In summary, our study provides evidence that germline variants at the TYMS-ENOSF1 locus give rise to severe thymidylate synthase deficiency that disrupts the nucleotide metabolism pathway and that this disruption drives molecular features of genome instability and senescence in a homogenous cohort of DC individuals. The gene discussed is ENOSF1; the disease is hyperinsulinemic hypoglycemia, familial, 4.