Disease: N/A, variant present in F12 gene

Patient: 36 yo, Female, Saudi descent

Variant:F12 NC_000005.9:g.176,830,269 G>A; p.Gly506Asp Homozygous mutation, exon 12 Located in peptidase S1 domain of F12

Family:

Consanguineous family history (parents first-degree cousins)

No family history of bleeding or thrombosis

Phenotypes:

Significantly high activated partial thromboplastin time

No history of bleeding during deliveries or tooth extractions

No history of thrombosis or skin manifestations

On no medications, physical examination unremarkable

Factor assays and VWF tests within normal ranges except Factor XII (Severely deficient)

variant is proposed to be deleterious but there is insufficient evidence to support this claim.

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

for - article - The End of Scarcity? From ‘Polycrisis’ to Planetary Phase Shift - Nafeez Ahmed - gene-culture coevolution - adjacency - indyweb dev - individual / collective evolutionary learning - provenance - tracing the evolution of ideas - gene-culture coevolution

adjacency - between - indyweb dev - individual / collective evolutionary learning - provenance - tracing the evolution of ideas - gene-culture coevolution - adjacency relationship - As DNA and epigenetics plays the role of transmitting biological adaptations, language and symmathesy play the role of transmitting cultural adaptations

Case: patient is named case #2, male

Disease Assertion: UCD/OTCD

Family Info:

Case Presenting HPOs: Hyperammonemia (HP:0001987), oriticaciduria (HP:0003218), low plasma citrulline (HP:0003572), neonatal onset(HP:0003623), Hyperglutaminemia (HP:0003217)

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: GDNA was isolated from lymphocytes. To examine the small mutations in the coding region of the OTC gene, all 10 exons and their flanking intron regions were amplified using PCR, and the nucleotide sequences of the amplified products were determined. To determine the intron 5 sequence of case 2, PCR was performed using primers OTCex5F and OTCint5R, and primers OTCint5F and OTCex6R (Table 1, Fig. 3). The amplified products were subcloned into the pT7 vector and the inserted DNA was sequenced using an automated DNA sequencer. Allopurinol test

Supplemental Data: TABLE 1, Notes:

Variant: NM_000531.6: c.540+265G>A

ClinVarID: NA

CAID: CA658658977

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: Patient #8, Female, Spanish

DiseaseAssertion: UCD/OTCD

FamilyInfo: Family history of disease

CasePresentingHPOs: Hyperammonemia (HP:0001987), Hyperglutaminemia (HP:0003217), Low plasma citrulline (HP:0003572), Oroticaciduria (HP:0003218), Childhood onset (HP:0011463)

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: Patients referred for mutational study because of enzymatically proven and/or laboratory proven OTC deficiency; genomic DNA extracted using commercial kit; amplified through PCR; SSCP analysis; sequenced using ABI Prism 3100 automated sequencer

SupplementalData: Table 1

Variant: NM_000531.6: c.391_397dup (p.Ser133Ilefs*3)

ClinVarID: 597358

CAID: CA913190354

gnomAD:

Case: Patient Proband SS, Female, Caucasian

DiseaseAssertion: UCD/OTCD

FamilyInfo: De novo inheritance, no family history of disease

CasePresentingHPOs: Hyperammonemia (HP:0001987), oroticaciduria (HP:0003218), Childhood onset (HP:0011463)

CaseHPOFreeText:

CaseNOTHPOs: Positive allopurinol test

CaseNOTHPOFreeText:

CasePreviousTesting: Genomic DNA isolated from peripheral blood leukocytes or cultured skin fibroblasts. Amplification by PCR used. SSCP analysis performed. Sequencing of both free and immobilized single strands carried out by dideoxy chain termination method.

SupplementalData: Table 1: Mutations in the Ornithine Transcarbamylase Gene of 17 Females

Variant: NM_000531.6:c.77+1G>A

ClinVarID: 97313

CAID: CA224773

gnomAD:

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 #16, Male

DiseaseAssertion: UCD/OTCD

FamilyInfo: N/A

CasePresentingHPOs: Neonatal onset (HP:0003623), Hyperammonemia (HP:0001987)

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: N/A

Variant: NM_000531.6: c.77+2dupT

ClinVarID: 567293

CAID: CA891844248

gnomAD:

Case: Patient #50, Male

DiseaseAssertion: UCD/OTCD

FamilyInfo: N/A

CasePresentingHPOs: Neonatal onset (HP:0003623), Hyperammonemia (HP:0001987)

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: N/A

Variant: NM_000531.6: c.174G>A (p.Trp58*)

ClinVarID: 97127

CAID: CA224490

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 #32, Female

DiseaseAssertion: UCD/OTCD

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: N/A

Variant: NM_000531.6: c.140dup (p.(Asn47LysfsTer8))

ClinVarID:

CAID:

gnomAD:

Case: Patient #7, Female

DiseaseAssertion: UCD/OTCD

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: N/A

Variant: NM_000531.6: c.29_32del (p.Asn10fs)

