From genotype to phenotype: reverse phenotyping of a novel INSR variant in a large family with hyperinsulinemic hypoglycemia.

The insulin receptor gene (INSR) encodes a ligand-activated tyrosine kinase that plays a central role in glucose homeostasis. Pathogenic variants in INSR are associated with a spectrum of insulin resistance syndromes. Here we report a novel INSR variant in a large multigenerational family. A 53-year-old woman presented to the endocrinology clinic with recurrent hypoglycemic episodes. Exome sequencing was performed for the index case, and variant segregation analysis was conducted in family members by Sanger sequencing. Genetic testing revealed a likely pathogenic variant in exon 19 of the INSR gene, NM_000208.4:c.3473G > C,p.(Arg1158Pro). Segregation analysis identified eight heterozygous carriers among thirteen tested family members. Reverse phenotyping revealed recurrent hyperinsulinemic hypoglycemia. Affected individuals demonstrated normal body mass index, low adiposity, and preserved fat-free mass, distinguishing this phenotype from classical insulin-resistance syndromes. Female carriers frequently exhibited hyperandrogenic features including hirsutism, menstrual irregularities, and acanthosis nigricans. These findings expand the clinical spectrum of INSR-related disorders and highlight the importance of considering INSR variants in patients with familial hyperinsulinemic hypoglycemia, particularly when clinical features mimic insulinoma.