Congenital hyperinsulinism as part of a multisystem disease caused by a compound heterozygous variant in the YARS1 gene

Abstract Tyrosyl-transfer RNA (tRNA) synthetase, encoded by YARS1, is essential for protein synthesis, catalyzing the attachment of tyrosine to its cognate tRNA during translation. Pathogenic biallelic YARS1 variants cause infantile-onset multisystem neurological, endocrine, and pancreatic disease type 2 (IMNEPD2; OMIM #619418), an orphan disorder. Hypoglycemia in IMNEPD2 remains poorly characterized, with few reported cases. We describe an infant with a compound heterozygous YARS1 genotype (c.176T>C and c.1261G>A) who presented with severe hyperinsulinemic hypoglycemia, notable for a discordance between insulin and C-peptide concentrations and a lack of response to diazoxide and octreotide.