ClinVarID: 97157

CAID: CA224540

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: Patient #15, Female

DiseaseAssertion: UCD/OTCD

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

Variant: NM_000531.6: c.77+1G>A

ClinVarID: 97313

CAID: CA224773

gnomAD:

Case: patient #10, Male, Argentine

Disease Assertion: UCD/OTCD

Family Info: family history of the disease,

Case Presenting HPOs: Neonatal onset(HP:0003623), Hyperammonemia HP:0001987

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: The OTC gene mutations were identified using PCR amplification, classical sequencing (Sanger), and multiplex ligation-dependent probe amplification.10,11 Mutations were identified by comparison with the GenBank reference sequence for human OTC (GenBank entries: NG_008471.1, NP 000522.3, NM 000531.5, NC 000023.11) Missense mutations were analyzed using different computational algorithms: CLUSTALW2 (http://www.clustal.org/clustal2/), SIFT (http://blocks.fhcrc.org/sift/SIFT.html),Polyphen2(http://genetics.bwh.harvard.edu/pph/),PoPMuSiC(http://babylone.ulb.ac.be/popmusic/), and SIFT Indel(http://siftdna.org/www/SIFT_indels2.html).

Supplemental Data: Table 1 Notes: died at 6 months and had 2 brothers that died a neonatal stage

Variant: NM_000531.6: c.540+1G>A

ClinVarID: 1458773

CAID: CA412724226

gnomAD: X-38381340-A-T

Gene Name: OTC (ornithine transcarbamylase)

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: 24 yo Laotse patient , female

Disease Assertion: UCD/OTCD

Family Info:

Case Presenting HPOs:Hyperammonemia(HP:0001987), Adult onset (HP:0003581), Elevated circulating alanine aminotransferase concentration(HP:0031964), Elevated circulating aspartate aminotransferase concentration(HP:0031956), oriticaciduria(HP:0003218), Aminoaciduria(HP:0003355, Prolonged prothrombin time(HP:0008151), Cerebral edema(HP:0002181),

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: " Genomic DNA from the patient was isolated from cultivated fibroblasts. Nine pairs of primers were designed from the published sequence of the OTC gene6,7 to allow amplification of all 10 exons including adjacent intron sequences. Single-strand conformational polymorphism analysis of the polymerase chain reaction–amplified individual exon 8 yielded an unusual migration pattern of exon 9

Supplemental Data: Case report section Notes: Patient had a pregnancy 2 years prior and lost the baby. In this case report, She was a 14weeks pregnant(2nd pregnancy) 24yo . She died during this of severe hyperammonemia 5 days after being administered amino acids through parenteral nutrition. She developed signs of encephalopathy stage 4 with maximal dilated unresponsive pupils, brisk oculocephalic reflex, and severe hyperventilation, requiring mechanical ventilation. MRI revealed revealed diffuse cortical edema with loss of white to gray matter distinction. Increased excretion of Gly, Gln, Ser, Thr, and Lys was found in her urine. Treatment with benzoate was started but didn't save the patient.

Variant: NM_000531.6: c.892_893del(p.Trp298Aspfs*15)

ClinVarID: 97348

CAID: CA224820

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #11, female, 35yo, slovenian

Disease Assertion: UCD/OTCD

Family Info: family history of the disease,

Case Presenting HPOs: Adult onset(HP:0003581), hyperammonemia(HP:0001987), protein avoidance (HP:0002038)

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: Sequencing was performed at a 3rd-party sequencing center using a standardized seq of procedures following PCR-free WGS library preparation protocol Illumina TrueSeq DNA Nano and sequenced on Illumina NovaSeq 6000 platform with a mean autosomal depth greater than 30×. Variants were interpreted by a medical doctor specialized in the NGS sequencing data analysis and those classified as likely pathogenic or pathogenic according to the ACMG/AMP standards and guidelines were considered for reporting, while variants of uncertain clinical significance, were not considered. Likely pathogenic and pathogenic variants were further evaluated by the referring clinical geneticist and were considered and reported if they were classified as both a likely diagnostic finding and if they were compatible with the clinical presentation of referral.

Supplemental Data: Table 4 and section 3.1(Case description) Notes:

Variant: NM_000531.6: c.540+265G>A

ClinVarID: 449382

CAID: CA658658977

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #113, Male

Disease Assertion: UCD/OTCD

Family Info:

Case Presenting HPOs: Neonatal onset(HP:0003623), Hyperammonemia HP:0001987

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: GDNA from blood, cultured skin fibroblasts, liver from patients suspected for otc deficiency was used to amplify all 10 exons and exon/intron boundaries using primers listed in Table 1. The amplified DNA fragments were then screened by single-strand conformational polymorphism (SSCP) and the abnormally migrating DNA fragments were sequenced directly from PCR products (w/o subcloning) to identify the mutation. The amino acid residue substitution created by the mutation is examined using an alignment of 26 OTCase sequences from 23 species.

