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

Hertzog, Ashley; Selvanathan, Arthavan; Halligan, Rebecca; Fazio, Timothy; Jong, Gerard de; Bratkovic, Drago; Bhattacharya, Kaustuv; Tolun, Adviye A.; Bennetts, Bruce; Fisk, Katrina

doi:10.1002/jmd2.12289

Cited by 3 publications

(5 citation statements)

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“…We have previously reported three patients with OTC deficiency with late-onset disease, all of whom did not have a pathogenic variant identified by standard molecular analysis of coding regions ( Hertzog et al, 2022 ). Sequencing of the promoter region identified a c.-106C>A variant, which had been reported previously in three other males with late-onset disease ( Jang et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Intronic variants in inborn errors of metabolism: Beyond the exome

et al. 2022

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Non-coding regions are areas of the genome that do not directly encode protein and were initially thought to be of little biological relevance. However, subsequent identification of pathogenic variants in these regions indicates there are exceptions to this assertion. With the increasing availability of next generation sequencing, variants in non-coding regions are often considered when no causative exonic changes have been identified. There is still a lack of understanding of normal human variation in non-coding areas. As a result, potentially pathogenic non-coding variants are initially classified as variants of uncertain significance or are even overlooked during genomic analysis. In most cases where the phenotype is non-specific, clinical suspicion is not sufficient to warrant further exploration of these changes, partly due to the magnitude of non-coding variants identified. In contrast, inborn errors of metabolism (IEMs) are one group of genetic disorders where there is often high phenotypic specificity. The clinical and biochemical features seen often result in a narrow list of diagnostic possibilities. In this context, there have been numerous cases in which suspicion of a particular IEM led to the discovery of a variant in a non-coding region. We present four patients with IEMs where the molecular aetiology was identified within non-coding regions. Confirmation of the molecular diagnosis is often aided by the clinical and biochemical specificity associated with IEMs. Whilst the clinical severity associated with a non-coding variant can be difficult to predict, obtaining a molecular diagnosis is crucial as it ends diagnostic odysseys and assists in management.

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Section: Discussionmentioning

confidence: 99%

Intronic variants in inborn errors of metabolism: Beyond the exome

et al. 2022

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“…Once hyperammonemia is established, diagnostic biochemical investigations including plasma amino acids and urine organic acids should be performed. Plasma amino acids will aid the diagnosis—showing high plasma glutamine and low plasma citrulline—and urine organic acids should show orotic aciduria [ 13 , 24 , 25 , 33 , 39 ]. The urine extraction of orotic acid results from excess carbamoylphosphate, which diverts into the pyrimidine pathway [ 16 ].…”

Section: Diagnosismentioning

confidence: 99%

“…Laboratory investigations may only be diagnostic during an acute, symptomatic phase, therefore increasing the importance of a genetic diagnosis [ 12 , 27 ]. Approximately 80–90% of cases are detected through a mutation analysis [ 25 , 27 , 41 , 42 ]. In some laboratories, the likelihood of not confirming the mutation in a biochemically confirmed OTC family is as high as 30% (personal observation).…”

Section: Diagnosismentioning

confidence: 99%

“…They include neurological (encephalopathy and migraine headaches), psychiatric (bipolar-disorder-like symptoms) or gastrointestinal symptoms (hepatic dysfunction and cyclic vomiting). All symptoms can present as a combination [ 23 , 24 , 25 , 26 ]. Symptoms can be triggered by stressors such as prolonged fasting, certain medications and pregnancy, and may lead to death if not treated immediately [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

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Diagnostic and Management Issues in Patients with Late-Onset Ornithine Transcarbamylase Deficiency

et al. 2023

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Ornithine transcarbamylase deficiency (OTCD) is the most common inherited disorder of the urea cycle and, in general, is transmitted as an X-linked recessive trait. Defects in the OTC gene cause an impairment in ureagenesis, resulting in hyperammonemia, which is a direct cause of brain damage and death. Patients with late-onset OTCD can develop symptoms from infancy to later childhood, adolescence or adulthood. Clinical manifestations of adults with OTCD vary in acuity. Clinical symptoms can be aggravated by metabolic stressors or the presence of a catabolic state, or due to increased demands upon the urea. A prompt diagnosis and relevant biochemical and genetic investigations allow the rapid introduction of the right treatment and prevent long-term complications and mortality. This narrative review outlines challenges in diagnosing and managing patients with late-onset OTCD.

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“…In two separate publications in Journal of Inherited Metabolic Disease (2022), Hertzog 1 and co‐authors in Australia and Han/Bjornsson et al 2 from the U.S. and Iceland have further elucidated the molecular pathophysiology in a subgroup of predominantly male patients with late‐onset ornithine transcarbamylase deficiency (OTCD), an X‐linked urea cycle disorder. The authors put the spotlight on pathogenic variants affecting the regulatory regions of the OTC gene, specifically the OTC promoter variant c.‐106C>A.…”

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confidence: 99%

Ornithine transcarbamylase deficiency: A diagnostic odyssey

Knerr

Cassiman²

2022

J of Inher Metab Disea

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Iceland have further elucidated the molecular pathophysiology in a subgroup of predominantly male patients with late-onset ornithine transcarbamylase deficiency (OTCD), an X-linked urea cycle disorder. The authors put the spotlight on pathogenic variants affecting the regulatory regions of the OTC gene, specifically the OTC promoter variant c.-106C>A. This leads to impaired promoter function of the OTC gene and may present as late-onset OTCD in apparently healthy individuals; however, when metabolic stress is increased, impaired upregulation of OTC gene activity can then be followed by hyperammonaemia.Parallel to both of these reports, two additional males (16 and 20 years of age, respectively) with, thus far, clinically very mild late-onset OTCD, were diagnosed in Ireland by our group. They had been under surveillance with "sick day" management and L-arginine supplements due to a positive family history of hyperammmonaemia with a biochemical diagnosis of OTCD in their older brother. This Irish family had extensive genetic testing done, including OTC gene sequencing in different diagnostic laboratories, which came back negative. The two younger brothers' diagnosis was based on an allopurinol load performed 10 years previously. Further to diagnostic findings of Jang et al. 3 which describe the pathogenic variant c.-106C>A in the promoter region of the OTC gene, a diagnosis of OTCD could be genetically confirmed for the two Irish patients. Whole exome sequencing also verified that no other pathogenic variant was identifiable relating to their biochemical findings. These biochemical results include, for example, normal plasma ammonia measurements to date and, intermittently, marginally raised transaminases.The difficult diagnostic journey with its serendipitous outcome, described by Hertzog and collaborators, underscores how metabolic medicine is sometimes not unlike detective work, particularly when confirmatory testing

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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

Cited by 3 publications

References 8 publications

Intronic variants in inborn errors of metabolism: Beyond the exome

Intronic variants in inborn errors of metabolism: Beyond the exome

Diagnostic and Management Issues in Patients with Late-Onset Ornithine Transcarbamylase Deficiency

Ornithine transcarbamylase deficiency: A diagnostic odyssey

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