Variable phenotype in mutations: extrarenal manifestations distinguish affected individuals from the population with congenital anomalies of the kidney and urinary tract.

Background: Mutations in () have been associated with congenital anomalies of the kidney and urinary tract (CAKUT) in humans. Diabetes and other less frequent anomalies have also been described. Variable penetrance and intrafamilial variability have been demonstrated including severe prenatal phenotypes. Thus, it is important to differentiate this entity from others with similar clinical features and perform confirmatory molecular diagnosis.

Methods: This study reports the results of screening in a cohort of 60 patients from 58 unrelated families presenting with renal structural anomalies and/or non-immune glucose metabolism alterations, and other minor features suggesting mutations.

Results: This study identified a pathogenic variant in 23 patients from 21 families. The most frequent finding was bilateral cystic dysplasia or hyperechogenic kidneys (87% of patients). Sixty percent of them also fulfilled the criteria for impaired glucose metabolism, and these were significantly older than those patients with an mutation but without diabetes or prediabetes (14.4 versus 3.3 years, P < 0.05). Furthermore, patients with mutations had higher frequency of pancreatic structural anomalies and hypomagnesaemia than patients without mutations (P < 0.001 and P = 0.003, respectively). Hyperuricaemia and increased liver enzymes were detected in some patients as well.

Conclusions: Renal anomalies found in patients with mutations are frequently unspecific and may resemble those found in other renal pathologies (CAKUT, ciliopathies). Active searching for extrarenal minor features, especially pancreatic structural anomalies or hypomagnesaemia, could support the indication for molecular diagnosis to identify mutations.