Supplemental Data: Table 4 Notes:

Variant: NM_000531.6: c.867+1G>A

ClinVarID: 97342

CAID: CA224813

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #20, Male

Disease Assertion: UCD/OTCD

Family Info: NA

Case Presenting HPOs: Hyperammonemia (HP:0001987), oriticaciduria (HP:0003218), low plasma citrulline (HP:0003572), neonatal onset (HP:0003623)

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: Genomic DNA was isolated using PUREGENE blood kit from peripheral leukocytes of patients and related family members with informed consents. Amplification by PCR of all 10 exons of the OTC gene was performed using nine pairs of primers designed to span all exons and their adjacent intronic regions. PCR products were subsequently sequenced using ABI3100 Genetic analyzer with BigDye termination ver.3.0.To analyze the activity of OTC protein expressed in the COS-7, high-pressure liquid chromatographic (HPLC) analysis was performed with a Water system, consisting of a model 510 pump and a UV-visible 420 detector.

Supplemental Data: Table 1 Notes:

Variant: NM_000531.6: c.796_805del(p.Ile265AspfsX20)

ClinVarID: NA

CAID: CA2695233326

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #1, female Disease Assertion: UCD/OTCD

Family Info:

Case Presenting HPOs: Hyperammonemia (HP:0001987), Juvenile onset (HP:0003621)

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: "DNA samples were obtained from either peripheral white blood cells or liver biopsies of probands. Patient 1 total liver RNAs were extracted by the acid-phenol-guanidium method and reverse-transcribed in cDNA by hexanucleotide priming using Superscript 11' (Life Technologies, Cergy-Pantoia, France). First strand cDNA was further PCR-amplified using forward and reverse primers specificons 7 and 9 of the OTC gene, respectively. Sequence comparisons were conducted using the FASTA option of the BISANCE package. Secondary protein conformational changes induced by sequence mutations were predicted using the algorithms of the BISANCE package. Nucleotidic changes potentially altering splice sites were studied using the Senapathy's algorithm from the BISANCE package."

Supplemental Data: TABLE 1, Notes:

Variant: NM_000531.6: c.731_739del(p.Leu244Profs)

ClinVarID: 97307

CAID: CA224765

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #273, Male

Disease Assertion: UCD/OTCD

Family Info: NA

Case Presenting HPOs: Neonatal onset (HP:0003623)

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: NA

Supplemental Data: Supplemental table file Notes:

Variant: NM_000531.6: c.818del (p.Glu273Glyfs*16)

ClinVarID: 97338

CAID: CA224807

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient MW

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: NA Notes: mutation might cause exon 8 kipping durring splicing.

Variant: NM_000531.6: c.718-2A>G

ClinVarID: 97303

CAID: CA224761

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #5, male, German Disease Assertion: UCD/OTCD

Family Info: Family history of the disease, Variant found in mother of the patient

Case Presenting HPOs: infantile onset (HP:0003593), oritic aciduria(HP:0003218), hyperammonemia(HP:0001987), hyperglutaminemia(HP:0003217), low plasma citrulline (HP:0003572)

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: Liver tissues were used to extract RNA that was later used to synthesize cDNA. The products were compared to healthy controls in order to detect variants. gDNA, in order to determine the size of deletions in patient 3 and 4 , a set of intronic primers presumably flanking the deletions was used and specific primers allowed sequencing of exactly those critical regions(sequencing on paper). To estimate the relevance of the identified intronic variants in terms of their capability to induce splicing, we used a score developed by Shapiro and Senapathy. This splice score offers information about the usage of a certain splice site

Supplemental Data: TABLE 1, Notes: died at 11 months, was given medication and low protein diet and was asymptomatic during that time. Died from sever cerebral edema.

Variant: NM_000531.6: c.1005+1091C>G

ClinVarID: N/A

CAID: CA2695233334

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #1, male, turkish

Disease Assertion: UCD/OTCD

Family Info: Family history of the disease, Variant found in mother of the patient

Case Presenting HPOs: infantile onset (HP:0003593), coma(HP:0001259), episodic hyperammonemia(HP:0001951), oriticaciduria(HP:0003218)

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: Liver tissues were used to extract RNA that was later used to synthesize cDNA. The products were compared to healthy controls in order to detect variants. gDNA, in order to determine the size of deletions in patient 3 and 4 , a set of intronic primers presumably flanking the deletions was used and specific primers allowed sequencing of exactly those critical regions(sequencing on paper). To estimate the relevance of the identified intronic variants in terms of their capability to induce splicing, we used a score developed by Shapiro and Senapathy. This splice score offers information about the usage of a certain splice site

Supplemental Data: TABLE 1, Notes: very mild movement disorder, the diagnosis was prenatal so measures were taken from birth,. 2 biopsies were performed and the revealed respectively a 30% and 50 % decrease on OTC activity.

