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

ABSTRACT: 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

SUBMITTER: Rivero-Garcia P 

PROVIDER: S-EPMC12756615 | biostudies-literature | 2026 Mar

REPOSITORIES: biostudies-literature