Precision diagnosis for monogenic diabetes requires ethnicity specific criteria for genetic testing
Jones, Sophie Knupp, Julianne Pandya, Snehal Groom, Olivia Goodall, Cleo Sebastian, Ann Baynes, Kevin Bellary, Srikanth Brackenridge, Anna Huda, Mohammed SB
Jones, Sophie
Knupp, Julianne
Pandya, Snehal
Groom, Olivia
Goodall, Cleo
Sebastian, Ann
Baynes, Kevin
Bellary, Srikanth
Brackenridge, Anna
Huda, Mohammed SB
Abstract
The detection of monogenic diabetes illustrates the potential of precision medicine, with treatments tailored to specific genes and diagnosis involving targeted genetic testing. Current detection criteria are derived from White populations. We investigated detection of monogenic diabetes in an unselected multiethnic cohort comprising 1,706 participants diagnosed with diabetes before the age of 30-years.
Using broad biomarker criteria (triple pancreatic antibody negative and detectable C-peptide) to select for next generation sequencing of monogenic diabetes genes, we found a non-significantly different minimum cohort prevalence of monogenic diabetes of 2.1% in White, 2.0% in South Asian, 2.5% in African-Caribbean, and 3.6% in Mixed participants. The detection rate, however, varied significantly (17.7% in White, 5.3%in South Asian, 8.0% in African-Caribbean, and 15.2% in Mixed participants, p<0.001). Those without monogenic diabetes showed significant variations in BMI. No difference in phenotype of monogenic diabetes across ancestry groups was observed. Non-white ethnicity participants were significantly more likely to have undiagnosed monogenic diabetes than White with on average a 10-year duration before receiving a correct diagnosis. By applying ancestry-specific BMI cut-offs (White <30, South Asian <27, African-Caribbean and Mixed <35 kg/m²), the overall detection rate increased from 8.8 to 16%, reducing the number needed to test to identify one case from 11 to 6 and boosting detection rates to 39, 11, 9 and 26% in White, South Asian, African-Caribbean and Mixed-ethnicity participants, respectively. These findings were validated in an external real-world dataset.
Applying broad biomarker criteria for initial selection, mitigates clinical biases leading to misclassification of monogenic diabetes in non-White ethnicities. However, further tailoring criteria with ethnic-specific BMI cut-offs doubled detection rates, improving cost-effectiveness by minimising unnecessary testing. Our study highlights the need to develop precision medicine approaches accounting for phenotypic variation across diverse populations, to ensure accurate diagnoses and cost-efficient healthcare provision.
MIDER Authors
Affiliations
Imperial College London; London North West University Healthcare NHS Trust; Aston University, Birmingham; University Hospitals Birmingham NHS Foundation Trust; Guy’s and St. Thomas’ NHS Foundation Trust, London; Barts Health NHS Trust, London; South Warwickshire University NHS Foundation Trust; Chelsea and Westminster Hospital NHS Foundation Trust, London; East Lancashire Hospitals NHS Trust; University of Exeter; Royal Devon University Healthcare NHS Foundation Trust; Imperial College Healthcare NHS Trust, London
Date
2026-2-6
Type
Article
Collections
Citation
Jones S, Knupp J, Pandya S, Groom O, Goodall C, Sebastian A, Baynes K, Bellary S, Brackenridge A, Huda MSB, Mahto R, Rangasami JJ, Ramtoola S, Hattersley AT, Johnston DG, Colclough K, Shields B, Houghton JAL, Misra S. Precision diagnosis for monogenic diabetes requires ethnicity specific criteria for genetic testing. medRxiv [Preprint]. 2026 Feb 6:2026.02.05.26345659. doi: 10.64898/2026.02.05.26345659.
Journal / Source Title
PMID
Publisher
Publisher’s URL
Publisher’s statement
The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.