Variant: NM_000531.6: c.867+1126A>G

ClinVarID: 571311

CAID: CA891843643

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #2, male, Saudi Arabian

Disease Assertion: UCD/OTCD

Family Info: Family history of the disease, Variant found in mother of the patient, Brother died of hyperammonemic crisis

Case Presenting HPOs: intellectual disability (HP:0001249), Neonatal onset (HP:0003623), seizure(HP:0001250), episodic hyperammonemia(HP:0001951), intellectual disability (HP:0001249)

Case HPO FreeText: hyperammonemic encephalopathy

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: Liver tissues were used to extract RNA that was later used to synthesize cDNA. The products were compared to healthy controls in order to detect variants. gDNA, in order to determine the size of deletions in patient 3 and 4 , a set of intronic primers presumably flanking the deletions was used and specific primers allowed sequencing of exactly those critical regions(sequencing on paper). To estimate the relevance of the identified intronic variants in terms of their capability to induce splicing, we used a score developed by Shapiro and Senapathy. This splice score offers information about the usage of a certain splice site

Supplemental Data: TABLE 1, Patient was severely mentally retarded after the age of 2. Low OTC activity

Variant: NM_000531.6: c.540+265G>A(p.Gln180_Glu181insX4)

ClinVarID: 449382

CAID: CA658658977

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.665del(p.(Gly222ValfsTer8)

ClinVarID: 97289

CAID: CA224738

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.663+2T>C

ClinVarID: 97285

CAID: CA224732

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: no patient #ID, male 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.663+1G>A

ClinVarID: 97283

CAID: CA224730

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)

https://www.reddit.com/r/movies/comments/kzc5o3/are_gene_hackman_characters_in_the_conversation/<br /> Are Gene Hackman characters in The Conversation (1974) and Enemy of the State (1998 ) connected?

I want to circle back to this as I've had this idea since I saw Enemy of the State as a rough cut.

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)

Case: no patient ID#, 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 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.541-2A>G

ClinVarID: 97243

CAID: CA224675

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

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)

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 from family 1, male

Disease Assertion: UCD/OTCD

Family Info: Family history of the disease

Case Presenting HPOs: coma(HP:0001259), lethargy(HP:0001254), hyperammonemia (HP:0001987), Neonatal Onset HP:0003623

Case HPO FreeText: Poor feeding, poor spirit

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: Genomic DNA was extracted using the QIAamp DNA Blood Midi Kit (Qiagen, Duesseldorf, Germany). Quality control assessment of DNA samples was performed using the NanoDrop 2000 ultra-microvolume nucleic acid and protein spectrophotometer (Thermo, Waltham, MA, USA). The purity of DNA was required to be between 1.8 and 2.0.

Supplemental Data: TABLE 1, admitted to neonatal department because of poor feeding, poor spirit, coma, and lethargy. The maternal grandmother of the proband in this family had given birth to 3 boys and 2 girls. Two boys died within 1 month after birth

Variant: NM_000531.6: c.867+1G>C

ClinVarID:N/A

CAID: CA412723994

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #5, female

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.53del (p.His18Profs*20)

ClinVarID: 97239

CAID: CA224671

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #85, 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: 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.449_451del(p.Leu151Trpfs*36)

ClinVarID: N/A

CAID: CA2759533410

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #154, 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.664-1G>A

ClinVarID: 97288

CAID: CA224811

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 #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)

Case: patient #220, 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.1005+2T>C

ClinVarID: 97090

CAID: CA224431

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #335, 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.861_862insAC (p.Met288Thrfs*2)

ClinVarID: N/A

CAID: CA2759522140

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 #212, 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.561delA(p.Gly188Valfs*18)

ClinVarID: N/A

CAID: CA2499307429

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 #55, male, Japanese

Disease Assertion: UCD/OTCD

Family Info: N/A

Case Presenting HPOs: Seizure (HP:0001250), Hyperammonemia (HP:0001987), Intellectual disability (HP:0001249)

Case HPO FreeText: abnormal brain MRI and brain waves, acute liver failure, corneal opacity

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.c.929_931del(p.Glu310Valfs*45)

ClinVarID: 858012

CAID: CA916083888

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: 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)

Case: patient #51, male, Japanese

Disease Assertion: UCD/OTCD

Family Info: N/A

Case Presenting HPOs: neonatal(HP:0003623), intellectual disability (HP:0001249), seizure (HP:0001250),Hyperammonemia (HP:0001987)

Case HPO FreeText: Hypertonus, Autism, Acute liver failure. very high blood ammonia

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.867+1G>C

ClinVarID: N/A

CAID: CA412723994

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #50, male, Japanese

Disease Assertion: UCD/OTCD

Family Info: N/A

Case Presenting HPOs: Seizure HP:0001250, hyperammonemia HP: 0001987

Case HPO FreeText: Hepatomegaly, Abnormal brain MRI and brain waves, Acute liver failure, Corneal opacity

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.834_840del(p.Gln279Serfs*8)

ClinVarID: N/A

CAID: CA2695233329

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: no patient ID, Female

Disease Assertion: UCD/OTCD

Family Info: N/A

Case Presenting HPOs: HP:0001951, HP: 0001987

Case HPO FreeText: episodic hyperammonemia, 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.1052delA(p.Lys351Serfs*44)

