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

Sep 28, 2026

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Balanced translocations interrupting HNF1A are rarely documented in MODY-3. This study investigates a three-generation family with early-onset, non-autoimmune diabetes consistent with MODY-3. Conventional karyotyping identified a balanced reciprocal translocation t(2;12)(q35;q24.31), then long-read genome sequencing mapped precise breakpoints in HNF1A and a nearby intergenic region. Segregation analysis showed cosegregation with disease across three generations, supporting a loss-of-function mechanism. After molecular diagnosis, sulfonylureas improved outcomes for affected relatives, highlighting the clinical value of long-read sequencing to resolve balanced rearrangements and guide therapy.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages7

Reading Time18 min

AccessFree to download

Introduction

MODY overview and diagnostic challenges

MODY-3 and HNF1A function

Conventional sequencing limitations

Methods and genetic diagnosis (from abstract)

Karyotyping and breakpoint mapping

Segregation analysis and functional interpretation

Therapeutic impact (from abstract)

Sulfonylurea treatment outcomes

Metabolism Open 29 (2026) 100430 Contents lists available at ScienceDirect Metabolism Open journal [homepage:](homepage: www.sciencedirect.com/journal/metabolism-open)[ www.sciencedirect.com/journal/metabolism-open](homepage: www.sciencedirect.com/journal/metabolism-open) | 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
Pamela Rivero-Garcíaa, Osvaldo M. Mutchinick a, Eira Huerta-´Avila a, Ilse A. Colorado b, Cristy Alfonso-L´opez a, Renata Rivera-Ju´areza, Virginia Santiago-Canoa,
Juan Jos´e Morales-Su´areza, Alfredo Hidalgo-Miranda b, Yevgeniya Svyryda,*
a Department of Genetics, Instituto Nacional de Ciencias M´edicas y Nutrici´on Salvador Zubir´an (INCMNSZ), Vasco de Quiroga 15, Secci´on XVI, Tlalpan, Mexico City, 14080, Mexico
b Cancer Genomics Laboratory, Instituto Nacional de Medicina Gen´omica (INMEGEN), Perif´erico Sur 4809, Arenal Tepepan, Tlalpan, Mexico City, 14610, Mexico | | | | --- | --- | --- | | A R T I C L E I N F O | | A B S T R A C T | | Keywords: Diabetes MODY MODY type 3
HNF1A gene mutation
Long read sequencing
Personalized medicine | | 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. | 1. Introduction Maturity-onset diabetes of the young (MODY) is a rare disease and the most common form of monogenic diabetes, accounting for less than 5 % of diabetes cases [1]. To date, 14 genes have been identified as responsible for distinct types of MODY [2]. Differentiating MODY from type 1 diabetes (T1D) and type 2 diabetes (T2D) is particularly challenging due to overlapping clinical features, underscoring the importance of genetic testing to ensure an accurate diagnosis and guide personalized therapeutic options. However, a significant number of patients still lack a definitive genetic diagnosis. Indeed, genetic testing panels for MODY and whole-exome sequencing (WES) have an estimated diagnostic yield of approximately 27–57 %, meaning that around half of patients remain without an identified genetic cause despite extensive molecular testing [1,3–5]. MODY types 1, 2, 3, and 5 are the most frequently reported, with significant variation among populations [6]. Among them, MODY type 3 (MODY-3), caused by pathogenic variants (PVs) in the HNF1A gene located at 12q24.31, is the most prevalent subtype in European populations. Among other functions, HNF1A encodes hepatocyte nuclear factor-1 alpha (HNF-1α), a transcription factor essential for pancreatic β-cell development, insulin secretion, urinary glucose reabsorption, lipid This article is part of a special issue entitled: Insulin

FAQs

What genetic event explains the MODY-3 diagnosis in the reported family?

A balanced reciprocal translocation t(2;12)(q35;q24.31) interrupts HNF1A, and long-read sequencing resolves breakpoints consistent with disruption in intron 1.

How did long-read genome sequencing contribute compared with conventional karyotyping?

Karyotyping detected the balanced translocation, while long-read sequencing mapped breakpoints at specific genomic coordinates, resolving the structure near the monogenic diabetes locus.

What was the clinical impact after the molecular diagnosis?

Sulfonylureas were added for four affected relatives, leading to favorable clinical outcomes, consistent with the strong treatment response described for MODY-3.

Sep 28, 2026

Uploaded by Marglet