PatientID: None

KindredID: 1

Case: M, 2Y0M, Danish

DiseaseAssertion:Asymptomatic

FamilyInfo: The patient's father had the p.P2P VHL mutation as well as another VHL mutation (p.P81S) and presented with renal cell carcinoma. The patient's uncles had this p.P81S mutation but were both asymptomatic. The patient's paternal grandmother also had this mutation and had breast cancer. See Figure 1 for family pedigree.

CasePresentingHPOs: N/A

CaseHPOFreeText:N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P2= (c.6C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 456593 https://www.ncbi.nlm.nih.gov/clinvar/variation/456593/

CAID: N/A

gnomAD: 0.000 https://gnomad.broadinstitute.org/variant/3-10183537-C-G

VariantEvidence: N/A

MutationType: synonymous_variant

CivicName: P2= (c.6C>G)

MultipleGeneVariants: N/A

GroupID: 2

DiseaseAssertion: VHL

Group size: 1

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

Group Info: Retrospective analysis of a longitudinal cohort of 21 VHL germline mutation carriers and retinal haemangioblastomas. All patients were categorized in two genotypic categories: missense mutations and truncating mutations.

GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

GroupHPOFreeText: The patient presented with retinal capillary hemangioma.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1

Variant: Exon 1-2 deletion

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: cDNA level information: c.(?_1)_463+?del

MutationType: exon_loss_deletion

CivicName: Exon 1-2 deletion

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: F, 24Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: Third child of healthy unrelated parents; she has two healthy older sisters.

CasePresentingHPOs: HP:0001511; HP:0001999; HP:0000952; HP:0001943; HP:0001508; HP:0000851; HP:0001250; HP:0002650; HP:0001332; HP:0001263; HP:0006880 (Intrauterine growth retardation, Abnormal facial shape, Jaundice, Hypoglycemia, Failure to thrive, Congenital hypothyroidism, Seizure, Scoliosis, Dystonia, Global developmental delay, Cerebellar hemangioblastoma)

CaseHPOFreeText: Normally born after 37 weeks pregnancy. During the prenatal period, she showed intrauterine growth retardation of unknown cause. At birth, dysmorphic features were noted (full list in table 1). After birth, she was treated for physiological jaundice and hypoglycemia. In addition, she has problem for failure to thrive and feeding difficulties associated with poor sucking and regurgitation. Furthermore, she was diagnosed with a congenital hypothyroidism in the neonatal screening. At 26 months old, she developed epilepsy. At 7Y, was considered to have Rett syndrome because of stereotypic hand movements since 2 years old, scoliosis and dystonia. Her psychomotor development was severely delayed: she had no ability to move by herself, visual contact, or social interaction. Brain MRI was performed at 1 year old and 6 years old. Both of these showed no abnormal findings. At 16 years old, follow-up MRI unexpectedly demonstrated a solid tumor with peritumoral edema at right cerebellum; diagnosed a cerebellar hemangioblastoma and confirmed through histopathology.

CaseNotHPOs: HP:0002012 (Abnormality of the abdominal organs)

CaseNotHPOFreeText: Repeat brain MRI, fundoscopy, abdominal echography and CT, blood and urine testing revealed no other tumors associated with VHL.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Complete Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: No mutation was detected in MECP2 on chromosome Xq28. At 5 months old, her chromosome analysis of the white blood cells revealed a distal deletion of the short arm of chromosome 3. Genomic DNA from the patient and her parents revealed a de novo 11.0-Mb deletion at 3p26.3-25.3 that included VHL and a paternally inherited 740-kb gain at Xp22.2-22.13, which was predicted to be a benign copy number variation. Unfortunately, since the mutation analysis of VHL was not performed using resected tumor tissues in the present case, “the second hit” could not be confirmed. Thus, the reason remains unclear why a cerebellar hemangioblastoma developed in her.

MutationType: deletion

CivicName: 3p26.3-25.3 11Mb del

MultipleGeneVariants: see VariantEvidence.

PatientID: None

KindredID: 1

Case: M, 31Y0M, Danish

DiseaseAssertion: VHL

FamilyInfo: The patient's brother carried the mutation. The proband’s paternal uncle died from metastasizing RCC at 46 years of age, and the proband’s father died from urosepsis in relation to bladder cancer in situ at the age of 56. Neither of these men were able to undergo genetic testing. The patient's mother was found to carry the mutation and had breast cancer. The maternal grandmother as well as a half brother were found to harbour the mutation but were asymptomatic. The proband's child was found to have a different VHL mutation (p.P2P). See Figure 1 for family pedigree.

CasePresentingHPOs: HP:0005584 (renal cell carcinoma)

CaseHPOFreeText: The patient presented with renal cell carcinoma at age 29.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P2= (c.6C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 456593 https://www.ncbi.nlm.nih.gov/clinvar/variation/456593/

CAID: N/A

gnomAD: 0.000 https://gnomad.broadinstitute.org/variant/3-10183537-C-G

VariantEvidence: N/A

MutationType: synonymous_variant

CivicName: P2=(c.6C>G) and P81S(c.241C>T)

MultipleGeneVariants: Germline, VHL, c.241C>T (p.Pro81Ser)

GroupID: 63

DiseaseAssertion: VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Japanese

GroupAgeRange: N/A

GroupInfo: 3 individuals from a single family (ID 63).