ClinVarID: 915468

CAID: CA1139667400

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: no patient ID, Female

Disease Assertion: UCD/OTCD

Family Info: N/A

Case Presenting HPOs: HP:0001951, HP: 0001987

Case HPO FreeText: episodic hyperammonemia, 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.568dupA(p.Thr190Asnfs*35)

ClinVarID: 870328

CAID: CA916083887

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: no patient ID, male

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.217-2A>G(IVS2)

ClinVarID: 915470

CAID: CA412716751

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: Patient #27, male, Korean

Disease Assertion: UCD/OTCD

Family Info: N/A

Case Presenting HPOs: HP:0003593, HP:0003218, HP: 0001987

Case HPO FreeText: Infantile 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, 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.929_931del(p.Glu310Valfs*45)

ClinVarID: N/A

CAID: CA916083888

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: Patient #37, 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, 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.1043delA(p.Gln348Argfs*47)

ClinVarID: N/A

CAID: CA2695233335

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 #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)

Case: Patient #6, male, Korean

DiseaseAssertion: UCD/OTCD

FamilyInfo: N/A

CasePresentingHPOs: HP:0011463, HP:0001987, HP:0003218

CaseHPOFreeText: Neonatal onset, hyperammonemia, 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, 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.461_471del(p.Glu154Alafs*18)

ClinVarID: N/A

CAID:CA2695233305

gnomAD:

GeneName: OTC (ornithine transcarbamylase)

Case: Patient #15, male, Korean

DiseaseAssertion: UCD/OTCD

FamilyInfo: N/A

CasePresentingHPOs: HP:0011463, HP:0001987, HP:0003218, HP:0003572

CaseHPOFreeText: Neonatal onset, hyperammonemia, oroticaciduria, low plasma citrulline

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, mother is a carrier, 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.796_805del(p.Ile265_Gly268delinsAspfs*19)

ClinVarID: N/A

CAID:CA2695233326

gnomAD:

GeneName: OTC (ornithine transcarbamylase)

Case: Patient #45, female, Korean

DiseaseAssertion: UCD/OTCD

FamilyInfo: variant in mother (father not tested) and brother

CasePresentingHPOs: HP:0003593, HP:0001987, HP:0003218

CaseHPOFreeText: infantile 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, mother is a carrier, the mutation was also found in patient 13(her brother), 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_000531.6c.664_667delinsAC(p.Gly222Thrfs*2)

ClinVarID: N/A

CAID:CA2695233319

gnomAD:

GeneName: 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 #44, female, Korean

DiseaseAssertion: UCD/OTCD

FamilyInfo: variant in mother (father not tested)

CasePresentingHPOs: HP:0011463, HP:0001987, HP:0003218, HP:0003217

CaseHPOFreeText: Childhood onset, hyperammonemia, oroticaciduria, hyperglutaminemia

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, mother is a carrier, 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.799_800insA (p.Ser267Lysfs*26)

ClinVarID: N/A

CAID:CA2695233327

gnomAD:

GeneName: OTC (ornithine transcarbamylase)

Case: Patient #30, male, Chinese

DiseaseAssertion: UCD/OTCD

FamilyInfo: no family history of the disease

CasePresentingHPOs: HP:0003593, HP:0001987, HP:0003218

CaseHPOFreeText: infantile 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)

Variant: NM_000531.6:c.929_931del(p.Glu310Valfs*45)

ClinVarID: 858012

CAID:CA916083888

gnomAD:

GeneName: OTC (ornithine transcarbamylase)

Case: Patient #61, female, Chinese

DiseaseAssertion: UCD/OTCD

FamilyInfo:

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, drug treatment(L-arginine, L-Citrulline, sodium benzoate, and sodium phenylbutyrate)

Variant: NM_000531.6:c.868-1G>C

ClinVarID: N/A

CAID:CA412725475

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)

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)

Case: Patient #60, female, Chinese

DiseaseAssertion: UCD/OTCD

FamilyInfo: family history of the disease

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.718-1G>A

ClinVarID: N/A

CAID: CA412722112

gnomAD:

GeneName: OTC (ornithine transcarbamylase)

Case: Patient #58, female, Chinese

DiseaseAssertion: UCD/OTCD

FamilyInfo: variant pin proband's mother and father CasePresentingHPOs: HP:0003593, HP:0002038, HP:0001987, HP:0003218, HP:0003572

CaseHPOFreeText: infantile onset , protein avoidance, hyperammonemia, oroticaciduria, low plasma citrulline

CaseNOTHPOs: N/A

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 purifed 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 amplifcation analysis was performed for samples in which Sanger sequencing or WES failed to detect any disease-causing mutation.

