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John Christodoulou

Publications and source records attributed to John Christodoulou.

14 recordsLinked to original sources
PubMed2026

An economic evaluation of functional genomic testing for individuals with undiagnosed rare disorders.

PURPOSE: Functional genomics (FG) approaches, such as RNA-seq and proteomics, offer a complementary diagnostic modality for individuals whose cases remain unsolved after genomic sequencing. This study evaluates the cost-effectiveness and cost-benefit of FG for individuals with suspected monogenic disorders relative to manual reanalysis of genomic data at 18 months. METHODS: A decision tree model compared the costs and outcomes of FG and 18-month reanalysis using data from two Australian Undiagnosed Disease Programs. Deterministic and probability sensitivity analysis were performed. RESULTS: With a diagnostic yield of 13%, FG enabled 4 additional diagnoses per 100 individuals tested at an additional cost of $390 (US $240), resulting in an incremental cost-effectiveness ratio of $8,550 ($5,313) and an 85% probability of being cost-effective. CONCLUSION: Functional genomics enables timely diagnosis for individuals with suspected monogenic disorders by evaluating the functional impact of variants of uncertain significance, offering an advantage over reanalyzing genomic data at 18 months. Integration into the Australian healthcare system, supported by collaborative networks and secure data-sharing infrastructure, coupled with addressing barriers to accessing funded genomic testing, could lead to an annual net benefit of up to $1.1 million ($0.7 M).

Functional genomics↗
PubMed2026

Elucidating the Role of SET as a Key Contributor to Neurodevelopmental Disability Within the 9q34.11 Deletion Syndrome Interval.

The 9q34.11 chromosomal region contains multiple neurodevelopmental genes involved in synaptic transmission, axonal structure and neuronal maturation. Pathogenic microdeletions, duplications and single nucleotide variants in numerous genes were previously linked with neurodevelopmental disorders (NDDs). Amongst them, SET has recently been implicated in a rare NDD with speech delay and facial dysmorphism. This study reports a female with a heterozygous de novo deletion impacting SET but not other NDD-associated genes at 9q34.11. The proband was initially diagnosed with atypical Rett syndrome with overlapping clinical features of SET haploinsufficiency. The deletion was confirmed using microarray and long-read sequencing. Subsequent quantitative proteomic evaluation identified a significant decrease of SET protein in patient-derived fibroblasts compared to control lines. This study provides insights into the proband's clinical course over their 28 year diagnostic odyssey, and emphasises the benefits of early speech therapy interventions. The proband had no functional speech, but regained the capacity to meaningfully communicate and articulate a limited vocabulary in adulthood, concordant with other reported non-paediatric cases of SET-NDD. This study expands current knowledge on the genotypic and phenotypic spectra of SET-NDD, and pinpoints a smaller 9q34.11 critical region excluding upstream NDD-associated genes, STXBP1 and SPTAN1, implicating SET as a significant NDD-associated gene.

Humans↗
PubMed2026

Unraveling a Diagnostic Enigma: A TECPR2 Case Solved Through Multi-Omic Genomics.

TECPR2 is a key regulator of autophagy, encoded by the TECPR2 gene. Pathogenic variants in this gene have been linked to a rare hereditary sensory and autonomic neuropathy with intellectual disability (HSAN9). We report a teenage female with a syndromic intellectual disability disorder associated with neuromuscular abnormalities. Multi-omics analysis including genomics, transcriptomics, and proteomics, together with muscle biopsy from the affected individual, were used in this clinical case. Through trio exome sequencing we identified two heterozygous variants in the TECPR2 gene, NM_014844.4: c.480G>A; p.(Gln160=) and c.2846C>A; p.(Ala949Glu). Both were classified as variants of uncertain significance due to the lack of supporting evidence for pathogenicity. Subsequent long-read sequencing phased the variants and confirmed they were in trans. Additional functional studies using RNAseq and proteomics analyses verified the pathogenicity of the variants. This case study demonstrated the value of a multi-omics assisted analysis, which complemented the traditional phenotype-first approach in reaching a definitive clinical diagnosis.

