gerber, P. P., Fatihi, S., Rathore, S., Zepeda, S. K., Papa, G., Kemp, S. A., Ikeda, T., Toyoda, M., Tan, T. S., Kuramochi, J., Mitsunaga, S., Ueno, T., … Gupta, R. K. (2022). Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts tropism and fusogenicity. Nature, 1–1. https://doi.org/10.1038/s41586-022-04474-x

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Harris, J. E. (2021). COVID-19 Incidence and Hospitalization During the Delta Surge Were Inversely Related to Vaccination Coverage Among the Most Populous U.S. Counties (p. 2021.08.17.21262195). medRxiv. https://doi.org/10.1101/2021.08.17.21262195

Le Page, M. (2021, November 22). What we know so far about AY.4.2 and other new coronavirus variants. New Scientist. https://institutions.newscientist.com/article/2298363-what-we-know-so-far-about-ay-4-2-and-other-new-coronavirus-variants/?utm_campaign=echobox&utm_medium=social&utm_source=Twitter

ReconfigBehSci. (2021, December 14). RT @thehowie: "...The vaccine provided 70 percent protection in fully vaccinated individuals against severe complications that would requir… [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1470749072160133128

How are new Covid cases impacting sport? (n.d.). BBC Sport. Retrieved December 23, 2021, from https://www.bbc.com/sport/59682938

ReconfigBehSci. (2021, December 14). RT @thehowie: BREAKING South Africa: 82% increase in cases, week over week. 34.9% positive rate. Record 7-day average. Not near platea… [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1470814593610047490

Dr Nisreen Alwan 🌻. (2021, December 23). We’re in unchartered territory. Https://t.co/O1GGcXpMll [Tweet]. @Dr2NisreenAlwan. https://twitter.com/Dr2NisreenAlwan/status/1474051397570248716

Kai Kupferschmidt. (2021, December 10). “the severity profile of Omicron cases must be interpreted along with an understanding of its capacity to re-infect (and infect the vaccinated)“ This is what I have been trying to explain the last few days. As usual @nataliexdean does it better (and in color)! [Tweet]. @kakape. https://twitter.com/kakape/status/1469270407995867139

Yaniv Erlich. (2021, December 8). Updated table of Omicron neuts studies with @Pfizer results (which did the worst job in terms of reporting raw data). Strong discrepancy between studies with live vs pseudo. Https://t.co/InQuWMAm4l [Tweet]. @erlichya. https://twitter.com/erlichya/status/1468580675007795204

ReconfigBehSci. (2021, December 12). RT @ryan_landay: > A new diverse genome has appeared within the B.1.1.529 lineage that has all of the shared mutations of B.1.1.529, some o… [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1470066521615605766

ReconfigBehSci. (2021, December 9). RT @RachelLavin: As Omicron reality dawns, consider investing in better masks: "....Tight-fitting FFP2 masks provide 75 times better pro… [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1474030898551087113

Campbell, D., Sabbagh, D., & Devlin, H. (2022, January 7). Military deployed at London hospitals due to Omicron staff shortages. The Guardian. https://www.theguardian.com/world/2022/jan/07/military-deployed-at-london-hospitals-due-to-omicron-staff-shortages

ReconfigBehSci. (2021, November 26). RT @mvankerkhove: Following the meeting of the @WHO TAG-VE today, WHO classifies B.1.1.529 as a variant of concern named Omicron. We call… [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1464302372100976650

ReconfigBehSci. (2021, December 12). RT @EricTopol: If you think Prior Covid protects against Omicron (B.1.1.529), think again https://medrxiv.org/content/10.1101/2021.12.08.21267491v1 and "Neutralizing antibo… [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1470434736304803845

ReconfigBehSci. (2021, November 26). vaccine equity has been a disaster, but I do wonder whether the exclusive focus on donations does the US/EU comparison justice. The EU allowed the export of huge numbers of EU produced doses at a time when the US did not (and EU itself was struggling to meet demand). [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1464255575416520749

ReconfigBehSci on Twitter: “RT @BNODesk: BREAKING: U.S. reports 716,714 new coronavirus cases, setting world record for cases in one day” / Twitter. (n.d.). Retrieved January 7, 2022, from https://twitter.com/SciBeh/status/1478987541332348933

Karan, A. (2022). We cannot afford to repeat these four pandemic mistakes. BMJ, 376, o631. https://doi.org/10.1136/bmj.o631

ReconfigBehSci. (2021, December 23). Risk of hospital stay 40% lower with Omicron than Delta, UK data suggests https://t.co/VupN8hY4qq [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1473916654421643266

ReconfigBehSci. (2021, November 26). maybe this is a good moment to remind people that makers of mRNA vaccines have been extensively prepping for the possibility of new variants. Biontech/Pfizer have given a timeline of 100 days to the delivery of a retooled version of their vaccine [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1464225264523747359

Kissane, E. (2021, December 23). We’re About to Lose Track of the Pandemic. The Atlantic. https://www.theatlantic.com/ideas/archive/2021/12/were-about-to-lose-track-of-the-pandemic/621097/

ReconfigBehSci. (2021, December 11). RT @MackayIM: Booster access brought forward to slow spread of Omicron COVID-19 variant https://t.co/PukbPydylw [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1469633384511119364

Eric Topol. (2022, January 2). As the world turns.....vertical the Omicron signature (|) @OurWorldInData https://t.co/LOBiaiBapD [Tweet]. @EricTopol. https://twitter.com/EricTopol/status/1477433315896430592

ReconfigBehSci. (2021, December 13). RT @DrEricDing: 11) Omicron is doubling every 1.6 days in UK 🇬🇧 according to @DrWilliamKu’s figure. That’s way faster growth than in South… [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1470451594378502154