SupplementalData: Table 3, low protein diet treatment and drug treatment(L-arginine, L-Citrulline, sodium benzoate, and sodium phenylbutyrate), neurological damage

Variant: NM_000531.6:c.540+265G>A

ClinVarID: 449382

CAID: CA658658977

gnomAD:

GeneName: OTC (ornithine transcarbamylase)

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)

Case: Patient #59, female, Chinese

DiseaseAssertion: UCD/OTCD

FamilyInfo: variant in proband's mother and father

CasePresentingHPOs: HP:0003621, HP:0001987, HP:0003218, HP:0003217

CaseHPOFreeText:juvenile onset, hyperammonemia , oroticaciduria, hyperglutaminemia

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, drug treatment(L-arginine, L-Citrulline, sodium benzoate, and sodium phenylbutyrate)

Variant: NM_000531.6:c.664-1G>A

ClinVarID: 97288

CAID: CA224737

gnomAD:

GeneName: OTC (ornithine transcarbamylase)

for - adjacency - scientific revolution in action - paradigm shift - ignored by scientific community - critique of gene centricity

adjacency - between - scientific revolution - paradigm shift - critique of gene centricity - ignored by scientific community - adjacency relationship - Ray and Denis Noble's work advocating for an alternative to gene centricity demonstrates scientific revolution in realtime. - They are at the stage of being ignored by the peers for scientifically invalid reasons. That's a good indicator of the early stages of a paradigm shift. - As they point out, this refusal to openly debate has realworld consequences. - The entire medical community is oriented towards the wrong direction, looking for medical interventions in gene therapies which aren't going to happen because the science does not allow it.

for - book - Understanding living systems - challenging selfishness - critique - of Richard Dawkins' Selfish Gene

• Ray Noble points out a contradiction in Richard Dawkin's use of the word selfish in his "Selfish gene".
  • Unless there is purposefulness, choice and agency, there cannot be any concept of selfishness

for - paradigms - science - gene centrism - critique - reductionism - behaviorists

paradigms - science - gene centrism - critique - reductionism - behaviorists - One of the problems of the behaviorists back in the 1960s and so on was that - to some extent they unrooted organisms from their environment and - put them into boxes and tested how they behaved under these extraordinary artificial circumstances - You you cannot understand intelligence by doing that because - intelligence is how we respond to the niche that we're involved in - People are increasingly aware of just how extraordinarily intelligent in the moment organisms are the decision making process even of the tiniest organisms

comment - see Michael Levin and problem solving spaces of organisms at different scales

for - key insight - reproduction is for adaptability, not to reproduce the gene pool

key insight - reproduction is for adaptability, not to reproduce the gene pool - for example, trees reproduce so they can move themselves - They are rooted so they cannot get up and walk - so they produce seeds that are transported by over living organisms and by the wind

for - adjacency - magic wand -;gene therapy - personalized medicine

for - problem with gene therapy - Very little association between genes and disease - very complex associations

for - adjacency - ecological crisis - gene centrism

adjacency - between - ecological crisis - gene centrism - adjacency relationship - The ecological crisis and climate crisis is a symptom of separation and alienation of humans from nature - Scientific paradigms that take away human agency and minimise it, treating it as secondary reinforced this lack of agency

for - Denis Noble - Ready Noble - evolutionary biology - critique of Richard Dawkins Selfish Gene theory - critique of gene centrism - book - Understanding Living Systems - human agency

summary - In this informative interview, brothers Denis and Ray Noble discuss their new book - Understanding Living Systems, and - dispel the 70 year old narrative of Gene centrism and the selfish gene as determining the high level behaviour of living organisms

for - purpose in nature - exorcism of - Ray Noble - quote - gene centered view - organisms as machines - exorcism - Ray Noble - gene centered view

for - Oded Rechavi - neurobiology - gene centrism - critique - from - youtube podcast interview - book - Understanding Living Systems - Ray Noble - Denis Noble

summary - Rechavi performed experiments with C Elegan and demonstrated that it possesses a type of neuron that - produces RNA that in response to elevated temperature change is transmitted to reproductive cells so that the offsprings encode it in the genome, and it is better adapted to deal with elevated temperatures

question - How many species do this? Is it generally found throughout nature?

from - outube podcast interview - book - Understanding Living Systems - Ray Noble - Denis Noble - https://hyp.is/OUlGVBXrEe-iaBeZhH_4DQ/docdrop.org/video/oHZI1zZ_BhY/

for - adjacency - progress trap - Crispr - gene therapy - Denis Noble - human genome project

adjacency - between - human genome project - gene therapy - Crispr - progress trap - adjacency relationship - The idea that we can find specific causal relationships between genes and disease and use gene therapy to cure disease, - an envisioned goal of the human genome project - can be very dangerous because - usually one gene collaborates with many other genes to bring about an effect - If we don't know all the relationships, we can bring about a progress trap

for - key insight - failure of the gene coding uni-causal model - key insight - failure of genetic determinism

for - quote - better approach than gene sequence as universal panecea

quote - better approach than gene sequence as universal panecea - (see quote below)

