The Phenotypic Variability Associated with Hepatocyte Nuclear Factor 1B Genetic Defects Poses Challenges in Both Diagnosis and Therapy

Abstract

The evolving landscape of clinical genetics is becoming increasingly relevant in the field of nephrology. HNF1B-associated renal disease presents with a diverse array of renal and extrarenal manifestations, prominently featuring cystic kidney disease and diabetes mellitus. For the genetic analyses, whole exome sequencing (WES) and multiplex ligation-dependent probe amplification (MLPA) were performed. Bioinformatics analysis was performed with Ingenuity Clinical Insights software (Qiagen). The patient's electronic record was utilized after receiving informed consent. In this report, we present seven cases of HNF1B-associated kidney disease, each featuring distinct genetic abnormalities and displaying diverse extrarenal manifestations. Over 12 years, the mean decline in eGFR averaged -2.22 ± 0.7 mL/min/1.73 m². Diabetes mellitus was present in five patients, kidney dysplastic lesions in six patients, pancreatic dysplasia, hypomagnesemia and abnormal liver function tests in three patients each. This case series emphasizes the phenotypic variability and the fast decline in kidney function associated with HNF-1B-related disease. Additionally, it underscores that complex clinical presentations may have a retrospectively straightforward explanation through the use of diverse genetic analytical tools.

Keywords: cystic kidney disease; genetic variability; hepatic nuclear factor 1B (HNF1B); multiplex ligation-dependent probe amplification (MPLA); whole exome sequencing (WES).

Figure 1

(A) Renal function deterioration trajectories (trends depicted as dotted lines) over time vary among various HNF1B genetic alterations. (B) Illustration of the primary clinical abnormalities associated with genetic alterations. Key annotations include diabetes mellitus (DM), pancreatic agenesis (PA), blue dots indicating renal cysts, yellow cylinders within the kidney denoting lithiasis, crossed dotted lines representing non-functional organs, red dot indicating a point mutation, a large blue circle representing a pancreatic cyst, and numerical identifiers within the family tree corresponding to patients 1, 2, 3, 4 and 5, respectively.