Prof. Christina Pagel. (2021, December 23). UKHSA surveillance report shows reinfections rising sharply as Omicron takes hold https://t.co/UGArY4sbOA [Tweet]. @chrischirp. https://twitter.com/chrischirp/status/1474041921249189896

Thomas, T., & Duncan, P. (2021, December 23). If Omicron is the dominant variant in UK, why is the number of confirmed cases so low? The Guardian. https://www.theguardian.com/world/2021/dec/23/if-omicron-is-the-dominant-variant-in-uk-why-is-the-number-of-confirmed-cases-so-low

ReconfigBehSci. (2021, December 13). Important update on the now withdrawn @BallouxFrancois tweet identifying hopeful turning of the corner in SA omicron data [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1470311016114364420

ReconfigBehSci. (2021, December 11). RT @DrEricDing: DOUBLING % in one day: The spike of probable #Omicron variant in Scotland🏴󠁧󠁢󠁳󠁣󠁴󠁿 has critically surged—Now at 13.3%, up fro… [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1469596523222781954

ReconfigBehSci. (2021, December 8). RT @kallmemeg: NEW: @UKHSA Mini Omicron Update Omicron VOC-21NOV-01 (B.1.1.529) update on cases, S gene target failure and risk assessment… [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1468673329494216726

John Burn-Murdoch. (2021, November 25). Five quick tweets on the new variant B.1.1.529 Caveat first: Data here is very preliminary, so everything could change. Nonetheless, better safe than sorry. 1) Based on the data we have, this variant is out-competing others far faster than Beta and even Delta did 🚩🚩 https://t.co/R2Ac4e4N6s [Tweet]. @jburnmurdoch. https://twitter.com/jburnmurdoch/status/1463956686075580421

CNN, I. K. (n.d.). Vaccine inequity and hesitancy made the Omicron variant more likely, scientists say. CNN. Retrieved December 23, 2021, from https://www.cnn.com/2021/11/28/world/omicron-coronavirus-variant-vaccine-inequity-intl-cmd/index.html

ReconfigBehSci. (2021, December 22). RT @chrischirp: Positivity rising steeply too—There are definitely many more people we aren’t catching https://t.co/4xDPwYQtrx [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1473695678610214927

ReconfigBehSci on Twitter: “RT @chrischirp: As well as Tom’s new one (B.1.1.529), C.1.2 seems to be spreading in S Africa—C.1.2 was the one with lots of worrying mut…” / Twitter. (n.d.). Retrieved December 23, 2021, from https://twitter.com/SciBeh/status/1463597407082532864

ReconfigBehSci. (2021, December 16). RT @MadsAlbertsen85: #Omicron update from Denmark. Omicron cases on the 12th of December adjusted up to 20.5% (+2%). Omicron is now having… [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1471516083819462670

ReconfigBehSci. (2021, December 11). RT @thehowie: BREAKING: Hospitalizations South Africa Hospitalizations⬆️67% week over week. Gauteng Province⬆️66%. GP⬆️1.6% from yesterd… [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1469685234149072897

ReconfigBehSci. (2021, December 9). a rather worrying development- a (local) newspaper “fact checking” the new German health minister simply by interviewing a virologist who happens to have a different view. There’s simply no established “fact” as to the severity of omicron in children at this point in time [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1469037817481334786

Trevor Bedford. (2021, December 11). We find that logistic growth of Omicron sequence fraction looks similar between the UK, the US and Germany with roughly 1% of sequenced cases in all three countries being Omicron on Dec 1. 3/10 https://t.co/De0t2xreU9 [Tweet]. @trvrb. https://twitter.com/trvrb/status/1469784757261127685

Gollub, R. L. (2022). Brain changes after COVID revealed by imaging. Nature. https://doi.org/10.1038/d41586-022-00503-x

ReconfigBehSci. (2021, December 17). RT @EricTopol: No evidence that Omicron is less severe, new @imperialcollege study reports https://ft.com/content/020534b3-5a54-4517-9fd1-167a5db50786 https://t.co/5YYzJ6tVtc [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1472156681098469380

ReconfigBehSci. (2021, November 26). RT @HZiauddeen: 🧵 COVID-19 & B.1.1.529: A chance for govt & others to change their mind and their approach? While we are still gathering d… [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1464200877888184324

ReconfigBehSci. (2021, December 22). RT @chrishendel: We need increased targeted measures now to slow the spread of #Omicron by @DrSarahHal via @bmj_latest https://t.co/3Tx… [Tweet]. @SciBeh. https://twitter.com/SciBeh/status/1473987200509521925

Perspective | Even the best-case scenario with omicron will still be bad. (n.d.). Washington Post. Retrieved December 23, 2021, from https://www.washingtonpost.com/outlook/2021/12/21/omicron-mild-cases-numbers/

Covid: Dutch go into Christmas lockdown over Omicron wave. (2021, December 18). BBC News. https://www.bbc.com/news/world-europe-59713503

Nature Portfolio. (2021, October 15). A study in @NatureMedicine indicates that the effectiveness of the Pfizer/BioNTech and Oxford-AstraZeneca vaccines against SARS-CoV-2 infections with symptoms or high viral burden is reduced with the Delta variant compared to the Alpha variant. Https://go.nature.com/3vecpoj https://t.co/XQdnMYguFz [Tweet]. @NaturePortfolio. https://twitter.com/NaturePortfolio/status/1449145321188216836

Prof. Shane Crotty. (2021, October 19). 1/ The regular vaccines give great booster responses against Delta and other variants This was first shown by Moderna, with “original recipe” vaccine booster, compare to Beta booster. Https://nature.com/articles/s41591-021-01527-y https://t.co/g7YDwGIURP [Tweet]. @profshanecrotty. https://twitter.com/profshanecrotty/status/1450489709050744833