A cross-sectional study of patients referred for HNF1B-MODY genetic testing due to cystic kidneys and diabetes.

Sztromwasser P1, Michalak A1,2, Małachowska B1, Młudzik P3, Antosik K3, Hogendorf A2, Zmysłowska A2, Borowiec M3, Młynarski W4, Fendler W1,5.

Author information

1: Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland.
2: Department of Pediatrics, Diabetology, Endocrinology, and Nephrology, Medical University of Lodz, Lodz, Poland.
3: Department of Clinical Genetics, Medical University of Lodz, Lodz, Poland.
4: Department of Pediatrics, Oncology and Hematology, Medical University of Lodz, Lodz, Poland.
5: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United States.

Abstract

BACKGROUND:

Patients referred for HNF1B testing present very heterogeneous phenotypes. Despite suggestive characteristics, many do not harbor mutations in HNF1B.

OBJECTIVES:

To evaluate the clinical characteristics of probands referred for HNF1B genetic testing through a nationwide monogenic diabetes screening programme.

SUBJECTS:

Probands tested for HNF1B mutations in the 2005-2018 period (N=50) were identified in the Polish Monogenic Diabetes Registry, which prospectively recruits primarily pediatric patients and their families on a nationwide scale.

METHODS:

Variants that had been reported pathogenic were reassessed using criteria of the American College of Medical Genetics and Genomics (ACMG). A structured medical interview was performed with all available individuals, their parents, and/or their physicians. For each patient, HNF1B-score was calculated based on available clinical information.

RESULTS:

The study group numbered 36 unrelated probands (28% lost to follow-up): 14 with pathogenic or likely-pathogenic variants in HNF1B, one with a variant of uncertain significance and 21 negative for HNF1B mutations. Presence of cystic kidneys (OR=9.17, 95%CI:1.87-44.92), pancreatic abnormalities (OR=15, 95%CI:1.55-145.23), elevated liver enzymes (OR=15, 95%CI:1.55-145.23) best discriminated HNF1B-positive cases from the negative ones. Presence of impaired glucose tolerance coupled with kidney disease in the proband and one parent was also highly predictive for HNF1B mutations (OR=11.11, 95%CI:1.13-109.36). HNF1B-score with recommended cut-off distinguished patients with and without HNF1B findings with 100% sensitivity and 47.6% specificity. Addition of four clinical variables to select patients based on HNF1B-score improved specificity to 71.4% (95%CI:47.8%-88.7%) whilst retaining 100% sensitivity.