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 #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 #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)