Breakpoint-resolved balanced t(2;12)(q35;q24.31) disrupting HNF1A in multigenerational MODY-3: Diagnostic utility of long-read genome sequencing and therapeutic impact.

Balanced translocations that interrupt HNF1A are seldom documented in MODY-3. We studied a three-generation family with early-onset, non-autoimmune diabetes consistent with MODY-3. Conventional karyotyping revealed a balanced reciprocal translocation, t(2; 12)(q35; q24.31). We then opted for long-read genome sequencing using ONT® PromethION™ (median coverage 22X; read N50 11.4 kb), which mapped breakpoints at chr12:120,984,209 (HNF1A intron 1) and chr2:218,759,723 (intergenic region). Segregation analysis revealed that the rearrangement cosegregates with diabetes across three generations (5 affected individuals; 1 carrier). Although expression assays were not performed, disruption of HNF1A within intron 1 is most consistent with loss-of-function and haploinsufficiency in this context. After molecular diagnosis, sulfonylureas were added to the treatment regimen of four affected relatives, resulting in favorable clinical outcomes. To our knowledge, multigenerational cosegregation of a balanced translocation directly disrupting HNF1A has not been previously reported. This case introduces a breakpoint-level mechanism for MODY-3 and demonstrates why long-read sequencing is crucial when a karyotype indicates a balanced rearrangement near a monogenic diabetes locus: it resolves the structure and shortens the path to a treatment decision.