The HNF1B score is a simple tool to select patients for HNF1B gene analysis

Abstract

HNF1B-related disease is an emerging condition characterized by an autosomal-dominant inheritance, a 50% rate of de novo mutations, and a highly variable phenotype (renal involvement, maturity-onset diabetes of the young type 5, pancreatic hypoplasia, and urogenital tract and liver test abnormalities). Given the current lack of pathognomonic characteristics and the wide overlap with other conditions, a genetic test is the diagnostic gold standard. However, pre-genetic screening is mandatory because genetic testing has substantial costs. Our aim was to develop a HNF1B score, based on clinical, imaging, and biological variables, as a pivotal tool for rational genetic testing. A score was created using a weighted combination of the most discriminative characteristics based on the frequency and specificity in published series. The HNF1B score is calculated upon 17 items including antenatal discovery, family history, and organ involvement (kidney, pancreas, liver, and genital tract). The performance of the score was assessed by a ROC curve analysis in a 433-individual cohort containing 56 HNF1B cases. The HNF1B score efficiently and significantly discriminated between mutated and nonmutated cases (AUC 0.78). The optimal cutoff threshold for the negative predictive value to rule out HNF1B mutations in a suspected individual was 8 (sensitivity 98.2%, specificity 41.1%, and negative predictive value over 99%). Thus, the HNF1B score is a simple and accurate tool to provide a more rational approach to select patients for HNF1B screening.

Hepatocyte Nuclear Factor 1β–Associated Kidney Disease

“…The prevalence of hypomagnesemia ranges from 0 to 100% in the different studies, but the prevalence in adults is consistently higher in those studies that included children and adults. 43,44,49 The same appears to be true with regard to the extrarenal phenotypes of elevated liver enzymes, pancreatic hypoplasia, and diabetes mellitus. These differences might be related to a delayed onset of the phenotypical changes.…”

“…A high risk score with a cutoff of $8 points was reported to make the presence of HNF1B mutation more likely (sensitivity 98%, specificity 91%, positive predictive value 19.8%). 49 This risk score may facilitate identification of undetected patients with HNF1B mutation-related disease. However, the risk tool has only been validated in the authors' own cohort, which was a very selected population of mostly pediatric patients with CAKUT who were previously selected for HNF1B mutational screening.…”

“…44 Faguer et al recently developed a 17-item HNF1b risk score to determine which individuals should be genetically screened for HNF1B mutations. 49 This score takes into account the presence of renal, pancreatic and genital abnormalities, electrolyte disorders, abnormal liver tests, and family history, all combined into a weighed scoring system. A high risk score with a cutoff of $8 points was reported to make the presence of HNF1B mutation more likely (sensitivity 98%, specificity 91%, positive predictive value 19.8%).…”

Hypomagnesemia as First Clinical Manifestation of ADTKD-HNF1B: A Case Series and Literature Review

“…Mutations in HNF1B are the most frequent monogenetic cause of congenital anomalies of the kidneys and urinary tract (CAKUT) and are observed in 10-30% of CAKUT patients in the prenatal period [4] . Importantly, diagnosing HNF1B mutations in the clinic is difficult due to high phenotypic variability between patients, incomplete penetrance, complicated detection of heterozygous gene deletions by sequencing and a high de novo mutation rate [2] .…”

“…HNF1B is a transcription factor that regulates genes that are cardinal to the development of the kidney, liver, pancreas and genital tract, and its impairment consequently leads to structural and functional anomalies of these organs [1][2][3] . Mutations in HNF1B are the most frequent monogenetic cause of congenital anomalies of the kidneys and urinary tract (CAKUT) and are observed in 10-30% of CAKUT patients in the prenatal period [4] .…”