Humans↗
PubMed2024

Upregulation versus loss of function of NTRK2 in 44 affected individuals leads to 2 distinct neurodevelopmental disorders.

PURPOSE: Heterozygous pathogenic variants in NTRK2 (HGNC: 8032) have been associated with global developmental delay. However, only scattered cases have been described in small or general studies. The aim of our work was to consolidate our understanding of NTRK2-related disorders and to delineate the clinical presentation. METHODS: We reported an extended cohort of 44 affected individuals, of whom 19 are from the literature and 25 were previously unreported. RESULTS: Our analysis led to splitting the cohort into 2 entities. CONCLUSION: One group had variants in the cholesterol-binding motif of the transmembrane domain, with most of these being the recurrent variant c.1301A>G p.(Tyr434Cys). These variants probably lead to upregulation of tropomyosin receptor kinase B activity and to a severe phenotype of developmental delay/intellectual disability, muscular hypotonia, therapy-refractory epilepsy, visual impairment and blindness, and feeding difficulties. The second group had truncating variants or variants that presumably disturb the 3D structure of the protein leading to loss of function. These individuals had a remarkably milder phenotype of developmental delay, obesity, and hyperphagia.

Humans↗
PubMed2024

Critically unwell infants and children with mitochondrial disorders diagnosed by ultrarapid genomic sequencing.

PURPOSE: To characterize the diagnostic and clinical outcomes of a cohort of critically ill infants and children with suspected mitochondrial disorders (MD) undergoing ultrarapid genomic testing as part of a national program. METHODS: Ultrarapid genomic sequencing was performed in 454 families (genome sequencing: n = 290, exome sequencing +/- mitochondrial DNA sequencing: n = 164). In 91 individuals, MD was considered, prompting analysis using an MD virtual gene panel. These individuals were reviewed retrospectively and scored according to modified Nijmegen Mitochondrial Disease Criteria. RESULTS: A diagnosis was achieved in 47% (43/91) of individuals, 40% (17/43) of whom had an MD. Seven additional individuals in whom an MD was not suspected were diagnosed with an MD after broader analysis. Gene-agnostic analysis led to the discovery of 2 novel disease genes, with pathogenicity validated through targeted functional studies (CRLS1 and MRPL39). Functional studies enabled diagnosis in another 4 individuals. Of the 24 individuals ultimately diagnosed with an MD, 79% had a change in management, which included 53% whose care was redirected to palliation. CONCLUSION: Ultrarapid genetic diagnosis of MD in acutely unwell infants and children is critical for guiding decisions about the need for additional investigations and clinical management.

Humans↗
PubMed2003

Effects of MECP2 mutation type, location and X-inactivation in modulating Rett syndrome phenotype.

Rett syndrome (RTT) is a clinically defined disorder that describes a subset of patients with mutations in the X-linked MECP2 gene. However, there is a high degree of variability in the clinical phenotypes produced by mutations in MECP2, even amongst classical RTT patients. In a large-scale screening project, this variability has been examined by looking at the effects of mutation type, functional domain affected and X-inactivation. Mutations have been identified in 60% of RTT patients in this study (25% of whom were atypical), including 23 novel mutations and polymorphisms. More mutations were found in classical patients (63%) compared to atypical patients (44%). All of the pathogenic mutations were de novo in patients for whom parent DNA was available for screening. A composite phenotype score was developed, based on the recommendations for reporting clinical features in RTT of an international collaborative group. This score proved useful for summarising phenotypic severity, but did not correlate with mutation type, domain affected or X-inactivation, probably due to complex interactions between all three. Other correlations suggested that truncating mutations and mutations affecting the methyl-CpG-binding domain tend to lead to a more severe phenotype. Skewed X-inactivation was found in a large proportion (43%) of our patients, particularly in those with truncating mutations and mutations affecting the MBD. It is therefore likely that X-inactivation does modulate the phenotype in RTT.

