Non-coding cis-regulatory variants in HK1 cause congenital hyperinsulinism with variable disease severity

Abstract

Background: We recently reported non-coding variants in a cis-regulatory element of the beta-cell disallowed gene hexokinase 1 (HK1) as a novel cause of congenital hyperinsulinism. These variants lead to a loss of repression of HK1 in pancreatic beta-cells, causing insulin secretion during hypoglycaemia. In this study, we aimed to determine the prevalence, genetics, and phenotype of HK1-hyperinsulinism by screening a large international cohort of patients living with the condition.

Methods: We screened the HK1 cis-regulatory region in 1761 probands with hyperinsulinism of unknown aetiology who had been referred to one of three large European genomics laboratories.

Results: We identified a HK1 variant in 89/1761 probands (5%) and 63 family members. Within the Exeter HI cohort, these variants accounted for 2.8% of all positive genetic diagnoses (n = 54/1913) establishing this as an important cause of HI. Individuals with a disease-causing variant were diagnosed with hyperinsulinism between birth and 26 years (median: 7 days) with variable response to treatment; 80% were medically managed and 20% underwent pancreatic surgery due to poor response to medical therapy. Glycaemic outcomes varied from spontaneous remission to hypoglycaemia persisting into adulthood. Eight probands had inherited the variant from a parent not reported to have hyperinsulinism (median current age: 39 years), confirming variable penetrance. Two of the 23 novel HK1 variants allowed us to extend the minimal cis-regulatory region from 42 to 46 bp.

Conclusions: Non-coding variants within the HK1 cis-regulatory region cause hyperinsulinism of variable severity ranging from neonatal-onset, treatment-resistant disease to being asymptomatic into adulthood. Discovering variants in 89 families confirms HK1 as a major cause of hyperinsulinism and highlights the important role of the non-coding genome in human monogenic disease.

Keywords: Congenital hyperinsulinism; Hexokinase 1; Monogenic disease; Non-coding; Variable penetrance.

Fig. 1

Schematic representation of the location of HK1 variants identified in probands with congenital hyperinsulinism. The ubiquitously expressed isoform (ENST00000359426) is depicted. The position of copy number variants (CNVs) within intron 2 is shown below the HK1 gene. The breakpoints of the large deletions have been defined in two cases, the remaining 15 are known to extend beyond the sequenced region but not into the coding sequence as depicted by the dashed line. The horizontal bars depict indels. Only bases within the indel that are affecting the minimal regulatory region are shown (Chr10:71,108,642–71108687). The g.71,108,688–71,108,691del has been named according to HGVS nomenclature, this variant deletes a TGTT repeated sequence that starts at g.71,108,683. Directly below the indels is the reference sequence. The greyed boxes around the nucleotide bases of the genomic sequence indicate the previously defined predicted transcription factor binding sites [3]. Single nucleotide variants (SNVs) are listed, according to position, below the genomic sequence. Black lines/text indicate variants classified as pathogenic or likely pathogenic and grey lines/text indicate those classified as variants of uncertain significance according to the current classification guidelines [–24]

Fig. 2

Pedigrees depicting inheritance of pathogenic and likely pathogenic HK1 variants (n = 65 families). Squares, males; circles, females; diamonds, unknown sex; filled black symbols, clinical diagnosis of hyperinsulinism; filled grey symbols, anecdotal evidence of hypoglycaemia; diagonal line through symbol, deceased; M, HK1 variant; N, no variant; *, obligate heterozygote; NA, DNA not available. The arrow indicates the proband in larger pedigrees