case_images: PMC7390877_01
case_images: PMC7390877_02
case_images: Pedigree of the three-generation family of the patient 2. Generations are shown as I to III. Males are indicated by squares, females by circles, affected members by a shaded black square or circles and the proband by an arrow. Shaded black square with slash indicates death.
case_images: fped-08-00321-g0001.jpg
case_images: PMC7390877_02_fped-08-00321-g0001.jpg
case_images: F1
case_images: Analysis of the pedigree disclosed a marked family history of an X-linked maternal inheritance in the family of patient 2 (Figure 1).
case_images: Whole-exome sequencing (WES) paired-end reads are loaded in the IGV genome browser and are shown for each patient. (A) The heterozygous mutation, c.365A>T, in patient 1. (B) The heterozygous mutation, IVS7+1G>A, in patient 2. (C) Location of the point mutations in the OTC gene.
case_images: fped-08-00321-g0002.jpg
case_images: PMC7390877_02_fped-08-00321-g0002.jpg
case_images: F2
case_images: We found a novel missense mutation, c.365A>T, in exon 4 of the OTC gene in patient 1 (Table 1 and Figures 2A,C) and a reported splice site mutation, IVS7+1G>A, in intron 7 of the OTC gene in patient 2 (Table 1 and Figures 2B,C).
case_images: Mutations in the OTC gene in the two families. Pedigrees of the two families show the affected (solid), unaffected (open), and asymptomatic carrier (circle with dot) members. Squares, males; circles, females; slashed symbol, deceased. The genotype is shown underneath each symbol; WT, wild-type. (A) Patient 1 and her mother carried a novel heterozygous missense mutation, c.365A>T (p.Glu122Val), in exon 4. Multiple-sequence alignment of the amino acid sequences of OTC from different species revealed a complete conservation of the p.Glu122 residue across species (red box). (B) Identification of a mutation, IVS7+1G>A, in the OTC gene in the family of patient 2. The results showed a maternal carrier, while the father and sister were normal. The GenBank reference sequences of the human OTC gene are NM_000531.6 for the mRNA sequence and NC_000023.11 for the exon-intron boundary.
case_images: fped-08-00321-g0003.jpg
case_images: PMC7390877_02_fped-08-00321-g0003.jpg
case_images: F3
case_images: Sanger sequencing (Figure 3). Such molecular investigation supports a definitive diagnosis for the two patients with OTCD. The amino acid sequences of OTC from human and other species were compared to identify the conservation at the mutant position. A glutamate residue at the position 122 was completely conservative among distinct species (Figure 3A). IVS7+1G>A mutation was heterozygous in patient 2 (Figure 3B). IVS7+1G>A may affect normal splicing of exon 7.