Australia↗
PubMed2003

RettBASE: The IRSA MECP2 variation database-a new mutation database in evolution.

Rett syndrome (RTT) is a neurodevelopmental disorder affecting primarily females, with an incidence of around 1 in 15,000 females. In 1999, mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2) were first reported in RTT subjects, and since that time there have been a number of publications describing cohorts of patients and their mutations. In addition, MECP2 mutations have been reported in patients who do not fit the diagnostic criteria for Rett syndrome. We have developed a new locus-specific database, RettBASE (http://mecp2.chw.edu.au/), loosely based on the PAHdb website. The aim is to obtain data relating to all known instances of MECP2 variations, including published ta and data directly submitted by one of various means (either by using an online submission form, or by sending the same form in Adobe portable document format (pdf) or Microsoft Word format by email or fax to the database curators). The database has a range of query capabilities, allowing for simple or complex interrogation of the database. To address the issue of patient confidentiality, we have incorporated an Excel spreadsheet algorithm that allows the generation of a unique number based on the subject's name and date of birth. We believe this database will prove to be a useful resource, allowing the development of accurate prevalence data for disease-causing mutations, providing a catalog of polymorphisms, and potentially allowing more accurate phenotype-genotype correlations to be drawn.

Chromosomal Proteins, Non-Histone↗
PubMed2003

Coronary calcium detected by digital cinefluoroscopy and coronary artery disease in patients undergoing coronary arteriography: effects of age and sex.

BACKGROUND: Coronary artery calcium, detected non-invasively, correlates well with angiographically documented coronary artery disease (CAD). This study was conducted to evaluate the diagnostic efficacy of coronary artery calcium detected by digital cinefluoroscopy for CAD and assess the effects of age and sex on it. METHODS: In 242 patients who underwent coronary angiography, coronary calcium status was determined and related to angiographic findings. RESULTS: Calcium detection had a sensitivity 85%, specificity 52%, positive predictive value 92%, negative predictive value 33% and diagnostic accuracy 81% for significant CAD. There was a better positive predictive value in men (95% vs. 80%) and negative predictive value in women (65% vs. 16%), while a higher sensitivity and diagnostic accuracy was found in older than in younger (90% and 86% vs. 78% and 74%). The sensitivity of the method increased with the number of the diseased vessels. CONCLUSIONS: Coronary calcium can be quite accurately detected by digital cinefluoroscopy. This, however, should be made in the context of sex and age.

Adult↗
PubMed2003

Prognostic significance of coronary artery calcium in asymptomatic subjects with usual cardiovascular risk.

BACKGROUND: Coronary calcium detected noninvasively is an attractive way to diagnose atherosclerosis before the development of symptoms. This study examines the prognostic value of coronary calcium in asymptomatic subjects with usual cardiovascular risk. METHODS AND RESULTS: In 425 asymptomatic subjects, 229 men (aged 45.1 +/- 14 years) and 196 women (aged 42.7 +/- 13 years), coronary calcium presence was studied by digital cinefluoroscopy. The majority (76%) had no or at most one risk factor. Subjects were followed up for 58.4 +/- 12.7 months for cardiac events. Coronary calcium was present in 76 of 425 (17.9%) subjects. Cardiac events were observed in 21 subjects: 2 cardiac deaths, 7 acute myocardial infarctions, 3 coronary artery bypass grafts, 3 coronary angioplasty procedures, 3 events of unstable angina, and 10 events of stable angina pectoris. Survival curve analysis showed significant differences in all the studied end points between subjects with and those without calcium. Coronary calcium was an independent predictor of all events (3.6-fold increase, P <.008), cardiac death/myocardial infarction/revascularization (13.9-fold increase, P <.02), and stable angina (7.4-fold increase, P <.007). However, calcium did not independently predict cardiac death/myocardial infarction or acute coronary syndromes. CONCLUSIONS: Coronary calcium in asymptomatic subjects with usual cardiovascular risk adds significant incremental information to risk factors information for the development of symptomatic coronary artery disease.

