Computational investigation of a novel uromodulin gene mutation (p.Y286C) in a family with autosomal dominant tubulointerstitial renal disease: A case study

Abstract

Autosomal dominant tubulointerstitial kidney disease caused by a pathogenic variant in the UMOD gene (ADTKD) is a rare tubulointerstitial nephropathy characterized by hyperuricemia, gout, and slowly-progressing chronic renal insufficiency. The disease invariably progresses to end-stage renal disease (ESRD), and is believed to be one of the most common monogenic forms of kidney disease. It presents complete penetrance and inter- and intrafamilial clinical heterogeneity. The index case is a 17-year-old female who, at the age of seven began her renal function evaluation due to a family history of chronic renal insufficiency without etiological diagnosis. At this time she was already presenting with joint pain and increased serum creatinine and uric acid. Genetic testing detected a heterozygous variation in UMOD gene, c.857 A>G; p.Y286C, in two tested affected individuals but not in an unaffected family member. Here, an in silico analysis of the impact of this variant was performed, which provided support as to the deleterious nature of the variant. We also described clinical and laboratory data of 6 affected members, whose age of ESRD showed high variability, in agreement with the literature. This case provides evidence of the pathogenicity of a novel variant detected in the UMOD gene, in addition to providing clinical and laboratory data of individuals carrying this variant, highlighting the intrafamilial clinical variability.