Quests can also be independent projects or activities for the students who have finished their work.
I've used these type of independent activities like this in other classes, and they seemed to be beneficial because they keep students engaged after finishing their work while allowing others to continue learning at their own pace.
Wilson Jones Co., est. 1893 by [[Made-in-Chicago Museum]]
Disease: Dystrophic epidermolysis bullosa (DEB) pruriginosa *Note: A novel vwf variant was found in this patient with these other variants in COL7A1 gene
Patient(s): 17 YO Korean male
Variant: VWF NM_000552.5: c.3310C>T p. (R1101W) Located in exon 26
Hadn't been reported previously Variant found to be inherited in trans from family analysis
According to the paper, they have classified with with ACMG guidelines as likely pathogenic.
Reasoning: Variant absent in the Korea Ref Genome Database and Allele Freq = 0.00086% in gnomAD (Evidence: PM2)
Variant detected in trans with another well-known pathologic variant (c.5797C>T) (Evidence: PM3)
Multiple missense variants are known to be pathogenic in RDEB (Evidence: PP2)
Various computational in silico predictive programs reported the variant as pathogenic (Evidence PP3)
Case: Female Patient #1, Female, Japanese
DiseaseAssertion: UCD/OTCD
FamilyInfo: N/A
CasePresentingHPOs: Childhood onset (HP:0011463)
CaseHPOFreeText: Onset at 2 years
CaseNOTHPOs:
CaseNOTHPOFreeText: 16% OTC activity
CasePreviousTesting:
Variant: NM_000531.5:c.67C>T (p.Arg23*)
ClinVarID: 97292
CAID: CA224742
gnomAD:
Case: Patient #38, Female, Chinese
DiseaseAssertion: UCD/OTCD
FamilyInfo: No family history of disease, mutation is inherited
CasePresentingHPOs: Hyperammonemia (HP:0001987), oroticaciduria (HP:0003218), vomiting (HP:0002013), coma (HP:0001259), lethargy (HP:0001254), seizures (HP:0001250), childhood onset (HP:0011463)
CaseHPOFreeText: Elevated plasma ammonia at 190 umol/L (Normal: 9-30 umol/L), Elevated urinary orotate at 202 mmol/mmol creatinine (Normal: 0-1.5 mmol/mmol creatinine)
CaseNOTHPOs:
CaseNOTHPOFreeText: Normal plasma glutamine at 13.5 umol/L (Normal: 6-30 umol/L), Normal plasma citrulline at 15.75 umol/L (Normal: 7-35 umol/L)
CasePreviousTesting: gDNA extracted from peripheral blood leukocytes. PCR all coding exons and exon–intron boundaries of the OTC gene using 9 pairs of synthetic oligonucleotide primers, and the primer sequences and annealing temperature. PCR products were then purified and bidirectionally sequenced. The library was sequenced using Illumina HiSeq4000 and generated 150 bp paired-end reads. Data analysis was performed as previously described [Sun Y, Hu G, Liu H, Zhang X, Huang Z, Yan H, et al. Further delineation of the phenotype of truncating KMT2A mutations: the extended Wiedemann–Steiner syndrome. Am J Med Genet A. 2017;173:510–4.]. Multiplex ligation-dependent probe amplification analysis was performed for samples in which Sanger sequencing or WES failed to detect any disease-causing mutation.
