Biomedical subjects

Christian R Marshall

Publications and source records attributed to Christian R Marshall.

5 recordsLinked to original sources

PubMed2026

Case Report: Persistent isolated hyperhomocysteinemia in an adolescent with celiac disease and homozygous MTHFR c.665C>T polymorphism: a multifactorial disturbance of one-carbon metabolism.

UNLABELLED: Hyperhomocysteinemia in adolescence typically prompts investigation for classical inborn errors of sulfur amino acid metabolism, including cystathionine β-synthase deficiency and cobalamin-dependent remethylation disorders. However, persistent elevations may also arise from interactions between common genetic polymorphisms and acquired nutritional conditions that alter one-carbon metabolism. CASE PRESENTATION: We report an 18-year-old male with type 1 diabetes mellitus, celiac disease on a strict gluten-free diet, congenital unilateral sensorineural hearing loss, and persistent isolated hyperhomocysteinemia. At age 16, he presented with an acute visual field disturbance and right occipital cortical MRI changes suggestive of ischemia. Plasma homocysteine was persistently between 50 and 65 μmol/L.Extensive metabolic and genetic investigations, including targeted gene panels, whole-exome and research whole-genome sequencing, mitochondrial DNA sequencing, mitochondrial complex activities in fibroblasts, and fibroblast complementation, excluded classical homocystinuria and remethylation defects. Sequential trials of pyridoxine, hydroxocobalamin, and high-dose betaine produced modest or transient improvement. Re-analysis of exome data showed homozygosity for the common MTHFR c.665C>T (p.Ala222Val) variant. Family testing revealed that his father (TT) and mother (CT) had normal homocysteine (10.9 and 10.4 μmol/L), indicating that MTHFR TT alone is insufficient to cause a biochemical phenotype and functions as a susceptibility factor. Combined oral methylfolate (1,000 µg daily) and vitamin B12 (cyanocobalamin 1,000 µg daily) reduced homocysteine from 66 to 24.6 μmol/L in 8 weeks. CONCLUSION: This case illustrates multifactorial hyperhomocysteinemia arising from interactions between celiac disease-related micronutrient vulnerability and reduced MTHFR activity. Recognition of gene-nutrient interactions is important when classical metabolic disorders are excluded and may guide targeted therapy.

MTHFR polymorphism↗

PubMed2025

Barriers and facilitators to implementing clinical genome-wide sequencing: A scoping review of the global landscape.

PURPOSE: The global demand for clinical genome-wide sequencing (GWS) continues to grow. This study describes the global landscape of genetic service delivery and the barriers and facilitators to implementing clinical GWS. METHODS: A scoping review was conducted using MEDLINE and Embase (January 2009-July 2025) to identify studies related to genetic service delivery, exome and genome sequencing, and implementation. RESULTS: Ninety-six articles representing 35 countries were analyzed using the updated Consolidated Framework for Implementation Research. The most frequently reported barriers were within the outer setting: insufficient Local Conditions (ie, genetics workforce shortage; 54/96, 56%), limited Financing (29/96, 30%), and lack of national Policies and Laws (regulations) for genomic testing (20/96, 21%). Negative Local Attitudes about genomics were reported as a barrier in 11 South American, Middle Eastern, Asian, and African countries. Identified outer setting facilitators included Partnerships and Connections between interested parties (eg, government, academic institutions; 14/96, 15%) and dedicated Funding for national genomics initiatives (6/96, 6%). CONCLUSION: This scoping review identified common barriers to implementing GWS across countries with varying capacities for delivering these services. Findings may help countries to anticipate barriers, leverage facilitators, and develop strategies for implementing genomic testing and services.

Humans↗

PubMed2025

Screening rare genetic diagnoses for amenability to bespoke antisense oligonucleotide therapy development: A retrospective cohort study.