GroupPresentingHPOs: HP:0001732; HP:0005584; HP:0010797 (Abnormality of the pancreas, Renal cell carcinoma, Hemangioblastoma)

GroupHPOFreeText: CNS hemangioblastoma (2/3), renal cell carcinoma (3/3) and pancreatic cyst or tumor (unspecified) (1/3).

GroupNotHPOs: HP:0009711 (Retinal capillary hemangioma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S168Tfs*2 (c.503_513del)

LegacyVariant: c.716_726del (c.716del11bp)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573131812, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573131812

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion; minus_2_frameshift_variant

CivicName: S168Tfs*2 (c.503_513del)

MultipleGeneVariants: N/A

GroupID: 1

DiseaseAssertion: VHL

Group size: 1

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

Group Info: Retrospective analysis of a longitudinal cohort of 21 VHL germline mutation carriers and retinal haemangioblastomas. All patients were categorized in two genotypic categories: missense mutations and truncating mutations. 

GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

GroupHPOFreeText: The patient presented with retinal capillary hemangioma.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1

Variant: Exon 1-2 deletion

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Chr3(GRCh37): g.10182301_10188764del; c.-1231_463+444del6464

MutationType: exon_loss_deletion

CivicName: Exon 1-2 deletion

MultipleGeneVariants: N/A

for - Medium article - cogress - Part 1 - progress trap - James Gien Wong - definition - cogress - to - Medium article cogress - Part 2 - progress trap - James Gien Wong - https://hyp.is/t8FhpDGAEfC4J7f0NEFujg/medium.com/@gien_SRG/human-cogress-part-2-d6fd075a55c7 - to - Stop Reset Go hypothesis annotations - progress trap - Ronald Wright - https://jonudell.info/h/facet/?max=100&expanded=true&user=stopresetgo&exactTagSearch=true&any=ronald+wright - General - https://jonudell.info/h/facet/?max=100&expanded=true&user=stopresetgo&exactTagSearch=true&any=progress+trap - from - youtube - Planet Critical interview - Samuel Miller MacDonald - The Myth of Progress - https://hyp.is/r-hmFtjKEfCd8odATbINbA/www.youtube.com/watch?v=BEhmWEDkZUQ

for - definition - cogress - Medium article - Cogress - Part 2 - Stop Reset Go - Deep Humanity - James Gien Wong - from - Medium article - Cogress - Part 1 - Stop Reset Go - Deep Humanity - James Gien Wong - https://hyp.is/_Nyg2DF_EfCBeu_iuDroYg/medium.com/@gien_SRG/human-cogress-part-1-5159a575e1c4 - to - Stop Reset Go hypothesis annotations - progress trap - Ronald Wright - https://jonudell.info/h/facet/?max=100&expanded=true&user=stopresetgo&exactTagSearch=true&any=ronald+wright - General - https://jonudell.info/h/facet/?max=100&expanded=true&user=stopresetgo&exactTagSearch=true&any=progress+trap

This selection of texts raises multiple questions when we read it. The heaviest question that we see at the surface, seems to be "what validates our existence?" For Sherlock Holmes it seems to be the idea of busy work, or at least work that distracts you from the paralyzing monotony of our everyday lives. There is a quote from a twentieth century French philosopher Albert Camus who states something to the effect of: “the struggle itself towards the height is enough to fill a man’s heart. One must imagine Sisyphus happy." What does this mean? Simply, Camus argues it is imperative to our survival and our happiness that we are constantly at battle with something in our lives. Sherlock Holmes, who finds his everyday life to be too simplistic and monotonous for survival, seeks out means to stimulate his expansive and industrious consciousness from drowning in his own boredom and eternal cosmic impermanence as a means of validating his own existence. The very reason that Holmes takes cases that are overly puzzling and excessively complex is because it validates his existence and sedates his mind like narcotics in a bee hive, which is exactly what Camus states is essential to human survival. Sisyphus

This gives context to money in this time period. We know it is a large sum based on their reactions, obviously, but clarifies each person's situation based on their reaction as well. It gives Sherlock and Watson context to how well off Miss Morstan is, and it gives us, the reader, a base for Sherlock and Watson's financial situation as well.

Here is some segregation of cultures, I believe it is key to understanding more about 18th century customs and regulations. They are in a shabby neighborhood which is predominantly Indian, this could be intentional or just writing what was true at the time.

Sort of a little foreshadowing here, with Watson's emotions being displayed flamboyantly.

This is a classic Sherlock quote, it explains his intelligence in a way that fits Sherlock's attitude and presence. This is a really good way to have believable characters, they say things you would expect them to say.

It is interesting how much sarcasm is used in this story, it highlights the beliefs and the culture of the time in a way that we in the future can interpret similarly.

It is actually a little comical how nonchalant this seems, though for historical context, this was actually quite common, most of the poverty that was exhibited during this time involved addiction to opiates or other now-illegal drugs.