Endocrine Abstracts

JOINT684

Introduction: Hepatocyte nuclear factor 1-b (HNF1-β)-associated disease is a multisystem entity.

Objective: To describe the degree of dysglycemia in patients with HNF1-β variants diagnosed at INGEMM between 2009 and 2024.

Methods: Multicenter retrospective observational study including 67 patients (33 pediatric and 34 adult, 29 cases were family cases) with HNF1-β variants identified by MLPA and a custom NGS panel (including 473 genes associated with dysglycemia). Variant filtering, classification and prioritization was performed with VarSeqV2.6.2 and Alamut Visual Plus V1.12, using confidence and quality criteria, (depth >100x; % bp 20x >95%) allele frequency <1% (gnomAD V2.1.1 controls) and in silico prediction of pathogenicity (CADD V1.6 score >20).

Results: 45/67 patients (67.2%) presented heterozygous SNV in HNF1-β (88.9% missense, 6.7% frameshift, 4.4% nonsense), 46.6% classified as VUS and 26.7% as probably pathogenic or pathogenic. 22/67 patients (32.8%) presented a heterozygous deletion in 17q12 including all HNF1-β exons. 13 variants were de novo, of which, 69.2% were 17q12 deletions. In the group with HNF1-β SNVs, diabetes mellitus (DM) was predominant (62.2%, 28/45 patients), with mean diabetic debut at 32.8 years (11-59 yrs), mean current HbA1c 7.2±0.9%; 20/28 (74%) had microvascular (17/20 nephropathy, 5/20 retinopathy, 3/20 neuropathy), and 4/28 (14.8%) macrovascular (3/4 ischemic heart disease, 1/4 peripheral arterial disease) complications. 18/28 (66.6%) are on insulin therapy (50% in combination with other hypoglycemic agents- OHAs). Normoglycemia and prediabetes were present in 22.2% and 15.6%, respectively. In 17q12 recurrent deletion syndrome (17q12RDS) cases, normoglycemia predominated (45.4%, 10/22), followed by prediabetes (36.4%, 8/22) and DM (18.2%, 4/22), with mean diabetic debut at 32.9 years (12-33 yrs), mean current HbA1c 6.9±0.7%, 1 patient presented microvascular complications (retinopathy and nephropathy), everyone under insulin therapy (75% in combination with OHAs). Among the prediabetes cases, there was 1 case with transient neonatal DM. In both groups, the most frequent comorbidities were urinary abnormalities (73.2% vs 100% mostly with neonatal diagnosis) and liver disease (56.1% vs. 59.1%). In the group with SNV, hyperuricemia/gout (32.5%), hypomagnesemia (30.8%) and pancreatic atrophy/agenesis (29.3%) stood out. In the group with 17q12RDS, hypomagnesemia (70%), neuropsychiatric disorders (36.4%), and genital abnormalities (22.7%) were the most frequent findings.

Conclusions: The clinical expression of HNF1-β-associated disease is highly variable, even within families, requiring a specialized multidisciplinary approach. Sporadic cases are frequent, especially in 17q12RDS, in which neonatally diagnosed genitourinary abnormalities, hepatopathy, hypomagnesemia and neuropsychiatric alterations predominate. Most cases with SNVs develop mainly insulin-dependent DM due to advanced nephropathy and pancreatic dysgenesis.