- Aug 2024
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drive.google.com drive.google.com
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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:
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- Jul 2024
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drive.google.com drive.google.com
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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)
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drive.google.com drive.google.com
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Case: no patient ID#, 36yo donor , female
Disease Assertion: UCD/OTCD
Family Info:
Case Presenting HPOs: adult onset (HP:0003581), oriticaciduria (HP:0003218), irritability (HP:0000737), protein avoidance
Case HPO FreeText: hyperammonemic encephalopathy
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: N/A
Supplemental Data: TABLE 1, She is vegeterian. The symptoms of OTCD started showing after the patient donated 60% of liver to her sibling. the information reported in this is the biochemical results during hyperammonemic episode following the transplantation. the patient became irritable and confused, and her level of consciousness deteriorated markedly. After hemodialysis the patient recovered.
Variant: NM_000531.6: c.429T>A(p.Tyr143*)
ClinVarID: 1072591
CAID: CA412723166
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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drive.google.com drive.google.com
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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)
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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)
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drive.google.com drive.google.com
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Case: no patient ID#, male
Disease Assertion: UCD/OTCD
Family Info:
Case Presenting HPOs: Neonatal onset (HP:0003623)
Case HPO FreeText:
Case NOT HPOs:
Case NOT HPO Free Text:
Case Previous Testing: GDNA was extracted from blood or liver tissues using salt and ethanol precipitation. multiplex amplification for exons 1, 5 and 9 to screen male patients with large deletions. Band intensities were measured using a molecular dynamics phosphoimager.
Supplemental Data: TABLE 2,
Variant: NM_000531.6: c.437C>G(p.Ser146*)
ClinVarID: 97201
CAID: CA224606
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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drive.google.com drive.google.com
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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)
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Case: patient #213, 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.962C>A(p.Ser321*)
ClinVarID: 97373
CAID: CA224859
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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drive.google.com drive.google.com
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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)
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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)
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drive.google.com drive.google.com
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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)
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Case: patient #52, 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
Variant: NM_000531.6:c.894G>A(p.Trp298*)
ClinVarID: N/A
CAID: CA412725724
gnomAD:
Gene Name: OTC (ornithine transcarbamylase)
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drive.google.com drive.google.com
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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)
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drive.google.com drive.google.com
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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)
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Case: Patient #30, female, Korean
DiseaseAssertion: UCD/OTCD
FamilyInfo: N/A
CasePresentingHPOs: HP:0011463, HP:0003218
CaseHPOFreeText: childhood onset, oroticaciduria,
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: "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, 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.491C>G(p.Ser164*)
ClinVarID: 97220
CAID: CA224642
gnomAD:
GeneName: OTC (ornithine transcarbamylase)
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drive.google.com drive.google.com
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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)
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drive.google.com drive.google.com
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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)
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Case: Patient #20, male, Chinese
DiseaseAssertion: UCD/OTCD
FamilyInfo:
CasePresentingHPOs: HP:0011463, HP:0001987, HP:0003218
CaseHPOFreeText: childhood onset, hyperammonemia, oroticaciduria
CaseNOTHPOs:
CaseNOTHPOFreeText: No 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, drug treatment (L-arginine, L-Citrulline, sodium benzoate, and sodium phenylbutyrate), deceased
Variant: NM_000531.6:c.794G>A(p.Trp265*)
ClinVarID: N/A
CAID:CA412722994
gnomAD:
GeneName: OTC (ornithine transcarbamylase)
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Case: Patient #3, male, Chinese
DiseaseAssertion: UCD/OTCD
FamilyInfo: Family history of the disease, variant in probands mother and father
CasePresentingHPOs: HP:0003623, HP:0001987, HP:0003218
CaseHPOFreeText: neonatal, hyperammonemia , oroticaciduria
CaseNOTHPOs: N/A
CaseNOTHPOFreeText: No 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, no therapy received, mutation inherited, family history, deceased
Variant: NM_000531.6:c.579G>A
ClinVarID: N/A
CAID: CA412725369
gnomAD:
GeneName: OTC (ornithine transcarbamylase)
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- May 2022
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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DICER1 syndrome is a rare genetic condition predisposing to hereditary cancer and caused by variants in the DICER1
GeneName: DICER1 PMCID: PMC7859642 HGNCID: Unavailable Inheritance Pattern: Autosomal dominant. Disease Entity: Familial pleuropulmonary blastoma (PPB), cervix embryonal rhabdomyosarcoma, multinodular goiter, nasal chondromesenchymal hemartoma, Ciliary body medulloepithelioma, Sertoli-Leydig Cell Tumor (SLCT), differentiated thyroid carcinoma, pituitary blastoma, pineoblastoma, cystic nephroma, Wilm's tumor and sarcomas of different sites including, amongst others, the uterine cervix, kidney and brain. Mutation: Germline Zygosity: Heterozygose Variant: No ClinVarID present. Family Information: No family outline Case: No specified information of patients included. CasePresentingHPO's: n/a CasePrevious Testing: n/a gnomAD: n/a Mutation Type: nonsense, frameshift, or splice affected.
Tags
- Zygosity: Heterozygous
- Mutation type: Frameshift
- Multinodular goiter
- Nasal chondromesenchymal hemartoma
- Inheritance Pattern: Autosomal dominant
- Cervix embryonal rhabdomyosarcoma
- Ciliary body medulloepitheliomma
- Differentiated thyroid carcinoma
- Wilm's tumor
- Gene: DICER1
- Familial pleuropulmonary blastoma (PPB)
- Mutation type: Nonsense
- Sertoli-Letdig Cell Tumor(SLCT)
- PMCID: PMC7859642
- Mutation: Germline
Annotators
URL
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- Apr 2022
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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DICER1 syndrome is a rare genetic condition predisposing to hereditary cancer and caused by variants in the DICER1 gene.
Gene Name: DICER1 PMID:33552988 HGNCID: Unavailable Inheritance Pattern:Autosomal Dominant Disease Entity: familial pleuropulmonary blastoma (PPB),cystic nephroma, ovarian Sertoli-Leydig cell tumor (SLCT), multinodular goiter, cervix embryonal rhabdomyosarcoma, Wilms’ tumor, nasal chondromesenchymal hamartoma, ciliary body medulloepithelioma, differentiated thyroid carcinoma, pituitary blastoma, pineoblastoma, and sarcomas of different sites. Mutation: Nonsense, Frameshift<br /> Zygosity: Heterosygosity Variant:No ClinVar ID present Family Information:no diseases mentioned in family Case: no specified case in this article gnomAD: n/a Mutation type: Nonsense. frameshift
Tags
- differentiated thyroid carcinoma
- Inheritance Pattern: Autosomal Dominant
- SLCT
- nasal chondromesenchymal hamartoma
- ciliary body medulloepithelioma
- cervix embryonal rhabdomyosarcoma
- familial pleuropulmonary blastoma
- Gene: DICER1
- PMID:33552988
- multinodular goiter
- pineoblastoma
- Zygosity: Heterosygosity
- ovarian Sertoli-Leydig cell tumor
- pituitary blastoma
- cystic nephroma
- Mutation: Nonsense
- sarcomas
- Wilms’ tumor
- Mutation: Frameshift
- PPB
Annotators
URL
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