Congenital hyperinsulinism

Gene: HK1

Green List (high evidence)

Variants have recently been identified in a previously described non-coding cis-regulatory element of HK1 in 89 probands with congenital hyperinsulinism (PMID: 40033430). Fourteen of these probands were previously reported by Wakeling et al. (PMID: 36333503). In 65 probands, sufficient evidence was available to classify the HK1 variant as pathogenic or likely pathogenic. This evidence included de novo occurrence in 40 individuals, absence of the variants within multiple large population datasets, immunofluorescence studies demonstrating aberrant HK1 expression in pancreatic tissue when available, inheritance patterns and co-segregation with phenotype, and in silico predictions indicating disruption of transcription factor binding motifs.

Created: 21 Jan 2026, 4:26 p.m. | Last Modified: 21 Jan 2026, 4:26 p.m.

Panel Version: 3.5

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Congenital Hyperinsulinism; hyperinsulinaemic hypoglycaemia

Publications

• PMID: 40033430, PMID: 36333503

Mode of pathogenicity
Other

Green List (high evidence)

The rating of this gene has been updated to Green and the mode of inheritance set to 'MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown' following NHS Genomic Medicine Service approval.

Created: 31 Jan 2023, 4:38 p.m. | Last Modified: 31 Jan 2023, 4:38 p.m.

Panel Version: 2.32

Green List (high evidence)

Fourteen non-coding de novo mutations affecting a 42bp conserved region, encompassed by a regulatory element in intron 2 of HK1 have been associated with congenital hyperinsulinism (Wakeling et al Nature Genetics 2022 (accepted for publication) medRxiv preprint doi: https://doi.org/10.1101/2021.12.03.21267240)

Created: 27 Sep 2022, 3:03 p.m. | Last Modified: 27 Sep 2022, 3:20 p.m.

Panel Version: 2.26

Comment on publications: this article is a preprint, the PMID will be added when available

Created: 27 Sep 2022, 1:57 p.m. | Last Modified: 27 Sep 2022, 3:22 p.m.

Panel Version: 2.26

Comment on list classification: Recommended for GREEN rating following GMS review. Sufficient cases. The paper has not yet been published but has been accepted for publication. Note that the variants are in a non-coding region and therefore may not be prioritised by tiering in the current Genomics England pipeline.

Created: 11 Oct 2022, 12:22 p.m. | Last Modified: 11 Oct 2022, 12:22 p.m.

Panel Version: 2.30

Review on behalf of Jayne Houghton and Kevin Colclough, Exeter Genomics Laboratory, SWGLH. Wakeling et al Nature Genetics 2022 (accepted for publication) medRxiv preprint doi: https://doi.org/10.1101/2021.12.03.21267240; HK1 non-coding pathogenic variants cause a beta-cell specific defect with no common additional features between patients. Medical management is often ineffective leading to pancreatic resection. Whilst bi-allelic loss-of-function HK1 variants cause non-spherocytic haemolytic anaemia, dominant or recessive coding variants have not been described in individuals with defects in glucose homeostasis. Variants in this region have revealed a new disease mechanism for non-coding variants that cause inappropriate expression of a disallowed gene. To date 14 probands with isolated hyperinsulinism have been identified in which 9 different de novo variants have been identified. In resected pancreatic tissue of individuals with non-coding variants within this regulatory region, HK1 was expressed and co-localised with insulin in the islets of affected tissue but not in unaffected controls. HK1 did not co-localise with glucagon (secreted by pancreatic alpha-cells) supporting the impact of the variants being beta-cell specific and confirming that the variants cause HK1 to be inappropriately expressed in the pancreatic beta cell and explain why there is increased insulin secretion in these individuals during hypoglycaemia.

Created: 14 Sep 2022, 4:39 p.m. | Last Modified: 14 Sep 2022, 4:39 p.m.

Panel Version: 2.12

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Congenital hyperinsulinism