ESPEYB25 2. Antenatal and Neonatal Endocrinology Hyperinsulinemic Hypoglycemia, Neonatal Diabetes (4 abstracts)
2.12. Non-coding CIS-regulatory variants in HK1 cause congenital hyperinsulinism with variable disease severity
Jasmin J. Bennett , Cecile Saint-Martin , Bianca Neumann , Jonna M. E. Mannisto , Jayne A. L. Houghton , Susann Empting , Matthew B. Johnson , Thomas W. Laver , Jonathan M. Locke , Benjamin Spurrier , Matthew N. Wakeling , Indraneel Banerjee , Antonia Dastamani , Huseyin Demirbilek , John Mitchell , Markus Stange , International Congenital Hyperinsulinism Consortium , Klaus Mohnike , Jean-Baptiste Arnoux , Nick D. L. Owens , Martin Zenker , Christine Bellanne-Chantelot & Sarah E. Flanagan
Genome Med 2025 Mar 3;17(1):17. doi: 10.1186/s13073-025-01440-w
Brief Summary: These investigators from genome centers in Exeter, UK, Paris, France and Magdeburg, Germany screened a cis-regulatory region of HK1(hexokinase 1) in 1761 probands with hyperinsulinism of unknown aetiology, to determine the frequency of this recently described genetic cause of congenital hyperinsulinism. HK1 is normally not expressed in pancreas or liver but is active in all other human tissues. Its aberrant reactivation in pancreatic tissue leads to abnormal glucose sensing and insulin secretion in the face of low plasma glucose. Large deletions, smaller insertions or deletions and single nucleotide variants in a 46 bp intronic region of HK1 can lead to HK1 transcription and thus cause autosomal dominant hyperinsulinism. An HK1 variant was found in 89/1761 (5%) probands and in 63 family members. This compares to a frequency of 3% in a Norwegian cohort1 and 9% in a previous UK series2 (162 probands also included in this paper).
Hyperinsulinism had a variable onset, between birth and 26 y (median 7 days, 16% childhood, 4% adult onset). Median birth weight Z-score and IQR was 0.48 [-0.12-1.97] . Treatment was variable: 77% received diazoxide, 8% somatostatin receptor analogue, 15% both drugs and 20% required pancreatic surgery. Evolution varied from spontaneous remission to hypoglycemia persisting into adulthood. They describe variable penetrance in 8 probands, whose transmitting parent was asymptomatic, and phenotypic variability between and within families for the same variants.
These results place HK1among the major causes of hyperinsulinemic hypoglycemia. Non-coding regions in at least 3 other genes have been found to cause hyperinsulinism, reinforcing the importance of the non-coding genome to disease.
References: 1. Velde CD et al, Clinical and Genetic Characteristics of Congenital Hyperinsulinism in Norway: A Nationwide Cohort Study. J Clin Endocrinol Metab 2025 Jan 21;110(2):554-563. doi: 10.1210/clinem/dgae459.2. Wakeling MN et al, Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism. Nat Genet. 2022;54(11):1615-1620. doi: 10.1038/s41588-022-01204-x.
Volume 22
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ESPE Yearbook of Paediatric Endocrinology
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