Variant: NM_000531.6:c.67C>T (p.Arg23*)
ClinVarID: 97292
CAID: CA224742
gnomAD:
Case: Patient #4, Female, Caucasian
DiseaseAssertion: UCD/OTCD
FamilyInfo: N/A
CasePresentingHPOs: Hyperammonemia (HP:0001987),
CaseHPOFreeText: Elevated plasma ammonia concentration at 123 uM/L
CaseNOTHPOs:
CaseNOTHPOFreeText: Anxiety, plasma citrulline at 2 uM/L
CasePreviousTesting: N/A
Variant: NM_000531.5:c.67C>T (p.Arg23*)
ClinVarID: 97292
CAID: CA224742
gnomAD:
Case: Patient #85, Male
DiseaseAssertion: UCD/OTCD
FamilyInfo: N/A
CasePresentingHPOs:
CaseHPOFreeText:
CaseNOTHPOs: Late Onset
CaseNOTHPOFreeText: Milder phenotype
CasePreviousTesting: N/A
Variant: NM_000531.6: c.298+1G>T
ClinVarID: 97160
CAID: CA224544
gnomAD:
Case: patient#5 , female, Italian
Disease Assertion: UCD/OTCD
Family Info:
Case Presenting HPOs: irritability(HP:0000737), lethargy(HP:0001254), vomiting(HP:0002013), Oriticaciduria (HP:0003218), low plasma citrulline (HP:0003572), Elevated circulating alanine aminotransferase concentration(HP:0031964), Elevated circulating aspartate aminotransferase concentration (HP:0031956), childhood onset (HP:0011463)
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: Total RNA was isolated from peripheral blood lymphocytes or lymphoblastoid cell lines and from frozen liver biopsy as described in Chomczynski and Sacchi (1987). For each patient two cDNA syntheses were performed: 10mg of total RNA with 800-1000 ng of oligo dT or 500ng of specific primer NR, mapping in the 3’UTR of OTC cDNA Identification of genetic lesions by amplification of the OTC mRNA, expressed in the liver tissue and intestine, from a non-specific tissue like PBL or lymphoblastoid cell lines. Some mutations, particularly those affecting splicing sites, may have a different expression in liver and PBL . In females, including manifesting carriers, this method allows the identification of deletions and gene rearrangements with certainty, but mutations, decreasing mRNA stability, are unlikely to be detected because the normal allele will constitute the majority of the RNA available for RT-PCR and will be preferentially amplified.
Supplemental Data: Case report section Notes: Hepatomegaly. This mutation, previously reported (Reish et al., 1993), has been correlated with a lethal disease form in a male patient, therefore the mild phenotype in our patient could be explained by a not completely unfavorable X-lyonization
Variant: NM_000531.6: c.928G>T(p.Glu310*)
ClinVarID: 97361
CAID: CA224838
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
Case: no patient #ID, female Disease Assertion: UCD/OTCD
Family Info: NA
Case Presenting HPOs: NA
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: NA
Supplemental Data: TABLE 1, Notes: NA
Variant: NM_000531.6: c.77+1G>T
ClinVarID: 97314
CAID: CA224774
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
Case: patient #573, male
Disease Assertion: UCD/OTCD
Family Info:
Case Presenting HPOs:hyperammonemia (HP:0001987), Neonatal onset (HP:0003623)
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: GDNA extracted from blood leukocytes using the proteinase K/phenol extraction procedure on a model 340 A nucleic acid extractor (Applied Biosystems). 5mg samples of DNA were digested with BamHI, MspI, or TaqI restriction endonuclease, electrophoresed through 1 % agarose gels, and transferred to a nylon membrane by standard procedures. The blots were then hybridized with a radiolabeled full-length cDNA probe for human OTC.
Supplemental Data: TABLE 3,
Variant: NM_000531.6: c.67C>T(p.Arg23*)
ClinVarID:97292
CAID: CA224742
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
Case: patient SM, male
Disease Assertion: UCD/OTCD
Family Info:
Case Presenting HPOs: Hyperammonemia (HP:0001987), Neonatal onset (HP:0003623)
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: GDNA extracted from blood leukocytes using the proteinase K/phenol extraction procedure on a model 340 A nucleic acid extractor (Applied Biosystems). 5mg samples of DNA were digested with BamHI, MspI, or TaqI restriction endonuclease, electrophoresed through 1 % agarose gels, and transferred to a nylon membrane by standard procedures. The blots were then hybridized with a radiolabeled full-length cDNA probe for human OTC.
