ESPE2024 Free Communications Fetal and Neonatal Endocrinology (6 abstracts)
Non-invasive prenatal testing can detect maternally and paternally inherited variants in the KCNJ11 and ABCC8 genes: implications for clinical management of neonatal diabetes during pregnancy and beyond
Pamela Bowman 1,2,3 , Elisa de Franco 2 , Natasha Philpott 1 , Eleanor M Gurnell 4 , Violeta Iotova 5 , Zsolt Gaal 6 , Naomi Howard-James 7 , Declan Cody 7 , Sarah E Flanagan 2 , Andrew T Hattersley 1,2 & Jayne AL Houghton 1
1Exeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, Exeter, United Kingdom. 2Faculty of Health and Life Sciences, University of Exeter, Medical School, Exeter, United Kingdom. 3National Institute for Health and Care Research, Exeter Clinical Research Facility, Royal Devon University Healthcare NHS Foundation Trust, Exeter, United Kingdom. 4Cambridge University Hospital NHS Foundation Trust, Cambridge, United Kingdom. 5University Hospital St Marina, Varna, Bulgaria. 6Josa Andras Hospital, Nyiregyhaza, Hungary. 7Department of Endocrinology, CHI Crumlin, Dublin, Ireland
Introduction/Background: Non-invasive prenatal testing (NIPT) represents a major development for families affected by rare monogenic conditions by facilitating early prenatal diagnosis without the risks associated with traditional more invasive methods. For most rare diseases NIPT is only available clinically for paternally-inherited variants. One exception is in GCK and HNF4A diabetes, where the detection of a maternally or paternally inherited pathogenic variant informs pregnancy management. NIPT could bring clinical benefit for families with KCNJ11 or ABCC8 neonatal diabetes (NDM). Activating variants in these genes cause reduced birth weight through impaired insulin-mediated growth, NDM and neurodevelopmental disorders. Confirming foetal genotype will inform postnatal surveillance and will enable the early identification and treatment of diabetes when a variant is detected leading to improved outcomes. There is also the possibility of improving the growth and neurodevelopment of the foetus by facilitating targeted treatment with sulphonylureas in utero (for maternally-inherited variants).
Aims: We aimed to assess the feasibility of NIPT for NDM caused by maternally and paternally inherited variants in the KCNJ11 and ABCC8 genes.
Methods: droplet digital polymerase chain reaction assay was used to detect the presence of a familial variant in the cell-free circulating DNA (cfDNA) extracted from maternal plasma samples taken between 12-35 weeks’ gestation of at-risk pregnancies.
Results: Samples were available from 8 at-risk pregnancies. Four pregnancies were at risk of inheriting a maternal variant and 4 were at risk of inheriting a paternal variant. Assays could be designed for 4 of the 5 different KCNJ11 / ABCC8 variants, enabling NIPT for 7/8 pregnancies. Testing of cfDNA from 5 pregnancies was undertaken which confirmed that 2/5 offspring had inherited the familial variant (one maternal and one paternal) and were at high-risk of NDM. The 3 foetuses without the familial variant were not predicted to be affected with the condition. For maternally inherited variants, results were confirmed using a cord blood sample. Testing is ongoing for the two remaining pregnancies.
Conclusion: Our data support the feasibility of NIPT to determine foetal genotype in NDM-related pregnancies, for maternally and paternally inherited ABCC8 and KCNJ11 variants. Work is ongoing to apply our methodology to different variants in these genes, with a view to future introduction as a clinical test. Further research will explore pregnancy management and clinical outcomes in affected children including the effects of in utero sulphonylurea treatment on growth and neurodevelopment in those with maternally inherited variants.
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