Chromosome 20p11.2 deletions cause congenital hyperinsulinism

Chromosome 20p11.2 deletions cause congenital hyperinsulinism.

Persistent hyperinsulinism (HI) is a rare genetic condition manifested by unregulated insulin production and hypoglycemia. Laver et al. examined 1,063 undiagnosed individuals that were pursuing genetic testing for hyperinsulinism with the aim of identifying new genetic causes of HI. Whole genome sequencing detected three individuals with concurrent deletions on chromosome 20p11.2. Deletions on chromosome 20p11.2 were identified in two individuals examined by other reasons. In four of the patients with an identified deletion in the 20p11.2 region, the mutation arose de novo and one patient inherited the mutation. These five deletions were between 3 and 8 Mb and occurred in non-imprinted regions of chromosome 20. Although the penetrance of 20p11.2 deletions is variable, the patients tended to share common symptoms such as developmental delay, midline defects, and dysmorphism. Extra-pancreatic features also manifested in all five of the individuals with an identified deletion of 20p11.2. The deletion in two patients included the FOXA2 gene and presented with pituitary hormone deficiencies in childhood. The pituitary hormone deficiencies may be attributed to the high levels of FOXA2 expression in human islet cells and pancreatic beta-cells. In the other three patients, deletions were adjacent to the FOXA2 gene affecting its control region. Two more cases of HI caused by deletions 20p11 were found in the literature. Although the deletion of FOXA2 was only confirmed in two patients in the study and one patient in the previous literature, Laver et al. propose that the FOXA2 gene is a strong candidate gene as an etiology of HI. In a few patients that had a confirmed 20p11.2 deletion without an affected FOXA2 gene, they presented with a deletion of the FOXA2 control region. This current study identifies a 2.4 Mb deletion of chromosome 20p11.2 as a cause of persistent hyperinsulinism and suggests that laboratories add the region of chromosome 20 to panels used to test for HI.

Laver et al. “Chromosome 20p11.2 deletions cause congenital hyperinsulinism via the loss of FOXA2 or its regulatory elements” . “Europ. J. of Human Genetics: EJHG” 2024, v. 32, 813-818.

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