Supplemental Data: TABLE 3,
Variant: NM_000531.6: c.274C>T(p.Arg92*)
ClinVarID:97151
CAID: CA224530
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
Case: patient #188, male
Disease Assertion: UCD/OTCD
Family Info: N/A
Case Presenting HPOs: Neonatal onset (HP:0003623)
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: gDNA testing involves PCR amplification of all 10 exons and exon/intron boundaries followed by screening for mutations or sequencing of all fragments, For these patients, confirmation of the diagnosis requires enzymatic assays. No specifications about the test
Supplemental Data: TABLE 1
Variant: NM_000531.6: c.835C>T(p.Gln279*)
ClinVarID: 97341
CAID: CA224811
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
Case: patient #303, female
Disease Assertion: UCD/OTCD
Family Info: N/A
Case Presenting HPOs:
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: No specific functional tests indicated
Supplemental Data: In supplemental data files
Variant: NM_000531.6: c.766G>T(p.256Gly*)
ClinVarID: 870326
CAID: CA412722685
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
Case: patient #198, male
Disease Assertion: UCD/OTCD
Family Info: N/A
Case Presenting HPOs: Neonatal onset (HP:0003623)
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: No specific functional tests indicated
Supplemental Data: In supplemental data files
Variant: NM_000531.6:c.538C>T(p.Gln180*)
ClinVarID: N/A
CAID: CA412724187
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
Case: patient #16, female, Japanese
Disease Assertion: UCD/OTCD
Family Info: N/A
Case Presenting HPOs:
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: The severity of missense mutations was assessed using conservation and solvent accessible area of the replaced amino acid, calculated destabilization of mutant proteins and their SIFT and PolyPhen2 scores
Supplemental Data: Kido_et_al_2022_fgene_Data Sheet 2
Variant: NM_000531.6:c.77+1G>T
ClinVarID: 97314
CAID: CA224774
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
Case: patient #56, female, Japanese
Disease Assertion: UCD/OTCD
Family Info: N/A
Case Presenting HPOs: ,Hyperammonemia (HP:0001987)
Case HPO FreeText: N/A
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: The mRNA ref seq were, wherein the “A” nucleotide of the start codon ATG constituted as +1 numbering of the cDNA sequence. Met encoded by the start codon ATG also represented +1 for the amino acid numbering as set forth by the preprotein seq. PolyPhen-2, SIFT, and I-Mutant 3 tools were used for predicting the potential impact of an amino acid alteration in missense mutations on the function of each enzyme.
Supplemental Data: Table 1, patient had a liver transplant at 12yo.
Variant: NM_000531.6:c.940G>T(p.Glu314*)
ClinVarID: N/A
CAID: CA412726302
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
Case: no patient ID, Female
Disease Assertion: UCD/OTCD
Family Info: N/A
Case Presenting HPOs: HP:0003623, HP: 0001987
Case HPO FreeText: Neonatal onset, hyperammonemia
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: "Genomic DNAs were extracted from leukocytes, The ten exons and intron-exon boundaries of the OTC gene were PCR amplified and analyzed by Sanger sequencing on an ABI3100 sequencer. Intragenic deletions/duplications were searched for by Multiple Ligation Probe Dependent Amplification assay. Potential impact of non truncating variants on mRNA and protein was predicted using Splice Site Prediction. OTC variants were split into two groups, “severe” and “mild,” based on their impact on the clinical phenotype and on the OTC protein.
Supplemental Data: Table 3, All nuclear family members were tested but no information about their genotype. the condition to be part of this study was the presence of at least one heterozygous female in the pedigree of the patient.
Variant: NM_000531.6:c.766G>T(p.Gly256*)
ClinVarID: 870326
CAID: CA412722685
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
Case: Patient #35, female, Korean
Disease Assertion: UCD/OTCD
Family Info: N/A
Case Presenting HPOs: HP:0011463, HP:0003218, HP: 0001987
Case HPO FreeText: childhood onset, oroticaciduria, hyperammonemia
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: "Potential impact of mutations on OTC function and/or folding assessed by multiple alignments of orthologous protein sequences and human OTC and structural data from Protein Data Bank (1C9Y and available orthologs). In M patients, the approximate extent of the deletions assessed by inspection of presence/absence of PCR products. In F patients, the deletions determined by the SALSA multiplex ligation probe amplification (MLPA) KIT P079 OTC (MRC-Holland, Amsterdam, the Netherlands) and the Affymetrix Human SNP 6.0 array (Santa Clara, CA). Sequence spanning 38,211,736 – 38,300,703 bp region on chromosome X (GRCh37) and including OTC was scanned for motifs CCTCCCT, CCTCCTT, CCTCCCTT, CCCCACCCC, CCNCCNTNNCCNC, GGNGGNAGGG and their complements known as being associated with recombination hotspots. Repeats capable of non-B DNA structure formation implicated in double strand breaks (DSBs) were sought by complexity analysis . X-inactivation ratio determined by analysis of methylation status of the human androgen-receptor locus (HUMARA)
Supplemental Data: Table 1&2, This is a large deletion. The minimum plasma ammonia, orotic acid and Gln+Glu concentrations depends on certain age range: Plasma ammonia: neonates <90μmol/l, other <60μmol/l. Urinary orotic acid: 0–1year <6.6mmol/mol creatinine, 1 – 10 years <3.5 mmol/mol creatinine, over 10 years <2.4 mmol/mol creatinine. Serum glutamate + glutamine: 0 – 1 month 200–1200μmol/l, 1 month–1year 200–1100μmol/l, 1year–18years 200–900μmol/l, over 18years 200–800μmol/l.