PURPOSE: To estimate the proportion of molecular genetic diagnoses in a real-world, phenotypically heterogeneous patient cohort that are amenable to antisense oligonucleotide (ASO) treatment. METHODS: We retrospectively applied the N=1 Collaborative's Variant Assessments toward Eligibility for Antisense Oligonucleotide Treatment guidelines to all diagnostic variants found by clinical genome-wide sequencing at a single pediatric hospital in 532 patients over a 6-year period. Variants were classified as either "eligible," "likely eligible," "unlikely eligible," or "not eligible" in relation to the different ASO approaches, or "unable to assess." RESULTS: In total, 25 unique variants across 26 patients (4.9% of 532 patients) were eligible or likely eligible for ASO treatment at a molecular genetic level, via canonical exon skipping (4), splice correction (3), or messenger RNA knockdown (19). Only 8 of these molecular genetic diagnoses were made within a year of symptom onset. After considering disease and delivery related factors, 11 diagnoses were still considered candidates for bespoke ASO development. CONCLUSION: A meaningful proportion of genetic diagnoses identified by genome-wide sequencing may be amenable to ASO treatment. These results underscore the importance of timely diagnosis, and the proactive identification and accelerated functional testing of genetic variants amenable to ASO treatments.

Humans↗

PubMed2025

Comparing the performance of exome and genome sequencing for rare disease diagnostics: A randomized implementation effectiveness trial.

PURPOSE: Exome sequencing (ES) and genome sequencing (GS) can improve rare disease diagnosis but are not routinely available in many jurisdictions. To inform implementation, we report on a randomized implementation effectiveness trial comparing ES and GS. METHODS: Eligible trios were randomized to receive ES or GS in the same clinically accredited laboratory. Patient-level data on diagnostic utility and turnaround times were collected. Outcomes were compared statistically between clinically important subgroups. RESULTS: Of 1048 patients, 68.5% had syndromic intellectual disability/developmental delay (ID/DD) and 20.5% had multisystem disorders without ID/DD. Most had prior genetic test(s) that were nondiagnostic (95.5%), and of these, 91.6% included chromosome microarray. Diagnostic yields were 33.8% and 33.6%, for ES (n = 526) and GS (n = 522), respectively. Within sequencing groups, diagnostic results were more frequent among those with ID/DD than those without (P < .005). For routine (ie, nonexpedited) patients (n = 1020), 87.0% were reported in <12 weeks, and the mean turnaround time was 55.5 days (SD: 24.0). Turnaround time for ES and GS did not differ; however, result type (P < .001) and age of onset (P < .005) significantly affected turnaround time. CONCLUSION: Findings provide robust evidence of diagnostic utility and timeliness of ES and GS and will inform policy related to the organization, delivery, and reimbursement of clinical-grade genome diagnostics for rare diseases.

Adolescent↗

PubMed2025

A microcosting and cost consequence analysis from a randomized controlled trial comparing genome sequencing with exome sequencing for genetic diagnosis.

PURPOSE: Diagnosing rare diseases is costly. The objectives were to microcost exome (ES) and genome sequencing (GS) trios and estimate the incremental costs of GS per additional diagnosis from an institutional payer perspective. METHODS: Trios (proband plus biological parents) that are referred for sequencing were randomly assigned to ES or GS. Laboratory workflow and sequencing were microcosted. Total and category cost per trio were estimated probabilistically. Effectiveness was expressed as diagnostic yield (rates of diagnostic or partially diagnostic variants detected). Incremental costs and effectiveness were calculated. RESULTS: The mean total cost per trio was CAD 2888.79 (95% CI 2567.72, 3492.72) for ES (n = 329) and 4364.02 (95% CI 3984.94, 5013.67) for GS (n = 324). Reagents accounted for 34% and 61% of total costs for ES and GS, respectively. The incremental cost of GS was 1475.23. The diagnostic yield was 35.9% for ES and 32.7% for GS with a difference of 0.032 (95% CI: -0.041, 0.104, P value .397). CONCLUSION: GS demonstrated higher costs and a similar diagnostic yield to ES but was limited by technical capabilities at the time of the study. The study provides comprehensive costs for the economic evaluation comparing alternative diagnostic pathways and impetus for further evaluating variants uniquely detectable by GS.

Humans↗