The Journal of clinical endocrinology and metabolism · 2026
Noncoding Variants in Intron 2 of HK1 Associated With Hyperinsulinism With Variable Clinical Phenotype.
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Boodhansingh Kara E, Lord Katherine, Sigal Winnie, Benjet Joshua E, Chen Pan, Juliana Christine A, Mitteer Lauren, Bhatti Tricia, Stanley Charles A, De Leon Diva D, Ganguly Arupa
Аннотация
CONTEXT: Noncoding variants in hexokinase 1 (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 noncoding variants in HK1 associated with variable HI phenotypes.
METHODS: We sequenced a 350 bp 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.
RESULTS: We identified 16 unique non-coding variants in intron 2 of HK1 in 18 individuals with genetics-negative HI (18/281, 6.4%). In 7 cases (7/18, 39%), the HK1 variant was inherited from a parent (2 maternal, 5 paternal); 2 are known to be affected with HI. In 9 cases, the HK1 variant was de novo (9/18, 50%). The age of presentation of HI ranged from day of life 1 to 21 months of age. Seven cases had diazoxide-responsive HI (7/18, 39%). Eleven cases were diazoxide unresponsive (11/18, 61%); 5 underwent pancreatectomy at ages ranging from 6 months to 3 years of age.
CONCLUSIONS: Noncoding 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.
METHODS: We sequenced a 350 bp 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.
RESULTS: We identified 16 unique non-coding variants in intron 2 of HK1 in 18 individuals with genetics-negative HI (18/281, 6.4%). In 7 cases (7/18, 39%), the HK1 variant was inherited from a parent (2 maternal, 5 paternal); 2 are known to be affected with HI. In 9 cases, the HK1 variant was de novo (9/18, 50%). The age of presentation of HI ranged from day of life 1 to 21 months of age. Seven cases had diazoxide-responsive HI (7/18, 39%). Eleven cases were diazoxide unresponsive (11/18, 61%); 5 underwent pancreatectomy at ages ranging from 6 months to 3 years of age.
CONCLUSIONS: Noncoding 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.