Variant: NM_000531.6:c.853C>T(p.Gln285*)
ClinVarID: N/A
CAID: CA412723777
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
Case: Patient #34, female, Korean
Disease Assertion: UCD/OTCD
Family Info: N/A
Case Presenting HPOs: HP:0011463, HP:0003218, HP: 0001987
Case HPO FreeText: childhood onset, oroticaciduria, hyperammonemia
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: "Potential impact of mutations on OTC function and/or folding assessed by multiple alignments of orthologous protein sequences and human OTC and structural data from Protein Data Bank (1C9Y and available orthologs). In M patients, the approximate extent of the deletions assessed by inspection of presence/absence of PCR products. In F patients, the deletions determined by the SALSA multiplex ligation probe amplification (MLPA) KIT P079 OTC (MRC-Holland, Amsterdam, the Netherlands) and the Affymetrix Human SNP 6.0 array (Santa Clara, CA). Sequence spanning 38,211,736 – 38,300,703 bp region on chromosome X (GRCh37) and including OTC was scanned for motifs CCTCCCT, CCTCCTT, CCTCCCTT, CCCCACCCC, CCNCCNTNNCCNC, GGNGGNAGGG and their complements known as being associated with recombination hotspots. Repeats capable of non-B DNA structure formation implicated in double strand breaks (DSBs) were sought by complexity analysis . X-inactivation ratio determined by analysis of methylation status of the human androgen-receptor locus (HUMARA)
Supplemental Data: Table 1&2, This is a manifesting heterozygote. Serum Gln+Glu was considered elevated. The minimum plasma ammonia, orotic acid and Gln+Glu concentrations depends on certain age range: Plasma ammonia: neonates <90μmol/l, other <60μmol/l. Urinary orotic acid: 0–1year <6.6mmol/mol creatinine, 1 – 10 years <3.5 mmol/mol creatinine, over 10 years <2.4 mmol/mol creatinine. Serum glutamate + glutamine: 0 – 1 month 200–1200μmol/l, 1 month–1year 200–1100μmol/l, 1year–18years 200–900μmol/l, over 18years 200–800μmol/l.
Variant: NM_000531.6:c.717+1G>T(IVS7+1G>T)
ClinVarID: 97298
CAID: CA224753
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
Case: Patient #42, female, Korean
DiseaseAssertion: UCD/OTCD
FamilyInfo: N/A
CasePresentingHPOs: HP:0011463, HP:0001987, HP:0003218
CaseHPOFreeText: Childhood onset, hyperammonemia, oroticaciduria
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: Genomic DNA was extracted from peripheral blood leukocytes. A total of 10 coding exons and exon–intron boundaries of the OTC gene were amplified by PCR with customized primers. PCR products were directly sequenced with the same primers . Sequencing results were compared with the established human OTC sequences(NM_000531.5). Multiplex ligation-dependent probe amplification analysis was performed for patients in whom no OTC mutations were identified by direct sequencing using the OTC MLPA kit.
Supplemental Data: Table 1, no range was given for blood ammonia concentration, range given in the tables for glutamine and urine orotate is slightly different than the one in the results paragraphs.
Variant: NM_000531.6:c.958C>T(p.Arg320*)
ClinVarID: 97371
CAID:CA285809
gnomAD:
GeneName: OTC (ornithine transcarbamylase)
Case: Patient #52, female, Chinese
DiseaseAssertion: UCD/OTCD
FamilyInfo: family history of the disease, variant in probands mother and father
CasePresentingHPOs: HP:0011463, HP:0001987, HP:0003218, HP:0003572
CaseHPOFreeText: childhood onset,, hyperammonemia, oroticaciduria, low plasma citrulline
CaseNOTHPOs:
CaseNOTHPOFreeText: neurological damage
CasePreviousTesting: gDNA extracted from peripheral blood leukocytes. PCR all coding exons and exon–intron boundaries of the OTC gene using 9 pairs of synthetic oligonucleotide primers, and the primer sequences and annealing temperature. PCR products were then purified and bidirectionally sequenced. The library was sequenced using Illumina HiSeq4000 and generated 150 bp paired-end reads. Data analysis was performed as previously described [Sun Y, Hu G, Liu H, Zhang X, Huang Z, Yan H, et al. Further delineation of the phenotype of truncating KMT2A mutations: the extended Wiedemann–Steiner syndrome. Am J Med Genet A. 2017;173:510–4.]. Multiplex ligation-dependent probe amplification analysis was performed for samples in which Sanger sequencing or WES failed to detect any disease-causing mutation.
