A deep intronic variant is a common cause of OTC deficiency in individuals with previously negative genetic testing

Kumar, Runjun D.; Burrage, Lindsay C.; Bartoš, Jan; Ali, Saima; Schmitt, Éric; Nagamani, Sandesh C.S.; LeMons, Cynthia

doi:10.1016/j.ymgmr.2020.100706

Cited by 10 publications

(8 citation statements)

References 15 publications

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“…Subsequently, analysis of mRNA from the patient's liver, identified an insertion of a 135‐nucleotide sequence between exons 5 and 6, caused by a deep intronic single nucleotide substitution, c.540+265G>A, which activated a cryptic splice site within intron five. 7 Additionally, Kumar and colleagues 8 identified the same variant in three out of seven patients who had no pathogenic variants identified by previous molecular investigations.…”

Section: Discussionmentioning

confidence: 93%

“…However, the further analysis identified deep intronic, promoter or enhancer variants within the OTC gene. [7][8][9] We report three additional cases of late-onset OTCD caused by a promoter variant in the OTC gene; c.-106C>A (NC_000023.10:g.38211844C>A). There was a substantial delay in ascertaining their molecular aetiology, as this variant was not clearly identifiable by routine molecular analysis.…”

Section: Introductionmentioning

confidence: 99%

“…However, the further analysis identified deep intronic, promoter or enhancer variants within the OTC gene. 7 , 8 , 9 …”

Section: Introductionmentioning

confidence: 99%

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A serendipitous journey to a promoter variant: The c.‐106C>A variant and its role in late‐onset ornithine transcarbamylase deficiency

et al. 2022

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Ornithine transcarbamylase deficiency (OTCD) is an X-linked urea cycle disorder characterised by reduced or absent OTC enzyme activity, resulting in the accumulation of neurotoxic ammonia. Approximately 80%-90% of the causative variants are identified by Sanger sequencing or multiplex ligationdependent probe amplification (MLPA) of the OTC gene. A 23-year-old male with biochemical evidence of OTCD was referred for molecular analysis. Initial Sanger sequencing yielded no pathogenic variants. MLPA testing raised suspicion of a mosaic deletion of exon 1; however, high-resolution microarray did not identify a copy number variant on the X chromosome. Sequencing over

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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A serendipitous journey to a promoter variant: The c.‐106C>A variant and its role in late‐onset ornithine transcarbamylase deficiency

et al. 2022

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“…Another limitation is that ES primarily assesses for small insertions/deletions and single nucleotide variants within or near exons. Alternative testing is needed if deep intronic variants, repeat expansions, large copy number variants or other classes of variation are of interest (Kumar et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Clinical exome sequencing uncovers a high frequency of Mendelian disorders in infants with stroke: A retrospective analysis

Kumar

Meng

Liu

et al. 2022

American J of Med Genetics Pt A

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Stroke causes significant disability and is a common cause of death worldwide. Previous studies have estimated that 1%-5% of stroke is attributable to monogenic etiologies. We set out to assess the utility of clinical exome sequencing (ES) in the evaluation of stroke. We retrospectively analyzed 124 individuals who received ES at the Baylor Genetics reference lab between 2012 and 2021 who had stroke as a major part of their reported phenotype. Ages ranged from 10 days to 69 years. 8.9% of the cohort received a diagnosis, including 25% of infants less than 1 year old; an additional 10.5% of the cohort received a probable diagnosis. We identified several syndromes that predispose to stroke such as COL4A1-related brain small vessel disease, homocystinuria caused by CBS mutation, POLG-related disorders, TTC19-linked mitochondrial disease, and RNASEH2A associated Aicardi-Goutieres syndrome. We also observed pathogenic variants in NSD1, PKHD1, HRAS, and ATP13A2, which are genes rarely associated with stroke. Although stroke is a complex phenotype with varying pathologies and risk factors, these results show that use of exome sequencing can be highly relevant in stroke, especially for those presenting <1 year of age.

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“…In humans, individuals with OTCD only develop the pathological condition after birth and the symptoms are sometimes overlooked for one to two days, resulting in delayed therapeutic care. More complicatedly, the intronic variant, which often goes unnoticed, can be a cause of late-onset OTCD [ 11 ]. Therefore, the OTCD trait should be diagnosed not only by conventional methodologies, but also by fetal genetic testing during pregnancy.…”

Section: Discussionmentioning

confidence: 99%

Characterization and Treatment Responsiveness of Genetically Engineered Ornithine Transcarbamylase-Deficient Pig

Enosawa

Hsu

Yanagi

et al. 2021

JCM

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To develop novel medical technologies, pig disease models are invaluable especially in the final stages of translational research. Recently, we established a genetically engineered ornithine transcarbamylase-deficient (OTCD) pig strain. Here, we report its characterization and treatment responsiveness. OTCD pigs were obtained by mating an OTCD carrier female (OTC-Xc.186_190delXWT) with a wild-type male. Due to the X-linked recessive mode of inheritance, the disease phenotype emerged only in males. Medication with nitrogen-scavenging agents was based on a clinical protocol. OTCD pigs were born smaller than their wild-type and carrier littermates, showing anemia and faltering. Biochemically, high levels of urinary orotic acid and loss of OTC activity were observed. The natural life course of OTCD pigs was characterized by a decrease in arterial percentage saturation of oxygen and body temperature, as well as an increase in blood ammonia levels; the pigs died in 24.0 ± 5.0 h (mean ± SD, n = 6). The established standard medication composed with nitrogen-scavenging agents and transfusion nearly doubled the survival time to 42.4 ± 13.7 h (n = 6). Our OTCD pig model appropriately mimicked the human pathology. Along with established protocols in handling and medication, this is a first step in developing a large animal disease model that is useful for translational research into novel medical technologies, such as cell transplantation and gene therapy, as well as in relation to urea cycle disorder.

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A deep intronic variant is a common cause of OTC deficiency in individuals with previously negative genetic testing

Cited by 10 publications

References 15 publications

A serendipitous journey to a promoter variant: The c.‐106C>A variant and its role in late‐onset ornithine transcarbamylase deficiency

A serendipitous journey to a promoter variant: The c.‐106C>A variant and its role in late‐onset ornithine transcarbamylase deficiency

Clinical exome sequencing uncovers a high frequency of Mendelian disorders in infants with stroke: A retrospective analysis

Characterization and Treatment Responsiveness of Genetically Engineered Ornithine Transcarbamylase-Deficient Pig

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