• Look at the high-level organization of the system
  • the living system
• Locate what is going wrong there and then work down to find what you might do
• at lower levels with a drug or any other kind of treatment for that matter to put it right
• That works much better than trying to go the other way because
  • going the other way, the space for
    • possible molecules and
    • possible effects and
    • even more possible combinations of effects
  • because those complex diseases are going to require combinations of treatment
  • There are too many
  • You can't do clinical trials on all of those possibilities
  • It's just far too expensive
  • So I think we just take need to take a different approach to medical research
    • to try to benefit from the human genome sequencing
    • in a way that's different from what they originally promised

for - quote - gene plays passive role - quote - Keith Baverstock

quote - gene plays a passive role - (see quote below)

• the gene plays a passive role as a Vital Information store
• it enables us to make all the proteins we need,
  • all the rnas we need but
• it is the phenotype,
  • that is you and me
• that plays the active role

for - author - Keith Baverstock - follow up - research paper - The Gene and Appraisal

to - paper - The Gene and Appraisal - https://hyp.is/UrvwdhVDEe-QWrPAx9y1aw/docdrop.org/video/bzXFSufDDn8/

for - Keith Baverstock - paper - The Gene and Appraisal

from - youtube - Biology Beyond the Gene - Denis Noble - https://hyp.is/UrvwdhVDEe-QWrPAx9y1aw/docdrop.org/video/bzXFSufDDn8/

Out of 3 patients one of the patient was identified with KCNQ1 RYR2 and NKX2 genes.

• for: cultural evolution, cultural evolution - Bruce Hood, cumulative cultural evolution, CCE, gene-culture coevolution

• paraphrase

  • Our evolving technology allowed us to expand into new territories and manipulate the environment in ways that gave us an edge.
  • Places like this remind me about how harsh nature can be.
  • We're so used to living in air conditioning, and having the comfort of the modern world, but when you go out into nature and experience it first hand, you're reminded very powerfully about how weak we are as an animal.
  • And this is because we are fundamentally a cultural species.
  • Culture is our life support system.
  • Our cumulative culture allows us to
    • cushion ourselves against the harsh realities of the environment and to
    • reshape the environment.

• for: progress trap, cumulative cultural evolution, gene-culture co-evolution, speed of cultural evolution, human genome project
• paraphrase
  • the human genome project took 10 years and cost 3 billion dollars
  • with NGS technology, 10 years later, the same job takes 1 day and costs $15,000 dollars

• for: for: ecological collapse, overshoot, progress trap, progress trap - cultural evolution, ultra-sociality, Lotka's maximum power, gene culture coevolution
• key finding
  • paraphrase
    • In AET,
      • multi-level selection acting on the genome and
      • occurring in concert with selective and non-selective mechanisms acting on culture and technology
    • results in a species that is prone to
      • niche construction and
      • ecosystem engineering,
    • and the scale of these processes continues to increase as the population rises.
    • This increasing scale
      • coupled with human propensity for niche construction
    • leads to human unsustainability

• for: ecological collapse, overshoot, progress trap, progress trap - cultural evolution, ultra-sociality, Lotka's maximum power
• paraphrase
  • to Gowdy and Krall, the ultra-social nature of human groups allowed for a shift in the primary level of selection
    • from the individual level
    • to the group level.
  • Thus, “With the transition to agriculture the group as an adaptive unit comes to constitute a wholly different gestalt
    • driven by the imperative to produce surplus

• for: gene culture coevolution, carrying capacity, unsustainability, overshoot, cultural evolution, progress trap

• Title: The genetic and cultural evolution of unsustainability

• Author: Brian F. Snyder

• Abstract

• Summary
• Paraphrase
  • Anthropogenic changes are accelerating and threaten the future of life on earth.
  • While the proximate mechanisms of these anthropogenic changes are well studied
    • climate change,
    • biodiversity loss,
    • population growth
  • the evolutionary causality of these anthropogenic changes have been largely ignored.
  • Anthroecological theory (AET) proposes that the ultimate cause of anthropogenic environmental change is
    • multi-level selection for niche construction and ecosystem engineering.
  • Here, we integrate this theory with
    • Lotka’s Maximum Power Principle
  • and propose a model linking
    • energy extraction from the environment with
    • genetic, technological and cultural evolution
  • to increase human ecosystem carrying capacity.
  • Carrying capacity is partially determined by energetic factors such as
    • the net energy a population can acquire from its environment and
    • the efficiency of conversion from energy input to offspring output.
  • These factors are under Darwinian genetic selection
  • in all species,
  • but in humans, they are also determined by
    • technology and
    • culture.
  • If there is genetic or non-genetic heritable variation in
    • the ability of an individual or social group
  • to increase its carrying capacity,
  • then we hypothesize that - selection or cultural evolution will act - to increase carrying capacity.
  • Furthermore, if this evolution of carrying capacity occurs - faster than the biotic components of the ecological system can respond via their own evolution,
    • then we hypothesize that unsustainable ecological changes will result.