SupplementalData: Table 3, inherited mutation, drug treatment(L-arginine, L-Citrulline, sodium benzoate, and sodium phenylbutyrate), low protein diet treatment, and continuous veno venous hemodialfiltration
Variant: NM_000531.6:c.703C>T
ClinVarID: N/A
CAID: CA412721652
gnomAD:
GeneName: OTC (ornithine transcarbamylase)
DICER1 syndrome encompasses a variety of benign and malignant manifestations including multinodular goitre
Gene: DICER1 PMCID: PMC8451242 PMID: 34552563 Pathogenic Inheritance Pattern: Autosomal Dominant MultipleDiseaseEntities Disease Entity: DICER1 syndrome, multinodular goitre, cystic nephroma, anaplastic renal sarcoma, Wilms tumour, differentiated thyroid carcinoma, gynandroblastoma, ciliary body medulloepithelioma, embryonal rhabdomyosarcoma, pineoblastoma, pituitary blastoma, kidney cyst, pulmonary cyst, Sertoli-Leydig Cell Tumor. Mutation: Germline MultipleGeneVariants Variant & Clinvar IDs: c.3452_3453del (485534), c.316del (no ClinVar ID), c.171_172insAC (no ClinVar ID), c.3434del (no ClinVar ID), c.988C>T (933007), c.5388dup (no ClinVar ID) Zygosity: None provided. Case: At time of operation, the goitre patients living in Denmark were ages 21, 12, 21, 8, 14, and 16. Four underwent total thyroidectomies, and two underwent partial thyroidectomies. The patient originally aged 21 previously had a kidney cyst at age 14 and a pulmonary cyst at an unknown age. The patient aged 14 at time of partial thyroidectomy later manifested a Sertoli-Leydig Cell Tumor at age 15. All six patients were female. CasePresentingHPO: None provided. CasePreviousTesting: thyroidectomy gnomAD: ENSG00000100697.10, https://gnomad.broadinstitute.org/gene/ENSG00000100697 Mutation Type: Frameshift, Nonsense
DICER1 syndrome is an autosomal-dominant, pleiotropic, tumor-predisposition disorder arising from pathogenic germline variants in DICER1, which encodes an endoribonuclease integral to processing microRNAs (1).
Gene Name: DICER1 PMCID: PMC5443331 PMID: 28323992 HGNCID: not found Inheritance Pattern: autosomal dominant Disease Entity: thyroid cancer and familial multinodular doiter Mutation: germline loss-of-function mutation Zygosity: not provided Variant: c.1870C>T; p.Arg624a, c.1870C>T; p.Arg624a, c.1870C>T; p.Arg624a, c.1870C>T; p.Arg624a, c.3726C>A; p.Tyr1242a, c.3675C>G; p.Tyr1225a, c.3675C>G; p.Tyr1225a Family Information: 145 individuals with a DICER1 germline mutation and 135 controls from 48 families Case: family members used; both males and females used and no significant differences seen among sex; ages range from 20-40 with carriers being significantly younger than controls; no significant differences seen among ethnicity but participants located from the US, UK, and Great Britain CasePresentingHPOs: thyroid cancer or MNG diagnosis common to those with a DICER! mutation but with no chemotherapy or radiation treatment yet CasePreviousTesting: tested levels of thyroid-stimulating hormone, thyroxine, thyroxine-binding globulin, and serum albumin; thyroid palpation; thyroid ultrasound; Sanger or next-generation sequencing assays gnomAD: n/a Mutation Type: missense
Embryonal rhabdomyosarcoma (ERMS) of the uterus has recently been shown to frequently harbor DICER1 mutations.
HGNCID:
https://deadline.com/2022/03/discovery-sets-board-of-directors-warnermedia-merger-1234979430/
New board for Warner Bros. Discovery after $43 billion merger.
But then his father finally said a resounding “No,” and nothing more would be spoken about it.
https://www.youtube.com/watch?v=8vpDIobFALk Jeremy Werner Anja Glumicic Hawken Paul Mark Chipollo