Disease: Platelet-type Von-willebrand Disorder (PT-VWD)

Patient: 17 yo, male, adopted

Variant: GP1BA NM_000173.7: c:580C>T p.(P.Leu194Phe), Heterozygous, gain-of-function

Phenotypes: moderate bleeding phenotype, ISTH-BAT bleeding score of 3, recurrent epistaxis, easy bruising, mild thrombocytopenia

Family: Adopted, no other family history mentioned, segregation studies not performed.

Genetic analysis performed: found variant in GP1BA, results obtained by sanger sequencing.

Variant present in gnomAD(rs368111193): low allele frequency, contradictory classifications

Variant is not present in ClinVar, LOVD, or HGMD databases

According to this paper, ACMG guidelines classified this variant as a VUS.

This paper entered it into Clinvar (var ID 1693270)

Disease: mild haemophilia A, influencing VWF levels

Patient: 20 yo, Female

Variant1: F8 NM_000132.3: c.1127T>G: p. Val376Gly (Exon 8, current clinvar interpretation not available)

Variant 2: F8 NM_000132.3: c.3780C>G: p. Asp1260Glu (Exon 14, current ClinVar interpretation is benign)

Variant 3: VWF NM_000552.5: c.1415A>G:p.His484Arg (Exon 13, current ClinVar interpretation is Benign/likely Benign)

Variant 4: VWF NM_000552.5: c.2365A>G:p.Thr789Ala (Exon 18, current ClinVar interpretation is Benign/ likely Benign)

Variant 5: VWF NM_000552.5: c.2771G>A:p.Arg924Gln (Exon 21, current ClinVar interpretation is conflicting interpretations of pathogenicity (VUS-3)(Benign-4)(Likely benign-1))

Variant 6: VWF NM_000552.5: c.4141A>G:p.Thr1381Ala (Exon 28, current ClinVar interpretation is Benign/ Likely Benign)

Variant 7: VWF NM_000552.5: c.6532G>T:p.Ala2178Ser (Exon 37, Conflicting interpretations of pathogenicity: (VUS-1) (Likely Benign-1))

Variant 8: F5 NM_000130.5: c.2773A>G:p.Lys925Glu (Exon 13, current ClinVar interpretation is Benign/Likely Benign)

Variant 9: F5 NM_000130.5: c.2594A>G:p.His865Arg (Exon 13, current ClinVar interpretation is Benign/Likely Benign)

Variant 10: F5 NM_000130.5: c.2573A>G:p.Lys858Arg (Exon 13, Conflicting interpretations of pathogenicity: (VUS-1) (Benign-2)(Likely Benign-1))

Variant 11: F5 NM_000130.5: c.5290A>G:p.Met1764Val (Exon 16, Conflicting interpretations of pathogenicity: (VUS-1) (Benign-2)(Likely Benign-1))

Variant 12: F13A1 NM_000129.4: c.103G>T:p.Val35Leu (Exon 2, Conflicting interpretations of pathogenicity: (VUS-1) (Benign-3))

Variant notes: All are heterozygous

Both variants in F8 are linked to reports associated with haemophilia, though second variant is considered benign.

Phenotypes: History of bleeding (Heavy mentrual bleeding since menarche)(Treated with transdermal oestrogen and Levonorgestel), iron deficiency anaemia. High Janssen score for pictorial blood assessment. Gum bleeding lasting longer than 10 minutes(Treated with local application of tranexamic acid), recurrent nosebleeds, high score for ISTH and BAT assessments. Decrease in VWF:Ag ratio, VWF:CB ratio decreased, VWF: GPIbR ratio decreased

Family: Maternal grandfather possibly haemophiliac, mother asymptomatic

https://web.archive.org/web/20070203045327/http://www.chass.utoronto.ca/~klausner/MUT.html

https://web.archive.org/web/19990501205918/http://www.madog.org/geiriadr.html

Mutational meltdown happens in a population of animals if their number is so low that negative mutations and deletions in their DNA accumulate.

Dr Emma Hodcroft. (2021, May 2). 🗓️https://t.co/wVE7ubYBoy is updated🗓️, with some cool new additions: - B.1.617.1/2 are added as 20A/S:154K & 20A/S:478K 🎉—Beautiful new name table 📑🍾—Mutation list displayed in full as a ‘side-sausage’🌭 Let’s take a tour... 😁 1/7 [Tweet]. @firefoxx66. https://twitter.com/firefoxx66/status/1388921325411053569

Mallapaty, Smriti. ‘Where Did Omicron Come from? Three Key Theories’. Nature 602, no. 7895 (28 January 2022): 26–28. https://doi.org/10.1038/d41586-022-00215-2.

the Guardian. ‘How a String of Failures by the British Government Helped Covid-19 to Mutate | Anthony Costello’, 22 December 2020. http://www.theguardian.com/commentisfree/2020/dec/22/uk-government-blamed-covid-19-mutation-occur.

ReconfigBehSci on Twitter: ‘RT @AdamJKucharski: Summary of NERVTAG view on new SARS-CoV-2 variant, from 18 Dec (full document here: Https://t.co/yll9beVI9A) https://t.…’ / Twitter. (n.d.). Retrieved 2 March 2021, from https://twitter.com/SciBeh/status/1341034652082036739

Could it be that the genetic background (or importantly surrounding environment or cross talk among cells) in the first generation that were exposed to 25 C temp might have changed, and conditioned subsequent generations?

After 14 generations, secondary changes in the propoagated genetic makeup (including cross talk) could have reverted phenotype and reset histone marks to repress gene expression.

See if how often c.elegans mutate or show CN changes, i.e., background vs stress induced by temp changes?