Case Report: Identification of a HNF1A exons 1–10 heterozygous deletion in a Chinese MODY family

Background Maturity-onset diabetes of the young (MODY) is an autosomal dominant monogenic diabetes, with HNF1A-MODY (MODY3) being a common subtype. Standard genetic testing for MODY often focuses on sequencing, which can lead to the misdiagnosis of cases caused by HNF1A copy number variants (CNVs). This study investigates the diagnosis of a Chinese family with a HNF1A (NM_000545.8):ex1_10del. Methods We evaluated a Chinese family with a clinical diagnosis of maturity-onset diabetes of the young (MODY). Clinical data and peripheral blood samples were collected from family members. A heterozygous HNF1A (NM_000545.8):ex1_10del was suspected by next-generation sequencing (NGS) using a hereditary diabetes gene panel.This finding was validated using multiplex ligation-dependent probe amplification (MLPA). We also conducted a literature review of previously reported HNF1A-MODY cases associated with heterozygous exon deletions. Results A heterozygous HNF1A (NM_000545.8):ex1_10del was identified by MLPA in the pedigree after next-generation sequencing (NGS) detected no pathogenic single-nucleotide variants (SNVs) or small insertions/deletions (indels). The deletion was classified as pathogenic according to ACMG/AMP and ClinGen guidelines. The family’s clinical phenotype aligned with previously reported HNF1A-MODY cases caused by whole-gene or exon deletions, showing similarities to phenotypes associated with SNVs and small indels. Following genetic diagnosis, the proband was transitioned from insulin to glimepiride, achieving optimal glycemic control. Conclusions This study identifies a HNF1A whole-gene deletion in a Chinese family with MODY, confirming the effectiveness of sulfonylureas for HNF1A-MODY management. Large HNF1A deletions, undetectable by standard sequencing, can cause MODY and necessitate copy number variant (CNV) analysis. MLPA is essential for definitive MODY diagnosis, particularly in cases with strong clinical suspicion but negative sequencing results. These findings broaden the known spectrum of HNF1A mutations and highlight the critical role of CNV detection in MODY genetic testing.