A homozygous exonic variant leading to exon skipping in ABCC8 as the cause of severe congenital hyperinsulinism

Congenital hyperinsulinism (CHI) is genetically heterogeneous, caused by pathogenic variants in multiple known genes regulating insulin secretion from the pancreatic beta-cells. The ABCC8 gene encodes the sulfonylurea receptor 1 (SUR1), a key player in insulin secretion, and pathogenic variants in ABCC8 are the most common cause of CHI. With increased application of genetic testing in clinical practice, variants of unknown clinical significance (VUS) are commonly reported. Additional functional investigation for variant pathogenicity is fundamental in establishing definitive molecular diagnosis and in guiding clinical management. However, due to the lack of ubiquitous tissue expression of these genes, obtaining functional studies on affected tissue has been challenging. We present a case of severe congenital hyperinsulinism which required a near-total pancreatectomy. CHI gene sequencing identified a homozygous silent variant in ABCC8 located on the last nucleotide of exon 38, c.4608G>A (p.Ala1536Ala). The total RNA was isolated from pancreas resected at the time of pancreatectomy. RNA sequencing and expression analysis demonstrated exon 38 skipping and decreased RNA expression, which supports the pathogenicity of this variant. This case highlights the feasibility of functional studies of VUS on resected pancreatic tissue. The result expands the mutation spectrum in ABCC8 and allows precise genetic counseling to affected families.