Best known example of gene-culture coevolution - co-evolution of pastoralism and lactose intolerance - the adoption of dairying set up a modified niche - in which the ability to digest lactose into adulthood was an advantage. - ancestors who were lactose tolerant could take advantage of a new source of calories. - Hence it is the learned acquisition of dairying which explains the natural selection of genes favoring lactase persistence, - the continued production of the enzyme lactase beyond weaning - Dual inheritance theory (Gene-culture coevolution) typically uses this example to explain - Dairying is inherited via a cultural channel - lactase persistence is inherited via a genetic channel - Recent supporters of this also make recent claims that it is not possible to distinguish between - what is biological from what is cultural

It has been suggested that - the human species may be undergoing an evolutionary transition in individuality (ETI).

there is disagreement about - how to apply the ETI framework to our species - and whether culture is implicated - as either cause or consequence.

Long-term gene–culture coevolution (GCC) i- s - also poorly understood.

argued that - culture steers human evolution,

Others proposed - genes hold culture on a leash.

After review of the literature and evidence on long-term GCC in humans - emerge a set of common themes. - First, culture appears to hold greater adaptive potential than genetic inheritance - and is probably driving human evolution. - The evolutionary impact of culture occurs - mainly through culturally organized groups, - which have come to dominate human affairs in recent millennia. - Second, the role of culture appears to be growing, - increasingly bypassing genetic evolution and weakening genetic adaptive potential. -Taken together, these findings suggest that human long-term GCC is characterized by - an evolutionary transition in inheritance - from genes to culture - which entails a transition in individuality (from genetic individual to cultural group). Research on GCC should focus on the possibility of - an ongoing transition in the human inheritance system.

• Title: Gene–culture coevolution and the nature of human sociality
• Author: Herbert Gintis

//Abstract - Summary - Human characteristics are the product of gene–culture coevolution, - which is an evolutionary dynamic involving the interaction of genes and culture - over long time periods. - Gene–culture coevolution is a special case of niche construction. - Gene–culture coevolution is responsible for: - human other-regarding preferences, - a taste for fairness, - the capacity to empathize and - salience of morality and character virtues.

• Title: Human niche construction in interdisciplinary focus
• Author:
  • Jeremy Kendal
  • Jamshid J. Tehrani
  • John Oding-Smee
• Abstract
  • summary
  • Niche construction is an endogenous causal process in evolution,
• reciprocal to the causal process of natural selection.
  • It works by adding ecological inheritance,
  • comprising the inheritance of natural selection pressures previously modified by niche construction,
  • to genetic inheritance in evolution.
  • Human niche construction modifies selection pressures in environments in ways that affect both human evolution, and the evolution of other species.
  • Human ecological inheritance is exceptionally potent
  • because it includes the social transmission and inheritance
  • of cultural knowledge, and material culture.
  • Human genetic inheritance
  • in combination with human cultural inheritance
  • thus provides a basis for gene–culture coevolution,
  • and multivariate dynamics in cultural evolution.
  • Niche construction theory potentially integrates the biological and social aspects of the human sciences.
  • We elaborate on these processes,
  • and provide brief introductions to each of the papers published in this theme issue.

at least in the US, no one is being forced to get a vaccine. Not only that, but there's no evidence anyone's even considered it: https://www.snopes.com/fact-check/forced-vaccines-covid-19/

Maybe they're talking about another population?

https://www.dalekeiger.net/untitled/

Dale Keiger is tap dancing his way into a definition for the underlying traits for encouraging and expanding on creativity. There's definitely something here worth pursuing further and giving a specific name to.

Some it is very akin to the ideas behind combinatorial creativity of working (dancing in Kelly's case) on the mundane with precision and drive and perhaps at least a soupçon of obsessiveness, but openness to the new.

How can we sharpen this set of ideas to settle on the right list of "ingredients"? Is there a way to hone in on this sort of creation of flow within a certain creative area while simultaneously not getting bored? Is it the small string of creative breakthroughs in the process of practice which open up new avenues and help create the flow to prevent boredom?

How might relate to Anders Ericsson's work on on deliberate practice or plateau principle coming into play, particularly to prevent boredom to encourage one to continue on with their practice?

I haven't put my finger on it but there were hints in it from a Yo-Yo Ma ad for Masterclass I saw the other day (https://www.youtube.com/watch?v=dbjgHkj-syM)..

Immunoprecipitation is a technique for the isolation of protein or a complex (protein-protein interactions) Sample is combined with a specific antibody for the epitope of interest. The antibody-protein complex is removed and analysed.

1. Molecules from biological sample (lysed) +incubated with antibodies (free or mounted onto support (like agarose bead, magnetic bead))
2. protein A or G coupled beads added.
3. Centrifuged
4. Results in Beads with protein A/G bound to antibody-POI complex.
5. Well separated in this way, differentially based on sedimentation coefficient.

Co-immunoprecipitation (can isolate one type of protein in its complex)

Isolate POI(s) Good with low conc. of POI Protein interactions Unknown proteins Determine if protein is actually being expressed in a given tissue.

Western blot is carried out to analyse the output.

Vary salt and detergent levels to preserve or destroy protein interactions.