Multisystem developmental abnormalities and insulin resistance in ADTKD-HNF1B with the p.E105K variant: A clinical conundrum.

Aims

HNF1B variants cause autosomal dominant tubulointerstitial kidney disease (ADTKD-HNF1B), but the phenotypic spectrum of variants of uncertain significance (VUS) remains incompletely defined. We aimed to characterise the multisystem phenotype associated with the HNF1B p.E105K variant and to examine the mechanism underlying insulin resistance in this setting.

Methods

A 15-year-old male proband with chronic kidney disease and multisystem developmental abnormalities underwent clinical, biochemical and genetic evaluation, including trio-based whole-exome sequencing. The identified variant was classified according to American College of Medical Genetics and Genomics/Association for Molecular Pathology criteria.

Results

The proband presented with chronic kidney disease G3b, bilateral renal cysts, growth delay, delayed puberty and borderline intellectual disability. A heterozygous HNF1B c.313G⟩A (p.E105K) variant was identified, currently classified as a VUS (PM2_supporting + PS3_moderate + PP3). Oral glucose tolerance testing showed impaired glucose tolerance with postprandial hyperinsulinaemia (2-h insulin 3556 pmol/L) and preserved β-cell function. His mother, who has diabetes with normal renal morphology, carried the same variant.

Conclusions

This case suggests a possible expansion of the p.E105K phenotypic spectrum and indicates that insulin resistance in ADTKD-HNF1B is best interpreted as multifactorial and predominantly chronic kidney disease-driven rather than variant-specific. Classification of p.E105K and its metabolic associations await confirmation in further cases and functional studies.