Maturity-onset diabetes of the young type 1 (MODY1) is caused by autosomal dominant variants in the hepatocyte nuclear factor 4 alpha (HNF4A) gene. This genetic defect results in a characteristic biphasic phenotype, typically manifesting as neonatal hyperinsulinism (HI) followed by the development of diabetes mellitus (DM) in young adulthood. HNF4A acts as a master transcriptional regulator for insulin gene expression and hepatic metabolic pathways, providing a molecular basis for understanding the link between neonatal hyperinsulinemic hypoglycemia and DM in young adulthood. Therefore, accurate molecular diagnosis is essential for appropriate clinical management. We report a case of a male infant who presented with neonatal HI and a family history of young-onset DM in his mother. Following the initial identification of a variant via next-generation sequencing, Sanger sequencing was utilized as the gold standard for familial segregation analysis to confirm the findings. The testing identified a novel heterozygous HNF4A variant, c.598G>C (p.Ala222Pro), in the proband and his mother. The variant was classified as likely pathogenic. The heterozygous state, characterized by the presence of one pathogenic and one wild-type allele, is consistent with an autosomal dominant inheritance pattern. This specific variant serves as the molecular fingerprint for the family’s MODY1 diagnosis. Identification of this variant enabled reconsideration of the mother's diabetes management, including potential therapeutic de-escalation from insulin. This case highlights that neonatal HI may facilitate the diagnosis of parental MODY1. Genetic testing for HNF4A variants should be considered in such cases, as it may broaden therapeutic options and support individualized management of DM.
Takasugi et al. (Tue,) studied this question.