Non-coding variants in intron 2 of HK1 associated with hyperinsulinism with variable clinical phenotype.

Abstract

Non-coding variants in HK1 were first associated with congenital hyperinsulinism (HI) in a large family with diazoxide-responsive HI in 2008. Since then, additional cases have been reported in the literature with non-coding variants in HK1 associated with variable HI phenotypes. We sequenced a 350bp region in intron 2 of HK1 in 281 individuals with genetics negative HI to identify additional cases related to non-coding HK1 variants and to characterize the clinical features of these cases. We identified 16 unique non-coding variants in intron 2 of HK1 in 18 individuals with genetics negative HI (18/281, 6.4%). In seven cases (7/18, 39%), the HK1 variant was inherited from a parent (2 maternal, 5 paternal), two are known to be affected with HI. In nine cases, the HK1 variant was de novo (9/18, 50%). The age of presentation of HI ranged from day of life one to 21 months of age. Seven cases had diazoxide-responsive HI (7/18, 39%). Eleven cases were diazoxide unresponsive (11/18, 61%); five underwent pancreatectomy at ages ranging from six months to three years of age. Non-coding variants in intron 2 of the HK1 gene have now been associated with HI in a growing number of cases. Our findings suggest that a significant proportion of individuals with negative genetics in genes currently known to be associated with HI may harbor HK1 intron 2 variants. Identifying these cases is important for clinical care as well as for assessing recurrence risk for families.