Adult↗
PubMed2002

Allogeneic bone marrow transplantation: cure for familial Mediterranean fever.

We describe data on a 7-year-old girl with congenital dyserythropoietic anemia (CDA), who also had familial Mediterranean fever (FMF). Repeated transfusions required since the age of 6 months to treat her CDA led to iron overload and a persistently high ferritin level. Her relapsing FMF made effective iron chelation therapy very difficult. Consequently, at the age of 4 years, she underwent allogeneic, sibling bone marrow transplantation (BMT). During conditioning for her BMT, symptoms of FMF, including splenomegaly, arthritis, and recurrent abdominal pain, began to resolve and she was gradually weaned off colchicine. Now, 2 years after the transplantation, she remains free from FMF symptomatology and is off all immunosuppressants. This case demonstrates that symptoms of FMF can be alleviated by the therapy used during allogeneic BMT. In this patient it is likely that the missing factor in FMF is now being provided by granulocytes derived from the stem cells within transplanted bone marrow.

Anemia, Dyserythropoietic, Congenital↗
PubMed2002

Quantitative fibroblast acylcarnitine profiles in mitochondrial fatty acid beta-oxidation defects: phenotype/metabolite correlations.

Mitochondrial fatty acid beta-oxidation (FAO) disorders are clinically and biochemically heterogeneous diseases mainly associated with intolerance to catabolic stress. These disorders can now be detected pre-symptomatically by newborn screening, and thus the clinical phenotype in an individual patient may be unclear. Correlation of clinical severity with concentrations of acylcarnitine species was investigated in fibroblasts from FAO-deficient patients presenting with various phenotypes and asymptomatic neonates detected by newborn screening. Intact cells were incubated in medium containing deuterium-labelled hexadecanoic acid and L-carnitine for 72h, and the accumulated acylcarnitines in the culture medium analysed using electrospray tandem mass spectrometery. Fibroblasts from patients with long-chain FAO disorders presenting at an early age and with poor clinical outcomes accumulated higher concentrations of long-chain acylcarnitine species compared with those from patients with milder phenotypes. This suggests that the in vitro quantitative acylcarnitine profiling could perhaps predict the prognosis of some FAO defects. This would be particularly useful information for the asymptomatic/pre-symptomatic FAO-deficient infant detected by the expanded newborn screening program, in whom the risk of developing symptoms later in life is not known.

Acyl-CoA Dehydrogenase↗
PubMed2002

Acylcarnitine profiles in fibroblasts from patients with respiratory chain defects can resemble those from patients with mitochondrial fatty acid beta-oxidation disorders.

Mitochondrial fatty acid beta-oxidation (FAO) is coupled to the respiratory chain (RC). Functional defects of one pathway may lead to secondary alteration in flux through the other. We investigated the acylcarnitine profiles in cultured fibroblasts obtained from 14 healthy subjects, 31 patients with 8 different primary enzyme deficiencies of FAO, and 16 patients with primary RC defects including both isolated and multiple enzyme complex defects. Intact cells were incubated in media containing deuterium-labeled hexadecanoic acid and L-carnitine, and the acylcarnitines analysed using an electrospray tandem mass spectrometer. All FAO-deficient cell lines revealed disease-specific acylcarnitine profiles related to the sites of defects. Some cell lines from patients with RC defects showed profiles similar to those of controls, whereas others had abnormal profiles mimicking those found in FAO disorders. The acylcarnitine profiles of patients with RC enzyme defects were not predictable, and in some patients defects caused by mutations in either nuclear-encoded or mitochondrial DNA were associated with acylcarnitine abnormalities. While in vitro acylcarnitine profiling is useful for the diagnosis of FAO deficiencies, abnormal profiles do not exclusively indicate these disorders, and primary defects of the RC remain a possibility. Awareness of this diagnostic pitfall will aid in the selection of subsequent confirmatory tests and therapeutic options.

Carnitine↗