Congenital hyperinsulinism caused by novel homozygous katp channel gene variants may be linked to unexplained neonatal deaths among kurdish consanguineous families
Abstract
Introduction: Neonatal hypoglycemia due to congenital hyperinsulinism (CHI) is a potentially life-threatening condition. Biallelic pathogenic variants in KATP channel subunit genes (ABCC8, KCNJ11), causing severe forms of CHI, are more prevalent in regions with a significant rate of consanguinity and may lead to unexplained neonatal deaths.
We hypothesized that KATP channel gene variants are the cause of CHI in three unrelated children from consanguineous Kurdish families with histories of four unexplained neonatal deaths with convulsions. Cases: (1) A girl presented on the 6th day of life with recurrent hypoglycemic convulsions (blood glucose 2.05 mmol/L, insulin 58 mIU/L, C-peptide 2,242 pmol/L). (2) A girl with severe developmental delay was diagnosed with CHI at 3 years of age (blood glucose 2.78 mmol/L, insulin 8.1 mIU/L, C-peptide 761 pmol/L) despite a history of recurrent hypoglycemia since neonatal age. (3) A girl presented at 3 weeks of age with convulsions and unconsciousness (blood glucose 2.5 mmol/L, insulin 14.6 mIU/L, C-peptide 523 pmol/L).
Coding regions of the ABCC8 and KCNJ11 genes were tested by Sanger sequencing. Potential variants were evaluated using the American College of Medical Genetics standards.
Three novel causative homozygous variants were found - p.Trp514Ter in the ABCC8 gene (Pt2), and p.Met1Val (Pt1) and p.Tyr26Ter (Pt3) in the KCNJ11 gene. Conclusion: CHI caused by KATP channel variants was elucidated in three children, providing a highly probable retrospective diagnosis for their deceased siblings.
Future lives can be saved by timely diagnosis of CHI when encountering a neonate with unexplained seizures or other signs of recurrent and/or persistent hypoglycemia.